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Flashcards in Microbiology & Immunology Exam Deck (1574):
1

2

what are the main components of a TCR?

1 antigen binding site • variable regions • constant regions • transmembrane region • α chain • β chain

3

what is the difference between a BCR and a TCR's CD molecules?

on a B cell IgM and IgD are associated with CD79 • TCR is associated with CD3

4

what are the 2 classes of TCR?

α:β • γ:δ

5

how are gene rearrangements in a TCR similar to gene rearrangements in a BCR?

VDJ segments for beta and gamma chains • VJ segments for alpha and delta chains

6

unlike a B cell where a B cell carries IgM and IgD as antigen receptors, a T cell carries what?

either alpha beta receptor or gamma-delta receptor

7

which has more variation, V region of alpha and beta chain or V region of gamma and delta chains

V region of alpha and beta chains

8

generation of the variable region of TCR is generated the same way like in BCR, except what?

that TCR does not undergo somatic mutation

9

which enzymes are involved in TCR development?

RAG1 and RAG2 • the same enzymes involved in TCR development

10

generation of antigen-binding diversity for TCR depends on what?

the same somatic recombination and junctional mechanisms used for BCR diversity

11

How is diversity created in TCR?

1. joining of VDJ segments for beta and gamma chains • 2. joining of VJ segments for alpha and delta chains • 3. RAG-1 and RAG-2 encoded recombinase and TdT are required for somatic recombination • 4. junctional diversity

12

is there somatic hypermutation in TCR?

NO

13

T cell progenitors originate from and develop where?

they originate from bone marrow and develop in the thymus

14

to what is the TCR's source of diversity in antigen recognition similar?

BCR because of random rearrangements of gene fragments VDJ and VJ

15

what is the structure of TCR?

has 2 peptides • α and β

16

how many epitope receptors does a TCR have?

1

17

how many CD3's is each TCR associated with?

2

18

what is the function of ζ peptides in TCR?

signal transduction

19

what are the co-receptor molecules of CDR's?

CD4 • CD8

20

when is Pre-TCR found?

on immature T cells; expressed early in development

21

when is TCR found?

on mature T cells

22

what is the major difference between pre-TCR and TCR?

pre-TCR has an incomplete α peptide: • pTα

23

how do T cell receptors recognize processed epitope?

in association with MHC

24

TCR require which co-receptors?

CD4 • CD8

25

which T cell type has co-receptor CD4?

Helper T cell

26

which T-cell type has the co-receptor CD8?

cytotoxic T cell

27

what is the MHC restriction of Helper T cells?

MHC II

28

what is the MHC restriction of cytotoxic T cells?

MHC I

29

what is the function of helper T cells?

B cells help macrophage activation • help for CD8 T cell cytokine secretion

30

what is the function of cytotoxic T cells?

killing virus infected cells • killing tumor cells

31

what are the parts of a CD4 co-receptor?

D1 • D2 • D3 • D4

32

what are the parts of the CD8 co-receptor?

α • β

33

what is the immune consequence of DiGeorge Syndrome?

thymic hypoplasia

34

What CD is expressed on a lymphoid precursor that just entered the thymus?

CD34

35

in the subcapsular zone of the thymus the cell becomes committed to develop to T cells by expressing what?

CD2

36

what are the two lines of development of committed CD2+ cells in the subcapsular zone?

beta-alpha expressing TCR • gamma-delta expressing TCR

37

in the beta-alpha line of development, the genes for beta gene segments are rearranged first and if it is productive, what happens next?

it is transcribe and translated to a beta chain that gets associated with a pTα.

38

what does a preT cell of the beta-alpha line express?

β • PTα

39

what happens if the pre T cell expressing β and PTα is functional?

the cell is signaled to rearrange the gene segments for α chain.

40

what is expressed on double positive T cells and where are they found?

double positive CD4+, CD8+ express TCR (βα) and are found in the cortex

41

What is positive selection in T cell development of the αβ line?

the TCR is checked if it can interact with MHC alleles of the person. • thymic epithelial cells present self antigen on MHC to the TCR. T cells expressing TCR that can interact with the MHC of the individual survive, if not they die

42

what is MHC restriction also known as?

positive selection

43

where and by what cells is negative selection in T cell development carried out?

by dendritic cells in the corticomedullary junction

44

what happens in negative selection during T cell development?

dendritic cells present self antigens on MHC I and II to the double positive cells. T cells with high affinity die, T cell with weak or intermediate affinity live. T cells that survive either become CD4 or CD8 depending on their affinity to either MHC I or MHC II

45

what happens in terms of CD during T cell development, to T cells with affinity to MHC I molecules?

CD8 marker retained • CD4 will be lost

46

what happens in terms of CD during T cell development to T cells with affinity to MHC II molecules?

CD4 will be retained • CD8 will be lost

47

what are single positive T cells?

CD4+ or CD8+ and self tolerant

48

which type of T cells leave the thymus after T cell development?

single positive

49

what is AIRE?

autoimmune regulator gene that plays a role in negative selection to T lymphocytes specific to self antigens not found in the thymus

50

what is the purpose for AIRE's existence?

not all self antigens are present in the thymus to cause deletion of self reacting lymphocytes • -AIRE gene induces the expression of such self antigens in the thymus-m so that they can be used in negative selection

51

what % of the T cell pool is CD4-, CD8-, γδ+?

2-10% of total T cell pool

52

where are CD4-, CD8-, γδ+ cells found?

in tissue just before the dermis

53

do CD4-, CD8-, γδ+ T cells undergo selection?

no

54

how do CD4-, CD8-, γδ+ T cells emigrate?

Emigrate as CD4CD8 to epithelial tissues in skin, intestines and lungs

55

what is the function of CD4-, CD8-, γδ+ T cells ?

immunosurveillance of transformed, damaged, or stressed epithelial cells

56

what do CD4-, CD8-, γδ+ T cells recognize?

non-peptides • lipids • not completely identified (microbes or stressed host cells

57

do CD4-, CD8-, γδ+ T cells require APC?

no

58

what is the level of diversity of CD4-, CD8-, γδ+ T cells ?

limited diversity

59

what do naive T CD4 cells do upon exposure to antigens presented by APC?

differentiate into effector T CD4 cells

60

what are the effector T CD4 cells?

Th1 • Th2 • Th17 • Treg

61

the development of effector T CD4 cells depends on what?

cytokines in the environment, produced by the APC

62

what happens in naive T CD4 cells when they are exposed to the cytokines in the surroundings?

different transcription factors are activated

63

what do the effector T CD4 cells do?

produce a variety of cytokines that mediate different immunological activities

64

does clonal selection theory apply to T cell post antigen exposure development?

yes

65

What happens in development of Th1?

naive T CD4, under the influence of IL-12 and IFN-γ, induces T-bet, producing Th1

66

what are the cytokines produced by Th1?

IL-2 • IFNγ

67

what is the major effector function of Th1?

Cell mediated immunity, • intracellular pathogens • Activate macrophages • Activate B cells and CD8

68

what happens in development of The2?

Naive T CD4, under the influence of IL-4, induces GATA-3, producing Th2

69

what are the cytokines produced by Th2?

IL-4 • IL-5 • IL-13 • IL-10

70

what are the major effector functions of Th2?

Humoral immunity, • B cell activation • extracellular pathogens • parasites and allergy

71

what happens in the development of Th17?

Naive T CD4, under the influence of IL-23, IL-6, IL-1 induces RORyt, producing Th17

72

what cytokines are produced by Th17?

Proinflammatory: • inflamamtion • autoimmunity • response to fungi and extracellular bacteria

73

what happens in the development of Treg?

Naive T CD4, under the influence of TGF-β, induces FoxP3, producing Treg

74

what cytokines are produced by Treg?

TGF-β, IL-10

75

what are the major effector functions of Treg?

Down regulation: • Suppress other T cell subsets- anti-inflammatory activity

76

cytokines produced by Th1 act on what?

macrophages • NK cells • CD8 cells • B cells to switch to IgG1

77

cytokines produced by Th2 act on what?

eosinophils • B cells to switch to other class of IgG and IgE

78

cytokines produced by Th17 act on what?

neutrophils and epithelial cells

79

Treg acts on what cells?

other lymphocytes to prevent T cell proliferation

80

how many peptides in BCR?

4

81

how many peptides in TCR?

2

82

how many antigen binding regions in BCR?

2

83

how many antigen binding regions in TCR?

1

84

do TCR or BCR have variable and constant regions?

both have both

85

do TCR or BCR have gene segments and gene rearrangement?

both have both

86

what is the signal transducer molecule on BCR?

CD79

87

what is the signal transducer molecule on TCR?

CD3

88

Can BCR recognize free unprocessed antigen without MHC?

YES

89

can TCR recognize free unprocessed antigen without MHC?

NO

90

how does TCR recognize antigen?

recognize processed antigen in association with MHC on antigen presenting cells

91

what are the co-receptor molecules on TCR?

CD4 or CD8

92

from where does Tcell progenitor cell originate?

bone marrow

93

once a T cell progenitor migrates to the thymus, what can it develop into?

1. γδ (CD4-, CD8-); • 2. αβ cells (CD4+ or CD8+) carrying TCR

94

how does the source of antigenic diversity of TCR relate to BCR?

source of antigenic diversity of TCR is similar to BCR

95

what is the difference between αβ and γδ T cell development?

α:β T lymphocytes undergo through positive and negative selection in the thymus while γδ cells do not

96

AIRE gene has a role in what type of disease?

autoimmune

97

CD3 and zeta associated with TCR serves as what?

signal transducer

98

CD4 and CD8 are coreceptors of what?

TCR

99

TCR recognizes epitopes associated with what?

MHC

100

Which CD interacts with which MHC in TCR?

CD4 interacts with MHC II and CD8 interacts with MHCI

101

under the influence of cytokines in the environment, naive CD4 (helper cells differentiate into what?

into Th1 • Th2 • Th17 • Treg

102

what is the function of Th1, Th2, Th17, and Treg?

these subsets of cells produce different set of cytokines with different roles in the immune system

103

what are the pre-antigen exposure B cell stages?

Pro B cell--> • Pre B cell --> • Immature B cell--> • mature B cell

104

what are the post antigen exposure B cell stages?

mature B cells become either Plasma cells or Memory cells

105

pre antigen b cell development involves what?

generation of antigen specific receptors which are immunoglobulin molecules of IgM and IgD isotypes

106

what is the specificity of BCR?

is antigen (epitope) specific

107

what type of immunoglobulin is BCR?

membrane immunoglobulin (mIg)

108

BCR is associated with which CD?

CD79 (Igα,β)

109

what is the function of CD79 (Igα,β)?

it's a signal transducer

110

BCR belong to which two isotypes?

IgM • IgD

111

what is the similarity of the IgM and IgD on a single B cell clone?

both belong to the same idiotype (specific to a particular antigen)

112

the maturation stages of the B cell can be identified by what?

1. changes in enzyme activity • 2. CD marker expression • 3. synthesis of BCR (IgM and IgD)

113

CD10, CD19, and CD20 are markers of what?

B cells

114

is CD 20 found on plasma cells?

no

115

what cells is CD 20 found on?

early to late B cell • lymphoma cells

116

how many B cell clones and repertoires can a person generate?

in any given individual it is possible to generate 10^9-10^10 different B cell clones, each with different epitope binding regions

117

construction of a unique variable region is possible by the process known as what?

somatic recombination

118

what factors contribute to somatic recombination?

1. existence of multiple copies of gene segments that code for the variable regions • 2. combinatorial diversity generated by random selection and combination of gene segments • 3. junctional diversity generated by addition of deletion of bases • 4. random assortment of light and heavy chains

119

on which chromosome is the λ light chain locus?

chromosome 22

120

on which chromosome is the κ light chain locus?

chromosome 2

121

on which chromosome is the heavy chain locus?

chromosome 14

122

immunoglobulins are encoded by how many gene complexes?

3 gene complexes located on separate chromosomes

123

what are the functions of the 3 gene complexes located on separate chromosomes?

one for all heavy chains • one for κ chains • one for λ chains

124

how continuous are the gene complexes that code for immunoglobulins?

these genes are discontinuous and require translocations to be activated

125

what are the segments that encode the variable region of the light chain?

V • J

126

what are the segments that encode the variable region of the heavy chain?

V • D • J

127

what post-transcriptional processing do the gene complexes that encode immunoglobulin chains require?

DNA rearrangement • RNA splicing

128

what is the term for the process of gene rearrangement that occurs in generating BCR?

Cut and Paste process

129

RAG1 and RAG2 are what and what do they code for?

Recombination activating genes code for RAG1 and RAG2

130

what is an example of alternative splicing in gene selection for BCR?

the rearranged VDJ segment recombines first with Cμ segment creating the heavy chain μ for IgM, followed by Cδ segment creating the heavy chain δ for IgD

131

what is the reason for the alternative splicing seen in gene selection during synthesis of BCR?

in this way, both the IgM and IgD expressed on a B cell have the same VDJ

132

what are the 6 sources of BCR diversity?

1. multiple copies of germline VDJ • 2. Random recombination of gene segments • 3. imprecision during cut and paste • 4. junctional diversity • 5. random reassortment of any light chain with any heavy chain • 6. somatic hypermutation

133

what is junctional diversity?

addition of sequence at the splice junction between V_D or D_J gene segments

134

what is somatic hypermutation?

fine tuning change after mutation

135

what is the cause of imprecise recombination in BCR formation?

the precise positions at which the genes for the V and J or VDJ segments are joined are not constant

136

imprecise DNA recombination can lead to what?

changes in the amino acid at the junctions

137

where does insertion of a new piece of DNA at the junctions take place?

at the junction of new segments

138

what is TdT?

terminal deoxynucleotidyl transferase

139

what is affinity maturation?

when somatic hypermutation improves the affinity of the antibody to the epitope

140

what is somatic hypermutation?

change in nucleotide in the rearranged variable gene segment of the light and heavy chain mainly in the CDR regions

141

the maturation stages of B cell development can be identified by what?

changes in enzyme activitiy • CD marker expression • synthesis of the BCR

142

what is allelic exclusion?

in a single B cell only one set of genes is expressed either maternal or paternal

143

what is Heavy chain rearrangement in the Pro B Cell?

DJ joined in both the chromosomes. Then VDJ is formed in one of the chromosomes

144

where do B cells develop?

in the fetal liver and adult bone marrow

145

when does heavy chain rearrangement take place?

in the pro B cell

146

what happens durring Ig Gene expression in the Pre B Cell?

VDJ get joined to the HCμ. μ chain together with surrogate chain is expressed

147

what is the μ chain together with the surrogate chain in the pre-Bcell called?

pre-B cell receptor

148

at the pro B cell level in the bone marrow, gene rearrangement of the H chain start with what?

a union of the D and J genes in both chromosomes (maternal and paternal)

149

what are the genes need to complete IgM?

VDJCμ

150

what happens if VDJCμ is productive- capable of being properly transcribed and translated?

further rearrangement of VDJ gene from the other chromosome is shut down, if not, the cell is given a second chance to use the other chromosome. if this fails, the cell dies by apoptosis

151

what is a surrogate light chain?

a false light chain

152

do the genes for VpreB and λ5 undergo rearrangement?

no

153

what do Igα and Igβ do in the pre-B cell?

singal the cell that has successfully rearranged its Ig H chain and has made functional μ chain to shut down further H chain rearragement

154

what is Bruton's tyrosine Kinase?

one of the enzymes involved in intracellular signalling by Igα/β

155

mutation in the Btk gene results in what?

lack of differentiation to proB cell level

156

what is the condition caused by deficiency or defect in Btk?

X-linked agammaglobinemia

157

what happens if in the maturation of a B cell the cell is not self reactive?

alternative mRNA splicing of heavy chain gene transcripts then produces the δ and μ expressing both IgD and IgM

158

what happens once a functional pro-B cell receptor is produced?

rearrangement of the light chain genes start

159

which light chain genes rearrange first?

κ chain

160

what is central tolerance?

negative selection of self reacting immature B cells

161

what is receptor editing?

alteration of speecificity: • further round of light chain (V and J) gene rearrangement

162

what happens when an immature B cell recognizes a multivalent self molecule?

DELETION: • clonal deletion or receptor editing --> apoptosis

163

what happens when an immature B cell recognizes soluble self molecules?

ANERGY: • migrates to the periphery

164

what happens when an immature B cell recognizes low affinity non cross linking self molecule?

IGNORANT: • migrates to periphery • Mature B cell is clonally ignorant

165

what happens to an immature be cell with no self reaction?

FUNCTIONAL: • it migrates to the periphery and becomes mature

166

do anergic B cells express IgD?

yes

167

do clonally ignorant B cells express Ig?

yes, IgM and IgD

168

what is a clonally ignorant cell?

ligand is present but is not able to activate the cell

169

what are the cell stages of B cell maturation?

1. Stem Cell • 2. Early Pro-B cell • 3. Late pro-B cell • 4. Large Pre-B cell • 5. small pre-B cell • 6. immature B cell • 7. Mature B cell

170

what is the status of the H-chain genes in a stem cell?

germ line

171

what is the state of the L chain genes in a stem cell?

germline

172

what is the state of surface Ig in a stem cell?

Absent

173

what is the state of H chain genes in an early pro-B cell

D-J rearranging

174

what is the state of L chain genes in an early pro-B cell?

Germline

175

what is the state of surface Ig in an early pro-B cell?

absent

176

what is the state of the H chain genes in a late pro B cell?

V-DJ rearranging

177

what is the state of the L chain genes in a late pro-B cell?

germline

178

what is the state of the surface Ig in a late pro-B cell?

absent

179

what is the state of the H chain genes in a large pre-B cell?

VDJ rearranged

180

what is the state of the L chain genes in a large pre-B cell?

germline

181

what is the state of surface Ig in a large pre-B cell?

μ chain transiently at surface as part of pre-B cell receptor. mainly intracellular

182

when does the μ + surrogate arrive in B cell maturation?

at the large pre-B cell stage

183

what is the state of the H chain genes in a small pre-B cell?

VDJ rearranged

184

what is the state of the L-chain genes in a small pre-B cell?

V-J rearranging

185

what is the state of the surface Ig in a small pre-B cell?

intracellular μ chain

186

at what stage in B cell maturation is the check to see if they recognize self antigens?

immature B cell stage

187

what is the state of the H chain genes in an immature B cell?

VDJ rearranged

188

what is the state of the L chain genes in an immature B cell?

VJ rearranged

189

what is the state of surface Ig in an immature B cell?

IgM expressed on cell surface

190

what is the state of the H chain genes in a mature B cell?

VDJ rearranged

191

what is the state of the L chain genes in a mature B cell?

VJ rearranged

192

what is the state of surface Ig in a mature B cell?

IgD and IgM made from alternatively spliced H-chain transcripts

193

what do naive B cells express on their surface?

IgM and IgD

194

what do plasma cells express on their surface?

plasma cells do not express surface Ig, but secrete Ig

195

what do memory cells express on their surface?

other Ig: • either IgG, IgA, or IgE

196

what is the clonal selection theory?

upon exposure to an antigen, a B cell with a BCR specific to that particular antigen proliferates to give rise to a clone of B cells expressing BCR of the same specificity

197

what happens in Ig class/isotype switch?

change of C domain, but not the VDJ because of alternative mRNA splicing

198

what does DNA recombination in isotype switch permit a cell to do?

enables the rearranged VDJ to be used with other heavy chain C chains

199

what is the first Ig produced after a B cell encounters an antigen?

IgM, followed by IgG or IgA with the same VDJ

200

what is affinity maturation?

mutation that takes place in the rearranged VDJ segment gives rise to antibodies with better affinity to epitopes

201

do antibodies produced in primary infection have more or less affinity for the epitope than Ab produced in subsequent infections?

less

202

what is detection of CD10/19/20 used for?

determine the developmental stage of leukemias and lymphomas of B cell origin

203

what does B cell coreceptor do?

increaes the sensitivity of B cell response to an antigen in the presence of complement activation and deposition of C3d

204

what is C3d?

a fragment of C3b of complement component

205

what are the 2 important subsets of B cells?

B2 • B1 (CD5+)

206

when do B2 cells develop?

after birth

207

when are B1 cells produced?

in fetal life

208

which type of B cell has a poorly understood developmental pathway?

B1

209

which type of B cell comprises the majority of B cells?

B2

210

What percentage of B cells are B1 cells?

5%

211

where are B2 cells found?

in secondary lymphoid organs

212

where are B1 cells found?

in body cavities

213

which surface Ig do B2 cells express?

both sIgM and sIgD

214

which surface Ig do B1 cells express?

sIgM but little sIgD

215

what type of antigens do B2 cells respond to?

protein antigens

216

which type of antigens do B1 cells respond to?

carbohydrate antigens • T independent antigens

217

which B cells require T cell help?

B2 cells

218

which B cells do not require T cell help?

B1 cells

219

which B cells secrete mainly IgM?

B 1 cells

220

which B cells give rise to plasma cells that secrete IgM, IgG, and IgA?

B2

221

which B cells leave memory?

B2 cells

222

which B cells leave little to no memory?

B1

223

B cells develop where in the body?

fetal liver • adult bone marrow

224

stages of B cell differentiation are defined by what?

Ig gene rearrangement 'status' and expression of certain CD 10, 19, 20

225

what is essential to the clonal nature of immunity?

allelic exclusion

226

how many opportunities do B cells have to rearrange their antigen receptors?

several

227

what are the possible fates of self reacting immature B cells expressing only IgM?

1. allowed for receptor editing • 2. deleted, made anergic or ignorant

228

why are IgM and IgD expressed simultaneously on mature B cells?

due to differential RNA splicing

229

what is the function of CD79?

signal transducer

230

what does a B cell do upon an exposure to an antigen?

proliferates and differentiates into plasma cells and memory cells

231

what is class switch and what does it refer to?

class switching is isotype switching and refers to changes in CH gene selection but with no change in other genes (V domains or antigen specificity) by alternative RNA splicing

232

what makes up B cell co-receptor?

CD19 • CD21 • CD81

233

what are the two subsets of B cell types?

B1 • B2

234

What are immunoglobulins/antibodies?

glycoprotein molecules produced by plasma cells in response to an immunogen that can recognize the immunogen/antigen

235

what is myeloma?

a cancer that affects B cells, the immune cells responsible for the production of antibodies

236

from where do immunoglobulins derive their name?

the finding that when antibody-containing serum is placed in an electrical field the antibodies migrated with the globular proteins

237

the Ig molecule is made up of how many proteins?

4 peptide chains

238

what is the composition of the 4 peptide chains in an Ig?

2 heavy identical chains • 2 light identical chains

239

what are the regions present in Ig molecules?

the chains have variable region and constant region

240

what are VL and CL?

variable and constant region of the light chain

241

what are VH and CH?

variable and constant region of the heavy chain

242

what are responsible for the folding in the domains of an Ig?

sulfide bonds

243

what makes up an Ig?

1. 4 peptide chains with heavy and light chains with variable and constant regions • 2. hinge region • 3. domains folded by sulfide bonds • 4. oligosaccharides

244

what are Ig classes/isotypes?

5 different classes based on the differences in the amino acid sequences in the constant region of the heavy chain

245

what are the 5 different heavy chains that determine the Ig classes?

1. γ • 2. μ • 3. α • 4. δ • 5. ε

246

What Ig is associated with the γ chain?

heavy chain of IgG

247

what Ig is associated with the μ chain?

heavy chain of IgM

248

what Ig is associated with the α chain?

heavy chain of IgA

249

what Ig is associated with the δ chain?

heavy chain of IgD

250

what Ig is associated with the ε chain?

heavy chain of IgE

251

what is the difference between the IgG subclasses?

differ in amino acid sequence in their constant region of H chain: • 1. IgG1- gamma 1 heavy chains • 2. IgG2- Gamma 2 heavy chains • 3. IgG3- Gamma 3 heavy chains • 4. IgG4- Gamma 4 heavy chains

252

what is the difference between IgA Subclasses?

differ in aa sequence in their H constant region: • 1. IgA1 • 2. IgA2

253

what are the 2 types of L chains of Ig?

Kappa- κ • Lambda- λ

254

what is the difference between κ and λ L chains of Ig?

they differ in amino acid sequences in their constant region

255

what is the prevalence of κ and λ chains in Ig?

both types occur in all classes of Ig, but any one Ig molecule contains only one of them, either λ or κ

256

how many subclasses of IgG?

4

257

how many classes of IgA?

2

258

What is the organization of H2L2 structures?

2 identical L chains • 2 identical H chains • the H chain defines the class (and subclass) of the Ig produced

259

what is the functional organization of H2L2 structures?

1. variable N terminal regions define the antigen binding site • 2. constant regions of the heavy chains define the functions of the immunoglobulin

260

in humans, what is the ratio of immunoglobulins containing two kappa vs two lambda chains?

2:01

261

how can the distinct fragments of the heavy chains be isolated into distinct fragments?

proteolysis

262

what happens when you reduce and acidify immunoglobulin?

you get isolated chains separated at the sulfide bonds

263

what happens when you treat an immunoglobulin with papain?

you get papain fragments

264

what does the Fc region do?

determines the biological function of Ig

265

what does the Fc region of Ig bind to?

Fc receptors on: • 1. phagocytic cells • 2. NK cells • 3. eosinophils • 4. Mast cells • 5. complement C1q • 6. placental cells

266

what are the different kinds of Fc receptors on cells?

different Fc receptors on these cells for the different Ig classes: • FcγR- IgG • FcμR- IgM • FcαR- IgA • FcεR- IgE

267

why is an antibody able to bind a particular antigenic determinant?

because it has a particular combination of VH and VL

268

specificity of antigen binding is determined by what?

hypervariability regions within the variable region domain

269

how many hyper-variable regions per variable region?

3

270

each variable region has 3 hyper-variable regions also called what?

complementary determining regions (CDR)

271

how many CDR's per antigen binding site?

an antigen binding site is composed of three light chain CDR's and 3 heavy chain CDRs

272

different combinations of a VH and VL result in what?

antibodies that can bind a different epitope

273

what is the antigen binding region called?

Fab Region

274

how is variability distributed in V domains?

there are discrete regions of hypervariability in V domains

275

what are the positions of CDR in the 2-D and 3-D models of the light chain and heavy chain?

-CDRs are separated in the linear 2D model of the peptide chains • - the hypervariable regions of the light chain and heavy chain are brought together in the folded 3D form of the intact antibody molecule

276

together the CDRs constitute what?

the combining site, which is complementary to the epitope

277

the variability in CDRs provides what?

the diversity required for the function of antibodies of different specificities

278

what is affinity in an Ab/Ag interaction?

strength of interaction between one epitope and one epitope binding site (the region between the variable region of heavy chain and light chain)

279

what is avidity in Ag/Ab interaction?

strength of interaction of multiple epitopes on a multivalent antigen molecule such as a big protein and several epitope binding site

280

what are hinge options?

the ability of an antibody to bind more than one protein with variable spacing on the surface of a bacterium

281

what is the structure of IgG?

monomer (7S)

282

how do the subclasses of IgG differ?

number of disulfide bonds and length of the hinge region

283

which is the most versatile Ig molecule?

IgG isotype

284

why is IgG isotype the most versatile immunoglobulin?

because it is capable of carrying out all of the functions of immunoglobulin molecules

285

what is the major Ig in serum?

IgG

286

how much of serum Ig is IgG?

75%

287

which is the major Ig in the extravascular spaces?

IgG

288

what are the capabilities of IgG?

1. neutralization • 2. fixes complement • 3. binding to cells • 4. opsonization

289

what is neutralization by IgG?

inhibit binding of toxins or pathogens on target cells

290

do all subclasses of IgG fix complement?

not all subclasses fix complement equally well; IgG4 does not fix complement

291

which IgG does not fix complement?

IgG4

292

which cells have Fc receptors for the Fc region of IgG?

1. macrophages • 2. monocytes • 3. PMNs • 4. NK cells

293

do all subclasses of IgG bind to cells?

not all subclasses bind equally well; • IgG2 and IgG4 do not bind Fc receptors

294

describe opsonization by IgG

IgG is a good opsonin. • a consequence of binding to the Fc receptors on PMN's, monocytes and macrophages is that the cell can now internalize the antigen better

295

what is the name for adaptive immune defense mediated by antibodies?

humoral immunity

296

which is the only Ig that crosses the placental barrier?

IgG

297

what is transfer of IgG across the placental barrier mediated by?

receptor on placental cells for the Fc region of IgG

298

do all IgG subclasses cross the placental barrier?

not all subclasses cross equally • IgG2 does not cross well

299

which IgG does not cross the placental barrier well?

IgG2

300

what is ADCC?

antibody dependent cell-mediated cytotoxicity

301

NK cells have Fc receptors for which IgG?

IgG1 and IgG3

302

binding of NK cells to human cells coated with IgG1 an IgG3 results in what?

killing

303

ADCC targets what kind of cells?

tumor cells and virally infected human cells

304

why are tumor cells and virally infected human cells targeted by NK cells in ADCC?

they express antigens that are not found in normal cells

305

what are the steps of ADCC by NK cells?

1. antibody binds antigens on the surface of target cells • 2. Fc receptors on NK cell recognize bound antibody • 3. cross-linking of Fc receptors signals the NK cell to kill the target cell • 4. target cell dies by apoptosis

306

what are the features of the structure of IgM?

Pentamer (19s) • extra domain (CH4) • J chain

307

in what 2 configurations can IgM exist?

1. IgM normally exists as a pentamer (19S) in serum • 2. can exist as a monomer as antigen receptor on B lymphocytes

308

which is the third most common Ig in serum?

IgM

309

what is the valence of an Ig?

it's epitope binding capacity

310

what is the similarity between chains in IgM when it is in its pentameric form?

all heavy chains are identical • all light chains are identical

311

what is the valence of IgM in its pentameric form?

10

312

what are the extra peptide features of IgM?

1. extra domain on the μ chain (CH4) • 2. another protein covalently bound via S-S bond called the J chain

313

what is the J chain on IgM?

another protein covalently bound to IgM via S-S bonds

314

which chain functions in polymerization of the IgM molecule into a pentamer?

J chain

315

what is the first Ig to be synthesized by B cells during infection in adults?

IgM

316

what is the first Ig produced in fetal life?

IgM

317

in the newborn, an increased level of IgM is an indication of what?

in utero stimulation of the immune system by pathogens such as rubella virus, CMV, syphilis, toxoplasmosis

318

what are the pathogens that cause increased IgM in a newborn?

1. rubella virus • 2. cytomegalovirus • 3. syphilis • 4. toxoplasmosis

319

which is the first type of antibody to appear in the primary response, between IgG and IgM?

IgM

320

what happens to IgG levels in the secondary response (compared to the primary response)?

IgG: • 1. appears earlier • 2. shows a more rapid rise • 3. has higher final concentration

321

what would happen if at the time of the second exposure to Ag1, a second, non-cross reacting Ag2 was injected?

a primary response to Ag2 would occur while a secondary response to Ag1 was occuring

322

how can the IgM Fc region affect complement?

the IgM Fc region can bind and activate complement

323

how many antigen binding sites does IgM pentamer have?

10

324

how many Fc regions for complement binding does an IgM pentamer have?

10

325

which Ig has the most efficient complement fixation?

IgM

326

which Ig is most efficient at agglutinating antigens?

IgM

327

how is the response of IgM to T cell independent (carbohydrate) antigens?

good

328

how is the structure of surface IgM different than serum IgM?

1. exists as monomer • 2. lacks J chain • 3. extra 20 amino acids at the C terminal end to anchor it to the membrane

329

what is the function of cell surface IgM?

receptor for antigen on B cells

330

what is the structure of serum IgA?

monomr

331

what are the structural features of secreted IgA (sIgA)?

Dimer (11s) • J chain • secretory component

332

when IgA exists as a dimer, what is associated with it?

J chain

333

when IgA is found in secretions it also has, in addition to the J chain, what associated with it?

another protein called the secretory piece

334

what is IgA in secretions called?

sIgA

335

where is most of IgA made?

in the plasma cell

336

unlike the remainder of the IgA which is made in the plasma cell, the secretory piece is made where? and when?

in the epithelial cells and is added to the IgA as it passes into the secretions

337

what is the function of the secretory piece?

the secretory piece helps IgA to be transported across mucosa and also protects it from degradation by enzymes in the mucosal secretions

338

during which part of secretion of sIgA is the secretory component added?

during trancytosis between the extracellular space and the lumen

339

for transcytosis and association with the secretory component to take place, the IgA dimer must bind what?

a membrane bound Fc receptor (poly-Ig receptor)

340

what is the second most common serum Ig?

IgA

341

IgA is the major class of Ig in what?

secretions: • 1. tears • 2. saliva • 3. colostrum • 4. mucus

342

how is IgA transferred from mother to child?

breast feeding

343

what type of immunity transfer is breast feeding?

passive transfer of immunity

344

since it is found in secretions, sIgA is important in what type of immunity?

local (mucosal) immunity

345

does IgA fix complement?

normally IgA does not fix complement unless aggregated

346

how does IgA function in mucosal immunity?

IgA inhibit by neutralizing adhesion of pathogens/toxins to epithelial cell on mucosal surface

347

what are the structural components of IgD?

monomer • tail piece

348

how does IgD exist?

IgD exists only as a monomer

349

is IgD found in serum?

IgD is found in low levels in serum

350

what is the role of serum IgD?

role in serum is uncertain

351

where is IgD primarily found?

on B cell surfaces

352

what is the function of B cell bound IgD?

receptor for antigen

353

which Ig's are found on the B cell surface?

IgD • IgM

354

IgD on the surface of B cells has what for anchoring to the membrane?

extra amino acids at C-terminal end

355

does IgD bind complement?

no

356

what are the structural components of IgE?

monomer • extra domain Cε4

357

which is the least common serum Ig?

IgE

358

why is IgE the least common serum Ig?

it binds very tightly to FcεR receptors on basophils and mast cells

359

IgE is primarily involved in what?

allergic reactions

360

why is IgE involved in allergic reactions?

as a consequence of its binding to basophils and mast cells

361

does IgE fix complement?

IgE does not fix complement

362

Binding of IgE to mast cell surface receptors does what?

primes the cell to respond to allergen

363

introduction of allergen and its subsequent binding to IgE on a mast cell induces what?

crosslinking of IgE and clustering of Fc receptors

364

clustering of Fc receptors on a mast cell post introduction of allergen does what?

initiates a signal transduction event that stimulates the mast cell to degranulate

365

besides allergic reactions, what does IgE play a role in?

parasitic helminth infections

366

what are the functions of IgE?

allergic reactions • parasitic helminth infections

367

why is measuring IgE levels helpful in diagnosing parasitic infections?

because serum IgE levels rise in parasitic diseases

368

how does IgE help kill parasites?

eosinophils have Fc receptors for IgE and binding of eosinophils to IgE-coated helminthes results in release of granular contents which kill the parasite

369

which Ig's predominate in the blood?

IgM, IgG and monomeric IgA predominate in the blood

370

which are the major Ig's in the extracellular fluid?

IgG and monomeric IgA

371

which Ig predominates in the secretions?

dimeric IgA

372

where is IgE found?

IgE is associated with mast cells and is therefore found in the connective tissue beneath epithelial surfaces, particularly of the skin, respiratory tract and the GI tract

373

which Ig's are in the brain?

THE BRAIN IS DEVOID OF IMMUNOGLOBULIN

374

isotypes of Ig have variations in what?

the Fc region, constant heavy chain

375

what are allotypes of Ig?

alleles: • variations in the Fc region found in members of the same species

376

when is the allotype of Ig important?

tissue typing for transplantation

377

what are idiotypes of Ig?

variation in the variable region

378

what does the idiotype of an Ig determine?

antigen specificity

379

what differentiating class of an Ig is present in all individuals of a species?

isotype

380

which differentiating class of an Ig is different alleles within a species?

allotypic determinants

381

which differentiating Ig class determines the antigen binding site?

idiotypic determinants

382

What is the degree of neutralization functionality of IgM?

+

383

what is the degree of neutralization function of IgD?

-

384

what is the degree of neutralization function of IgG1?

+++

385

what is the degree of neutralization function of IgG2?

+++

386

what is the degree of neutralization function of IgG3?

+++

387

what is the degree of neutralization function of IgG4?

+++

388

what is the degree of neutralization function of IgA?

+++

389

what is the degree of neutralization function of IgE?

-

390

which Ig's have + degree of neutralization function?

IgM

391

which Ig's have - degree of neutralization function?

IgD • IgE

392

which Ig's have +++ degree of neutralization function?

IgG1 • IgG2 • IgG3 • IgG4 • IgA

393

what is the degree of opsonization function of IgM?

-

394

what is the degree of opsonization function of IgD?

-

395

what is the degree of opsonization function of IgG1?

+++

396

what is the degree of opsonization function of IgG2?

* req complement

397

what is the degree of opsonization function of IgG3?

++

398

what is the degree of opsonization function of IgG4?

+

399

what is the degree of opsonization function of IgA?

+

400

what is the degree of opsonization function of IgE?

-

401

which Ig's have - degree of opsonization function?

IgM • IgD • IgE

402

which Ig's have + degree of opsonization function?

IgG4 • IgA

403

which Ig's have ++ degree of opsonization function?

IgG3

404

which Ig's have +++ degree of opsonization function?

IgG1

405

what is the degree of sensitization for killing by NK cells function of IgM?

-

406

what is the degree of sensitization for killing by NK cells function of IgD?

-

407

what is the degree of sensitization for killing by NK cells function of IgG1?

++

408

what is the degree of sensitization for killing by NK cells function of IgG2?

-

409

what is the degree of sensitization for killing by NK cells function of IgG3?

++

410

what is the degree of sensitization for killing by NK cells function of IgG4?

-

411

what is the degree of sensitization for killing by NK cells function of IgA?

-

412

what is the degree of sensitization for killing by NK cells function of IgE?

-

413

which Ig's have - degree of sensitization for killing by NK cells function?

IgM • IgD • IgG2 • IgG4 • IgA • IgE

414

what is the degree of sensitization of mast cells function of IgM?

-

415

what is the degree of sensitization of mast cells function of IgD?

-

416

what is the degree of sensitization of mast cells function of IgG1?

+

417

what is the degree of sensitization of mast cells function of IgG2?

-

418

what is the degree of sensitization of mast cells function of IgG3?

+

419

what is the degree of sensitization of mast cells function of IgG4?

-

420

what is the degree of sensitization of mast cells function of IgA

-

421

what is the degree of sensitization of mast cells function of IgE?

+++

422

which Ig's have - degree of sensitization of mast cells function?

IgM • IgD • IgG2 • IgG4 • IgA

423

which Ig's have + degree of sensitization of mast cells function?

IgG1 • IgG3

424

which Ig's have +++ degree of sensitization of mast cells function?

IgE

425

what is the degree of activation of complement system function of IgM?

+++

426

what is the degree of activation of complement system function of IgD?

-

427

what is the degree of activation of complement system function of IgG1?

++

428

what is the degree of activation of complement system function of IgG2?

+

429

what is the degree of activation of complement system function of IgG3?

+++

430

what is the degree of activation of complement system function of IgG4?

-

431

what is the degree of activation of complement system function of IgA?

+

432

what is the degree of activation of complement system function of IgE?

-

433

which Ig's have - degree of activation of complement system function?

IgD • IgG4 • IgE

434

which Ig's have + degree of activation of complement system function?

IgG2 • IgA

435

which Ig's have ++ degree of activation of complement system function?

IgG1

436

which Ig's have +++ degree of activation of complement system function?

IgM • IgG3

437

what is the degree of transport across epithelium of IgM?

+

438

what is the degree of transport across epithelium of IgD?

-

439

what is the degree of transport across epithelium of IgG1?

-

440

what is the degree of transport across epithelium of IgG2?

-

441

what is the degree of transport across epithelium of IgG3?

-

442

what is the degree of transport across epithelium of IgG4?

-

443

what is the degree of transport across epithelium of IgA?

#NAME?

444

what is the degree of transport across epithelium of IgE?

-

445

which Ig's are not transported across epithelium?

IgD • IgG1 • IgG2 • IgG3 • IgG4 • IgE

446

which Ig's are transported across epithelium to some degree?

IgM

447

which Ig's are transported across epithelium A LOT?

sIgA

448

what is the degree of transport across placenta of IgM?

-

449

what is the degree of transport across placenta of IgD?

-

450

what is the degree of transport across placenta of IgG1?

+++

451

what is the degree of transport across placenta of IgG2?

+

452

what is the degree of transport across placenta of IgG3?

++

453

what is the degree of transport across placenta of IgG4?

++

454

what is the degree of transport across placenta of IgA?

-

455

what is the degree of transport across placenta of IgE?

-

456

what Ig's are not transported across placenta?

IgM • IgD • IgA • IgE

457

which Ig's are transported across placenta to some degree?

IgG2 (+)

458

which Ig's are transported across placenta to a moderate degree?

IgG3 • IgG4 • (++)

459

which Ig's are transported across placenta A LOT?

IgG1 (+++)

460

what is the mean serum level (mg/mL) of IgM?

1.5

461

what is the mean serum level (mg/mL) of IgD?

0.03

462

what is the mean serum level (mg/mL) of IgG1?

9

463

what is the mean serum level (mg/mL) of IgG2?

3

464

what is the mean serum level (mg/mL) of IgG3?

1

465

what is the mean serum level (mg/mL) of IgG4?

0.5

466

what is the mean serum level (mg/mL) of IgA

2.5

467

what is the mean serum level (mg/mL) of IgE?

5 x 10^-5

468

what is an immunogen?

substance capable of inducing adaptive immune response

469

what is an antigen?

substance capable of being recognized by the adaptive immunity.

470

what is the relationship between antigens and immunogens?

All immunogens are antigens, but not all antigens are immunogens

471

what is an epitope?

the region(s) of the antigen in direct contact with the antibody, B-Cell Receptor, or T-Cell Receptor

472

what is a synonym for epitope?

antigenic determinant

473

how many epitopes are there per antigen?

there may be one or more epitopes per antigen

474

what is a hapten?

a small molecule which can function as an antigen, but by itself is incapable of inducing an immune response

475

is a hapten an immunogen?

no

476

what are the 3 types of antigen/immunogen receptor molecules?

1. BCR (b cell receptor) • 2. TCR (t cell receptor) • 3. MHC

477

of the 3 types of antigen/immunogen receptor molecules, which are surface immunoglobulins?

B-Cell Receptors

478

how many antigen recognition sites are there on a BCR?

two identical antigen recognition sites

479

how many antigen recognition sites are there on a TCR?

one antigen recognition site

480

where are MHC-I molecules expressed?

on all nucleated cells

481

where are MHC-II molecules expressed?

macrophages • dendritic cells • lymphocytes

482

which of the 3 types of antigen/immunogen receptor molecules is expressed on antigen presenting molecules?

MHC

483

which various antigens or sources of antigens are immunogens?

1. parasites • 2. foreign proteins • 3. bacteria • 4. viruses • 5. fungi

484

antigens are big molecules- however, the area that triggers the specific immunity is a small part, known as what?

epitope

485

how big is an epitope?

an epitope in a protein antigen could be as few as 20 amino acids long

486

what is the shape of an epitope?

could be linear, conformational

487

what type of cells recognize a conformational epitope?

BCR only, not TCR

488

what is the difference between a linear and conformational epitope?

in a conformational epitope, the sequence of amino acids is discontinuous, but they are brought into proximity by the protein's 3-D structure

489

what is a synonym for conformational epitope?

discontinuous epitope

490

when is there cross-reaction between different antigens?

when a different antigen has one identical determinant or a similar determinant

491

when is there no reaction between different antigens?

when there is no structural similarity

492

what is the receptor/binding activity of a BCR?

BCR--> Ag

493

what is the receptor/binding activity of a TCR?

TCR --> Ag/MHC

494

is MHC required for BCR?

no

495

is MHC required for TCR?

yes

496

does a BCR bind soluble antigen?

yes

497

does a TCR bind soluble antigen?

No

498

what is the chemical nature of BCR antigens?

protein • polysaccharides • lipids • nucleic acids

499

what is the chemical nature of TCR antigens?

proteins • some lipids, glycolipids

500

what type of epitope is recognized by BCR?

accessible, either linear or conformational

501

what type of epitope is recognized by TCR?

linear peptides (short)

502

what makes a good antigen/immunogen?

1. physical size : > --> better • 2. complexity: chemical composition and structural complexity • 3. solubility or degradability by antigen processing cells, macrophages, dendritic cells and B cells • 4. foreignness to the individual

503

what size are the best immunogens?

>=100kD

504

what is the minimum size for active immunogens (proteins)

>30kD

505

how immunogenic is an immunogen that is <5-10kD?

minimally immunogenic, usually require carrier

506

what is an example of a <5-50kD immunogen that is minimally active and requires a carrier?

hapten

507

How do the categories of chemical compounds rank in terms of their immunogenicity based on complexity in descending order?

HIGH IMMUNOGENICITY: • 1. proteins and glycoproteins • 2. Polysaccharides • 3. nucleic acids, phospholipids • 4. haptens • LOW IMMUNOGENICITY:

508

are proteins and glycoproteins good immunogens?

yes

509

how complex are proteins and glycoproteins in terms of their immunogenicity?

complex in composition and structure

510

can proteins and glycoproteins induce immunity?

can induce humoral and cell-mediated immunity

511

how complex are polysaccharides in terms of their immunogenicity?

repeating structures, generally low affinity

512

what type of response do polysaccharide immunogens elicit?

IgM response

513

do polysaccharides stimulate a cell-mediated immune response?

cannot be processed and presented as linear epitopes for T cells, thus do not induce cell-mediated response

514

how foreign are nucleic acids and phospholipids in terms of their immunogenicity?

evolutionarily conserved; less foreign

515

how do nucleic acids and phospholipids become better immunogens?

conjugation with proteins or polysaccharides

516

how immunogenic are haptens?

insufficient in size to be immunogenic. need carrier

517

what examples of natural haptens?

hormones, lipids, simple sugars

518

what are examples of synthetic haptens?

chemicals, drugs (penicillin)

519

what types of drugs can act like haptens and be associated with severe, life threatening anaphylactic reactions?

antibiotics, particularly penicillins

520

how do penicillins act as haptens?

they form covalent bonds with proteins to produce protein-drug adducts that elicit an immune response (hypersensitivities) in some individuals

521

what are the 3 types of epitopes in a hapten-conjugate complex?

1. the pure hapten • 2. the pure antigen • 3. the hapten-antigen complex

522

how can a hapten be made immunogenic?

immunizing with a hapten-carrier conjugate

523

do identical twins recognize each other's proteins as foreign?

no. • they have the same genetic makeup and their immune systems would recognize eachother as self

524

what are examples of immunologically privileged anatomical sites (sequestration)?

corneal, spermatic, CNS cell antigens

525

What are the types of antigens?

1. mitogens • 2. superantigens • 3. T cell independent • 4. T cell dependent

526

mitogens are characterized by what?

the same epitope repeated many times

527

how many types of B cells can mitogens activate?

more than one B cell type/clone

528

are mitogens B cell monoclonal or polyclonal activators?

B cell polyclonal activators

529

what are superantigens?

antigens that can activate more than one type of T cell

530

are superantigens polyclonal/monoclonal B/T cell activators?

polyclonal T cell activators

531

what effect do superantigens have on the immune system?

cause hyper activation of the immune system

532

what is an example of excessive T cell activation having drastic effects?

toxic shock syndrome

533

what does an antigen being T cell independent vs. T cell dependent depend on?

whether an anigen can stimulate B lymphocytes with or without the help from T lymphocytes

534

How do superantigens induce activation of multiple types of T cells?

they are polyclonal stimulators of T cells, binding to the MHC-TCRβ (on the outside of the polypeptide of TCR) complex, without regard for antigen specificity

535

How much of CD4 T cells are activated by super antigens?

up to 20%

536

what is the result of a superantigen activating up to 20% of circulating CD4 T cells?

massive production of cytokines such as IL1, IL2, and TNFα which causes systemic shock

537

what are examples of conditions that are caused by superantigens?

food poisoning • toxic shock syndrome

538

what microbes cause food poisoning and/or toxic shock syndrome?

bacterial exotoxins: • staphylococcal • enterotoxins • staphylococcal toxic shock toxin • staphylococcal exfoliating toxin • streptococcal pyrogenic exotoxins

539

what forms a bridge between CD4 T cell's receptor and the MHC II molecule?

superantigens

540

what do T cells do in response to a superantigen?

divide and differentiate into effector cells

541

what are T-independent antigens?

antigens which can directly stimulate B cells to produce antibody without the requirement for T cell help

542

do T independent antigens require to be presented by APC?

no

543

usually, T independent antigens are what?

mitogen and are resistant to degradation by antigen presenting cell

544

what are examples of T independent antigens?

pneumococcal polysaccharide • lipopolysaccharide • flagellar antigen

545

what are T dependent antigens?

antigens that require the help of T lymphocytes to activate be cells to produce antibody

546

are T dependent antigens degradable by antigen presenting cell?

yes

547

what type of compounds are T dependent antigens?

protein

548

in addition to size, molecular complexity and foreignness, immunogenicity of an antigen depends on what?

1. physical form • 2. degradability • 3. route • 4. dose • 5. adjuvant

549

which physical form of an antigen is more immunogenic, particulate or soluble?

particulate > soluble

550

why are particulate antigens more immunogenic than soluble ones?

particulate form are more easily taken up by antigen presenting cells

551

which physical form is more immunogenic, denatured or native?

denatured > native

552

what speed of release is important for immune response?

slow release

553

what are the relative immunogenicities of routes of administration?

subcutaneous > intraperitoneal > intravenous > intragastric

554

what is the limitation of the oral route of administration's immunogenicity?

oral route induces local mucosal immunity but not systemic immunity

555

what is low zone tolerance?

low doses appear to inhibit the specific antibody production

556

what is high zone tolerance?

very high doses of antigen inhibit immune responsiveness to a subsequent challenge

557

what is the effect of an adjuvant on immunogenicity?

substances mixed together with an antigen and enhance an immune response to an antigen

558

what is the difference between an adjuvant and a carrier molecule?

unlike carrier molecule an adjuvant does not form stable linkage with the antigen

559

what is an example of an adjuvant?

1. complete Freund's adjuvant • 2. aluminum hydroxide/aluminum phosphate

560

what is Complete Freund's Adjuvant?

water in oil emulsion containing killed mycobacteria

561

how does an adjuvant increase immunogenicity of an antigen?

1. insolubilize antigen for better phagocyte uptake • 2. insolubilize antigen for gradual release over time in lipid emulsions called liposomes with delayed time release of antigen • 3. stimulating the influx of phagocytic cells or other immune cells to the site

562

some adjuvants contain mycobacterial components capable of stimulating what?

the innate immunity- acitvation of macrophages

563

what can inflammation be thought of as?

a regulatory event aimed at mobilizing various innate immune effectors and trafficking them to the anatomic location where they can be most effective

564

what is the etymology of inflammation?

latin: inflammare- to set on fire

565

inflammation is initiated by the presence of what?

infectious agents • tissue damage • self (auto) antigens (autoimmunity)

566

in inflammation an innate or adaptive immune action?

combined action of several immune responses of both innate and specific immunity

567

inflammation leads to what?

1. vascular dilation/ increased vascular permeability • 2. accumulation of inflammatory cells • 3. destruction of initiating agent • 4. tissue repair • 5. tissue damage/scarring

568

what are the symptoms of inflammation?

rubor • tumor • calor • dolor • functio laesa

569

what are the cellular players in acute inflammation?

tissues mast cell • neutrophil • macrophage

570

what cells, in addition to the cellular players in acute inflammation, may also be found at site of inflammation?

eosinophils • basophils

571

what are the functions of tissue mast cells in acute inflammation?

release of histamine and other mediators

572

what are the functions of neutrophils in acute inflammation?

phagocytosis and killing

573

what are the functions of macrophages in acute inflammation?

phagocytosis and killing • antigen presentation

574

what are the functions of eosinophils in acute inflammation?

killing of parasites

575

inflammatory stimuli do what?

1. activate the complement system • 2. degranulate mast cells • 3. acitvate macrophages • 4. activate coagulation system

576

inflammatory stimulia activate the complement system, degranulate mast cells, activate macrophages and coagulation system leading to the production of what?

bradykinin, which increases vasodilation

577

in response to inflammatory stimuli, platelts are a mojor component of clotting, releasing what?

prostaglandins • hydrolytic enzymes • growth factors • other mediators that stimulate various cell types to contribute to antimicrobial defense, wound healing, and inflammation

578

microbes and/or their products that enter through a breach in the dermis induce what?

phagocytes to secrete pro-inflammatory cytokines (IL1, TNFα), also activate complement leading to the expression of adhesion molecules by vascular endothelium

579

the net movement of WBC's from circulation into tissue is called what?

extravasation

580

what are the steps of extravasation?

1. Rolling Adhesion • 2. Firm Adhesion (tethering and tight binding, margination) • 3. diapedesis (transendothelial migration) • 4. Migration toward the site of infection

581

Extravasation is driven by what compounds?

TNFα • IL1 • IL8 • C3a • C5a

582

how does rolling in extravasation work?

1. rolling uses selectins • 2. rolling is a low affinity adhesion • 3. E-selectin on endothelium bind to mucin like adhesion molecule on the phagocytic membrane briefly. • 4. force of blood moves rolling on

583

what are the proteins that bind in rolling during extravasation?

E-selectins on endothelium bind to mucin-like adhesion molecules (selectins/Sialyl Lewis sugars) on the phagocytic membrane briefly

584

what force causes rolling during extravasation to move on?

blood flow

585

describe activation by chemoattractants during extravasation

chemokines released during inflammation stimulate conformational change in integrin molecules in phagocytic membrane that incresae their affinity for ICAM adhesion molecules on the endothelium

586

what are the chemokines released during inflammation that stimulate conformational change in integrin molecules in phagocytic membrane that increase their affinity for ICAM adhesion molecules on the endothelium?

IL-8 • C5a

587

to what family of compounds does ICAM belong?

immunoglobulin superfamily

588

what proteins are associated with tethering and tight binding during extravasation?

integrins (LFA)

589

what is LFA?

lymphocyte function-associated antigen 1

590

what types of adhesions are formed in tethering and tight binding during extravasation?

firm adhesion to ICAMS

591

what is diapedesis?

transendothelial migration

592

diapedesis is mediated by what?

PECAM, now renamed CD31

593

what is PECAM?

platelet endothelial cellular adhesion molecule

594

where is CD31 expressed?

on endothelial cells and neutrophils

595

what happens to endothelial expression of E and P selectins under the influence of inflammatory stimuli?

endothelial expression of E and P selectins increases

596

to what family of compounds does LFA-1 belong?

part of the integrin family of leukocyte adhesin molecules

597

What is CD18?

common β chain of the leukocyte integrins

598

what does absence of CD18 cause?

leukocyte adhesion deficiency disease

599

what cytokine released by macrophages upregulate the expression of P selectin on endothelial cells?

TNFα

600

what do P and E selectin do?

together E and P selectin slow the motion of leukocytes through the bloodstream by causing them to roll along the endothelial surface, allowing other molecules to interact with the slowed leukocytes to stop them and promote their movement into the tissues.

601

what compounds stimulate E and P selectin expression?

IL-1 • LPS • TNFα

602

what is LPS a component of?

the membranes of many gram negative bacteria

603

what do LPS binding proteins on macrophages do when they come into contact with their ligand?

stimulate macrophages to release inflammatory cytokines

604

Both E and P selectins are known to bind with what?

Sialyl-Lewis x like glycans

605

where are Sialyl-Lewis x-like glycans expressed?

in relatively high numbers by circulating leukocytes

606

in addition to Sialyl Lewis glycans, what else does P selectin bind?

P-selectin glycoprotein ligand-1 (PSGL-1)

607

where is PGSL-1 expressed?

modestly expressed on human leukocytes

608

leukocyte recruitment by E and P selectin is analogous to what?

throwing a tennis ball at a velcro surface

609

tight adhesion to the rolling leukocyte is performed by what?

ICAM-1

610

what does ICAM-1 bind to?

integrins LFA-1 and CR3 on the leukocyte surface

611

what does ICAM-1 do?

binds to the Integrins LFA-1 and CR3 on the leukocyte surface and arrests the motion of the rolling leukocyte.

612

why does ICAM-1 stop the rolling leukocyte?

stopping the leukocyte allows it to enter the tissues by secreting proteases to breach the endothelial basement membrane

613

what is the acute phase response?

physiological processes that occur during inflammation or tissue damage, triggered by IL-1, IL-6, TNFα

614

which cytokines trigger the acute phase response?

IL-1 • IL-6 • TNF-α

615

on what systems do IL-1, IL-6, and TNFα act during the acute phase response?

hypothalamus • bone marrow • liver

616

what does the acute phase response cause by acting on the hypothalamus?

fever

617

what does the acute phase response cause by acting on the bone marrow?

stem cell differentiation and proliferation

618

what does the acute phase response cause by acting on the liver?

increase production of acute phase proteins

619

what are the purposes of the acute phase response?

- provides replenishment of cells and acute phase proteins used during an inflammation response • - increase metabolic activity

620

what are acute phase proteins?

heterogenous group of serum proteins that increase during inflammation

621

what do acute phase proteins do?

replace exhausted components and reinforce innate defenses against infection

622

what are the important acute phase proteins?

1. C-reactive protein • 2. mannose-binding lectin • 3. complement • 4. fibrinogen

623

what is CRP?

a protein found in the blood, the levels of which rise in response to inflammation

624

what does CRP do?

1. acts as an opsonin AND • 2. it binds to phosphocholine expressed on the surface of dead or dying cells (and some types of bacteria) in order to activate the complement system via the C1q complex (classical pathway in the absence of antibody)

625

what are the relative levels of CRP and MBL in the plasma?

the levels of CRP and MBL are low in the plasma, but levels can increase by up to 1000 fold during the peak of the acute phase response

626

when is the peak of the acute phase response?

about 2 days after its start

627

CRP and MBL both bind to what?

distinct structures that are common features of pathogens and not features of human cells

628

what is the clinical application of CRP?

levels of CRP are routinely measured in clinical diagnostic laboratories to indicate an acute inflammation

629

what does MBL do?

acts as opsonin and triggers complement activation via lectin pathway

630

what does fibrinogen do?

plays a role in blood clotting, which limits the spread of pathogens

631

IL1/IL6/TNFα elicit what acute phase response in the liver?

acute phase proteins (CRP, MBL)--> activation of complement/opsonization

632

IL1/IL6/TNFα elicit what acute phase response in the bone marrow endothelium?

neutrophil mobilization --> phagocytosis

633

IL1/IL6/TNFα elicit what acute phase response in hypothalamus?

increased body temperature --> decreased viral and bacterial replication

634

IL1/IL6/TNFα elicit what acute phase response from fat, muscle?

protein and energy mobilization to generate increased body temperature--> decreased viral and bacterial replication

635

what do pyrogens do?

increase body temperature

636

what is the purpose of fever?

1. increase metabolic activity • 2. inhibit multiplication of certain bacterial and viral agents • 3. human cells become more resistant to TNF-α

637

what does the acute phase reponse do to the supply of the recognition molecules of innate immunity?

increases the supply of the recognition molecules of innate immunity

638

what do bacteria do to induce synthesis of acute-phase proteins?

bacteria induce macrophages to produce IL-6, which acts on hepatocytes to induce synthesis of acute-phase proteins

639

what does the liver do in response to IL-6?

synthesize CRP, MBL, fibrinogen

640

what does CRP synthesized by the liver do to bacteria?

CRP binds phosphocholine on bacterial surfaces, acting as an opsonin and as a complement activator

641

what does MBL do to bacteria?

MBL binds to carbohydrates on bacterial surfaces, acting as an opsonin and as a complement activator

642

when does adaptive immunity play a role in inflammation?

in chronic inflammation: • non-digestible foreign material • chronic damage

643

what are the causes of chronic inflammation?

1. persistent infections and/or infections with resistant microorganisms such as mycobacterium • 2. autoimmune disease or malignancies (first response, acute followed by chronic) • 3. response to 'un-digestible' foreign material

644

does chronic inflammation involve innate or adaptive immunity?

both

645

what are the major cellular actors in chronic inflammation?

macrophages • Th1 (CD4) lymphocytes

646

what do macrophages do in chronic inflammation?

continue to produce pro-inflammatory cytokines (TNFα, IL-1, IL-8) and seek help from Th1

647

what do Th1 (CD4) lymphocytes do in chronic inflammation?

secrete several cytokines

648

what do IFNγ and CD40 ligand do in chronic inflammation?

regulate and strengthen the intracellular killing by macrophages and neutrophils

649

what does the secretion of TNFα, IL1, and IL8 by activated macrophages do in chronic inflammation?

promote recruitment of inflammatory cells to the area

650

how do Th1 and macrophages interact during chronic inflammation?

1. Th1 cell and infected macrophage come together • 2. T cell binds to and activates macrophage • 3. killing of intravesicular bacteria

651

when do granuloma form?

when an intracellular pathogen resists elimination even after receiving help from CD4 Th1

652

what do Th1 cells do when a pathogen resists intracellular killing?

play an important role in fighting such infections by producing different sorts of cytokines which bring more help to the macrophages

653

what are conditions in which granuloma form?

MTB • Leishmania

654

what cells make up and surround a granuloma?

macrophages make up the bulk of a granuloma and lymphocytes surround it

655

which type of inflammation is pyogenic, acute or chronic?

acute

656

which type of inflammation is granulomatous, acute or chronic?

chronic

657

what are the typical triggers for acute inflammation?

staphylococci

658

what are the typical triggers for chronic inflammation?

mycobacterial infecton • hepatitis B

659

what are the initiating cells in acute inflammation?

mast cells • macrophages

660

what are the initiating cells in chronic inflammation?

macrophages

661

what are the effector cells in innate system during acute inflammation?

neutrophil

662

what are the effector cells in the innate system during chronic inflammation?

macrophage • NK cell

663

what are the effector cells in the adaptive system during acute inflammation?

none involved

664

what are the effector cells in the adaptive system during chronic inflammation?

Th1

665

what are the mediators of acute inflammation?

complement, • GM-CSF, • TNF, • chemokines

666

what are the mediators of chronic immunity?

TNF • IL-12 • IL-18 • IFNγ • chemokines

667

what are the systemic effects of acute inflammation?

pus formation, abscesses

668

what are the systemic effects of chronic inflammation?

granuloma may be present

669

What happens in local infection with gram-negative bacteria?

1. macrophages activated to secrete TNF-α in the tissue • 2. Increased release of plasma proteins into tissue. Increased phagocyte and lymphocyte migration into tissue. Increased platelet adhesion to blood vessel wall • 3. phagocytosis of bacteria. local vessel occlusion. containment of infection. Antigens drain or are carried to local lymph node. • 5. survival. stimulation of adaptive immune system.

670

what happens in systemic infection with gram-negative bacteria?

1. macrophages activated in the liver and spleen secrete TNF-α into the bloodstream • 2. systemic edema causes decreased blood volume, hypoproteinemia, and neutropenia, followed by neutrophilia. decreased blood volume causes collapse of vessels. • 3. disseminated intravascular coagulation leads to wasting and multiple organ failure: septic shock. • 4. death

671

what do vascular endothelial cells make in response to TNF-α and what does it do to blood?

platelet activating factor, which triggers blood clotting and blockage of the local blood vessels.

672

what is the benefit of PAF released in response to TNFα by vascular endothelial cells?

restricts the leakage of pathogens into the circulation and prevents disseminated infection.

673

infection of the blood is known as what?

sepsis, septicemia

674

mutation of what has been linked to development of septic shock in patients?

mutation of TLR4 (a receptor for LPS on phagocytic cells)

675

What are the 3 classes of cellular effectors?

1. Degranulating Cells • 2. NK Cells • 3. Phagocytic Cells

676

What cells make up the degranulating cellular effectors of the innate immune system?

Mast Cells • Eosinophils

677

What cell line gives rise to NK Cells?

Lymphoid Line

678

with what degree of specificity do NK cells kill?

nonspecific killing

679

do NK cells participate in innate or adaptive immunity?

lymphoid line, but part of innate immune system

680

what do NK cells target?

intracellular pathogens • tumor cells

681

what do phagocytic cells target?

extracellular pathogens

682

what cells make up the phagocytic cellular effectors of the innate immune system?

neutrophils (PMNs) • monocytes/macrophages

683

part of the inflammatory response is the recruitment of what type of cells (the main line of defense in the non-specific immune system) to site of infection?

polymorphonuclear • eosinophils • macrophages

684

what are LAK cells?

Lymphokine Activated Killer Cells

685

what do NK and LAK cells do?

NK and LAK cells can nonspecifically kill virus infected and tumor cells

686

what do PMN cells do once they are recruited to the site of infection?

1. they phagocytose invading organisms and kill them intracellularly • 2. they contribute to collateral tissue damage that occurs during inflammation

687

what is the function of tissue macrophages and newly recruited monocytes which differentiate into macrophages in innate immunty?

1. phagocytosis and intracellular killing of microorganisms • 2. macrophages- contribute to tissue repair and act as antigen-presenting cells, which are required for the induction of specific immune responses

688

how do mast cells and eosinophils function in the innate immune response?

1. have proteins in granules that are effective at helping to recruit and enhance ann immune response • 2. eosinophils- killing certain parasites

689

where are mast cells found?

found posted throughout the body tissue

690

Mast cells can be stimulated to degranulate by what?

1. direct injury/ trauma • a. physical • b. chemical • 2. cross linking of IgE receptors • 3. activated complement proteins • a. C3a • b. C5a

691

what are the forms of chemical direct injury that cause mast cells to degranulate?

1. opioids • 2. alcohols • 3. certain antibiotics (polymyxins)

692

what are the inflammatory mediators released by the degranulation of mast cells?

1. histamine • 2. platelet activating factor • 3. prostaglandins • 4. leukotrienes

693

the degranulation of mast cells results in what?

1. recruitment of immune cells • 2. increase in vasopermeability

694

where are eosinophils found?

found circulating or in tissue

695

how are eosinophils recruited to the site of infection?

get recruited to the site of infection by cytokines

696

Eosinophils have receptors for which complement product?

C3b

697

what does C3b do to eosinophils?

stimulates degranulation

698

what types of cells are targeted by eosinophils?

big parasites

699

how do eosinophils kill big parasites?

1. producing oxygen radicals • 2. forming pores on target cells

700

are eosinophils phagocytic?

may be phagocytic and assist in clearing of foreign material at the site of injury or infection

701

how do eosinophils stain?

stain with acid dyes

702

chemotaxis of eosinophils to sites of infection is in response to what?

cytokines: • - IL8 • - Others belonging to chemokine family CXC and CC

703

NK cells participate in the recognition and killing of what target cells?

damaged or altered self cells • virally infected cells

704

what is the activation state of circulating NK cells?

circulate in partially activated state

705

what are the 2 mechanisms by which killing by NK is mediated?

1. secretion of perforins and granzymes lead to apoptosis of target cells • 2. FAS ligand mediated 'apoptosis'

706

what is the most important cytokine produced by NK cells?

IFN-γ

707

what are the CD markers present on NK cells?

CD16 • CD56

708

why do NK cells respond quickly to infection?

because they circulate in partly activated state, as seen from their large size and their cytoplasmic granules loaded with toxic effector molecules

709

what does stimulation of NK cells with IFN-α and IFN-β favor?

the development of the cell's killer functions

710

what does stimulation of NK cells with IL-12 favor?

the production of cytokines

711

what is the principal cytokine released by NK cells?

IFN-γ/ type II interferon

712

what is a major function of IFN-γ?

to activate macrophages

713

what are the receptors on NK Cells?

1. KAR- Killer activating receptor • 2. KIR- killer inhibiting receptor

714

what ligands on target cells are recognized by NK cells?

KAL- Killer activating ligand

715

what are some examples of KAL?

viral antigens • tumor antigens (stress protein) • MICA, MICB

716

killing by NK cells is regulated by binding of what to what?

KAR to KAL • KIR to MHC I

717

if a target cell expresses MHC I, will it be killed by NK or LAK cells?

no • MHC I binds Killer Inhibiting Receptor

718

what types of cells express MHC-I?

normal cells constitutively express MHC-I molecules on their surface

719

how do viruses and tumor affect MHC-I?

virus infected and malignant cells down regulate expression of class I MHC

720

Infection of cells may lead to the surface expression of what?

stress molecules

721

in response to viral infection, host cells may express what?

stress molecules: • MICA and MICB • and reduce surface expression of MHC-I

722

what are MICA and MICB?

MHC class I chain-related Genes

723

expression of MICA and MICB can be detected by what?

NK cells that seek to eliminate virally infected cells

724

what happens if both KIR and KAR on the NK cell are bound?

if insufficient KIR-MHC-I binding occurs, the NK cell will proceed to kill the target host cell. • sufficient binding by KIRs will override the KAR kill signal, sparing the life of the host cell

725

where are the MICA and MICB genes located?

within the HLA class I region of chromosome 6

726

are MICA and MICB similar to HLA class I genes?

their organization, expression and products differ considerably from classical HLA class I genes.

727

MICA and MICB are considered to be markers of what?

stress in the epithelia

728

what do MICA and MICB act as?

ligands for cells expressing a common activatory natural killer cell receptor • ---KALs---

729

is the FasL on the NK cell or the target cell?

the NK cell

730

is the Fas Receptor on the NK cell or the target cell?

target cell

731

what are the 2 NK cell killing mechanisms?

1. Granzymes • 2. FasL/FasR

732

what is the mechanism of cell death induced by NK cells?

apoptosis

733

what cell is responsible for phagocytosis of debris generated by NK cell killing?

macrophage

734

Absent NK activity is a component of what disease?

immunodeficiency disease Chediak-Higashi syndrome

735

what are the professional phagocytic cells?

polymorphonuclear neutrophils • mononuclear monocytes/macrophages

736

which class of professional phagocytic cell are granulocytes?

polymorphonuclear neutrophils

737

which class of professional phagocytic cells are agranulocytes?

mononuclear monocytes/macrophages

738

do professional phagocytic cells circulate in blood?

PMN- circulate in blood • monocytes- circulate in blood • macrophages-reside in tissues

739

which of the professional phagocytic cells is more committed to phagocytic activity?

PMNs- mainly phagocytic • Mononuclear monocytes- have function other than phagocytosis

740

what are the functions of mononuclear monocytes/macrophages other than phagocytosis?

1. produce inflammatory cytokines • 2. clear debris and damaged tissue • 3. link innate to adaptive immunity

741

what is the lifespan of the professional phagocytic cells?

PMN's live <2days • MM/M's live months-years

742

what are the inflammatory cytokines produced by MM/M's

IL8 • IL1 • IL6 • TNFα

743

what is the morphology of PMN's?

variable and irregular shape of nucleus, contain granules

744

when are PMN's found in the tissues?

not found in healthy tissue, but when there is infection they enter tissue

745

what calls the PMN's to enter the tissues?

cytokines produced by the macrophages

746

which professional phagocytic cells set the stage for tissue repair?

macrophages

747

which professional phagocytic cells clear tissue of products of inflammation and of remaining microbes?

macrophages

748

What are the 2 major mechanisms by which immune cells recognize pathogens in innate immunity?

1. Pattern Recognition Receptors (PRR) • 2. Pathogen Associated Molecular Patterns (PAMP)

749

where are PRR's found?

on the surface of immune cells and soluble molecules

750

what are some examples of cellular PRR's?

1. Toll Like Receptors (TLR's) • 2. Complement Receptors (CR3 and CR4) • 3. Mannose Receptor • 4. Glucan Receptor • 5. CD14, LPS Receptor • 6. Receptor/Scavenger Protein

751

what is an example of a soluble PRR?

complement

752

where are PAMP's found?

on the surfaces of microbes or microbial products

753

what are examples of PAMP's?

1. LPS of gram negatives • 2. Lipoteichoic acid of gram positives • 3. Lipoarabinoman of acid fast bacteria • 4. Mannose in glycolipids and glycopeptides (surface antigens) • 5. N-Formyl methionine peptides (soluble factor) • 6. dsRNA, ssDNA of viruses • 7. bacterial and viral unmethylated CpG DNA • 8. Bacterial Flagellin • 9. Glucans from fungal cell walls

754

which PAMP is associated with gram negative bacteria?

LPS

755

which PAMP is associated with gram positive bacteria?

Lipoteichoic acid • peptidoglycan

756

which PAMP is associated with acid fast bacteria?

Lipoarabinomannan

757

which PAMP's are assciated with surface antigens?

mannose in glycolipids and glycopeptides (surface antigens)

758

which PAMP is evidence of prokaryotic proteins?

N-formyl methionine

759

what is innate immunity designed to recognize?

molecules shared by groups of related microbes that are essential for the survival of those organisms and are not found associated with mammalian cells.

760

what are PAMP's?

unique molecules shared by groups of related microbes that are essential for the survival of those organisms and are not found associated with mammalian cells

761

what molecules on human cells can act as PAMP's?

DAMP's (Damage Associated Molecular Pattern)

762

how do toll like receptors sense infections?

with a horseshoe shaped structure- transmembrane polypeptides with pathogen recognition domain and a signalling domain

763

where might TLR's be expressed?

1. cell surface • 2. endosomes in the cytoplasm

764

what are the structural variations possible in TLR's?

1. single polypeptide • 2. homodimer • 3. heterodimer

765

which TLR is typically found as homodimer?

TLR4-TLR4

766

which TLR is typically found as heterodimer?

TLR1-TLR2

767

what are the ligands of the TLR1:TLR2 heterodimer?

Lipopeptides • GPI

768

what are the microorganisms recognized by TLR1:TLR2 heterodimer?

Bacteria • Parasites like trypanosomes

769

what cells carry the TLR1:TLR2 heterodimer?

monocytes • dendritic cells • eosinophils • basophils • mast cells

770

what are the ligands of the TLR2:TLR6 heterodimer?

lipoteichoic acid • zymosan

771

what are the microorganisms recognized by the TLR2:TLR6 heterodimer?

gram-positive bacteria • yeasts (fungi)

772

what are the cells carrying the TLR2:TLR6 heterodimer?

monocytes • dendritic cells • eosinophils • basophils • mast cells

773

what is the ligand of TLR3?

viral dsRNA

774

what microorganisms are recognized by TLR3?

viruses (west nile)

775

what cells carry TLR3?

NK cells

776

what is the ligand of the TLR4:TLR4 homodimer?

lipopolysaccharide

777

what microorganisms are recognized by the TLR4:TLR4 homodimer?

gram-negative bacteria

778

what cells carry the TLR4:TLR4 homodimer?

macrophages • dendritic cells • mast cells • eosinophils

779

what is the ligand of TLR5?

Flagellin

780

what microorganisms are recognized by TLR5?/

motile bacteria havign a flagellum

781

what cells carry TLR5?

intestinal epithelia

782

what is the ligand of TLR7?

viral ssRNA

783

what microorganisms are recognized by TLR7?

viruses like HIV

784

what cells carry TLR7?

plasmacytoid dendritic cells • NK cells • eosinophils • B cells

785

what is the ligand of TLR8?

viral ssRNA

786

what microorganisms are recognized by TLR8?

viruses like influenza

787

what cells carry TLR8?

NK cells

788

what is the ligand of TLR9?

unmethylated CpG-rich DNA

789

what microorganisms are recognized by TLR9?

Bacteria • viruses like herpes

790

what cells carry TLR9?

plasmacytoid dendritic cells • B cells • eosinophils • basophils

791

what is the ligand and microorganism of TLR10 homodimer and heterodimers with TLR1 and TLR2?

unknown

792

which cells carry TLR10?

plasmacytoid dendritic cells • basophils • eosinophils • B cells

793

what TLRs are carried by NK cells?

TLR3 • TLR7 • TLR8

794

what TLRs are carried by monocytes?

TLR1:TLR2 • TLR2:TLR6

795

what TLRs are carried by dendritic cells?

TLR1:TLR2 • TLR2:TLR6 • TLR4:TLR4

796

what TLRs are carried by eosinophils?

TLR1:TLR2 • TLR2:TLR6 • TLR4:TLR4 • TLR7 • TLR9 • TLR10 • TLR10:TLR1 • TLR10:TLR2

797

what TLRs are carried by basophils?

TLR1:TLR2 • TLR2:TLR6 • TLR9 • TLR10 • TLR10:TLR1 • TLR10:TLR2

798

what TLRs are carried by mast cells?

TLR1:TLR2 • TLR2:TLR6 • TLR4:TLR4

799

what TLRs are carried by macrophages?

TLR4:TLR4

800

what TLRs are carried by plasmacytoid dendritic cells?

TLR7 • TLR9 • TLR10 • TLR10:TLR1 • TLR10:TLR2

801

what TLRs are carried by intestinal epithelia?

TLR5

802

what TLRs are carried by B cells?

TLR7 • TLR9 • TLR10 • TLR10:TLR1 • TLR10:TLR2

803

which TLRs are found on cell surfaces?

TLR1:TLR2 • TLR2:TLR6 • TLR5 • TLR4

804

which TLRs are found inside the cytoplasm in endosome?

TLR7 • TLR8 • all the TLRs that recognize viral nucleic acids

805

What are the 2 possible fates of PRR+PAMP (danger signal)?

1. phagocytosis and killing • 2. cytokine production (inflammatory cytokines)

806

what do SOS signals include?

PAMP containing peptides released by bacteria • clotting system peptides • complement products • cytokines released from tissue macrophages that have encountered bacteria

807

phagocytic cells have what receptors on their cell membranes through which infectious agents bind to the cells?

1. complement receptors • 2. scavenger receptors • 3. toll like receptors

808

which component of complement do phagocytic cells have a receptor for?

C3b

809

binding of C3b coated bacteria to the receptor on phagocytic cells results in what?

enhanced phagocytosis and stimulation of the respiratory burst

810

what do scavenger receptors on phagocytic cells bind to?

a wide variety of polyanions on bacterial surfaces, resulting in phagocytosis of the bacteria

811

binding of infectious agents via toll like receptors on phagocytic cells results in what?

phagocytosis and the release of inflammatory cytokines by the phagocytes

812

what are the inflammatory cytokines released by phagocytic cells in response to TLR binding?

IL1 • TNFα • IL6

813

how does the Fc receptor work in adaptive initiation?

bacteria with IgG antibody on their surface have the Fc region exposed and this part of the Ig molecule can bind to the receptor on phagocytes

814

binding of IgG coated bacteria to Fc receptors on phago cytic cells results in what?

enhanced phagocytosis and activation of the metabolic activity of phagocytes (respiratory burst)

815

what does PAMP-PRR engagement do to phagocytes?

activates phagocytes to ingest and degrade the microbes

816

what happens in phagocytosis of a bacterium?

1. attachment of bacterium • 2. phagocyte begins to extend pseudopods around the bacterium • 3. pseudopods surround and engulf the bacterium • 4. bacterium is enclosed in a phagosome • 5. granules or lysosomes of the phagocyte fuse with the phagosome and empty their contents • 6. result is beacterium engulfed in phagolysosome which contains the contents of the granules or lysosomes

817

sensing of LPS by TLR4 on macrophages leads to what?

activation of the transcription factor NFκB and the synthesis of inflammatory cytokines

818

what does NFκΒ do in the nucleus of a macrophage?

activates transcription of genes for inflammatory cytokines, which are synthesized in the cytoplasm and secreted via the ER

819

PRR+PAMP sends signaling --> what?

cytokine production

820

what are the steps in phagocytosis by PMN's?

1. bacterium is phagocytosed by neutrophil • 2. phagosome fuses with azurophilic and specific granules • 3. pH of phagosome rises, antimicrobial response is activated, bacterium is killed • 4. pH of phagosome decreases, fusion with lysosome allows acid hydrolases to degrade the bacterium completely • 5. neutrophil dies by apoptosis and is phagocytosed by macrophage

821

why do neutrophils die?

the mature neutrophil cannot replenish its granule content, so once they are used up the neutrophils die by apoptosis and are cleared by macrophages

822

what do the contents of neutrophils' granules kill?

- microbes intracellularly during phagocytosis • - released extracellularly where they kill not only microbes but also surrounding cells and tissue

823

what are the 2 major types of neutrophil granules?

1. primary (azurophil) • 2. secondary (specific)

824

what are the contents of a primary granule in a neutrophil?

1. proteases • a. elastase • b. cathepsin G • 2. hydrolases • 3. myeloperoxidase • 4. defensins • 5. lysozyme • 6. BPI (bactericidal permeability increasing protein)

825

what keeps the contents of a primary granule inactive in a resting neutrophil ?

low pH

826

what are the contents of a secondary granule in a neutrophil?

1. lactoferrin • 2. lysozyme • 3. collagenase • 4. components of the NADPH oxidase system

827

what does BPI do?

binds to LPS and kills gram negative bacteria

828

what 2 mechanisms make up intracellular killing in neutrophils?

1. preformed compounds • 2. production of antimicrobial compounds

829

do preformed compounds in intracellular killing by neutrophils require oxygen?

no they are oxygen independent

830

where are preformed compounds in intracellular killing in neutrophils stored?

they are stored in cytoplasmic granules

831

do the antimicrobial compounds produced in intracellular killing in neutrophils require oxygen?

they are oxygen dependent • RESPIRATORY BURST

832

what is bystander damage?

when compounds involved in intracellular killing by neutrophils are released to the surrounding tissue and cause damage

833

what are the oxygen independent preformed microcidal compounds found in neutrophils that damage microbial membranes?

1. Cathepsin G • 2. Low molecular weight defensins • 3. high molecular weight cationic proteins • 4. bactericidal permeability • 5. BPI

834

what are the oxygen independent microcidal compounds in neutrophils that split mucopeptide in bacterial cell walls?

lysozyme

835

what oxygen independent microcidal compounds in neutrophils complex with iron?

lactoferrin

836

what oxygen independent microcidal compounds in neutrophils digest killed organisms?

proteolytic enzymes • other hydrolytic enzymes

837

how does lactoferrin exert its microcidal effect?

it chelates iron, which deprives bacteria of this required nutrient

838

which intracellular killing mechanism is more efficient, oxygen dependent or independent?

oxygen dependent

839

can patients with defects in oxygen dependent mechanism of itnracellular killing still kill bacteria?

yes

840

patients with defects in oxygen dependent microcidal pathways have what problem?

they are more susceptible and get more serious infections

841

What are three reactions involving superoxide and hydrogen peroxide in the oxygen dependent respiratory burst?

-

842

how is glucose metabolized during phagocytosis?

via the Pentose phosphate pathway and NADPH is formed

843

what is the respiratory burst

the increase in glucose and oxygen consumption during phagocytosis

844

what is the consequence of the respiratory burst?

a number of oxygen containing compounds are produced which kill the bacteria being phagocytosed

845

what are the 2 types of oxygen dependent intracellular killing?

1. oxygen dependent myeloperoxidase-independent intracellular killing • 2. oxygen-dependent myeloperoxidase-dependent intracellular killing

846

what is the role of cytochrome B in oxygen-dependent myeloperoxidase-independent intracellular killing?

cytochrome B, which was part of the specific granule, combines with the plasma membrane NADPH oxidase and activates it

847

what does NADPH oxidase do?

the activated NADPH oxidase uses oxygen to oxidize the NADPH, resulting in the production of a superoxide ion, some of which is converted to H2O2 and singlet oxygen by superoxide dismutase

848

what is the product of the reaction between H2O2 and superoxide?

hydroxyl radical and singlet oxygen

849

what are the toxic oxygen species produced in oxygen dependent myeloperoxidase independent intracellular killing?

O2- (superoxide ion) • H2O2 • OH* (hydroxyl radical)

850

when is myeloperoxidase released into the phagolysosome in oxygen dependent myeloperoxidase dependent intracellular killing?

as the azurophilic granules fuse with the phagosome

851

what does myeloperoxidase do?

utilized H2O2 and halide ions (Cl-) to produce hypochlorite, a highly toxic substance

852

what happens when some of the hypochlorite produced in oxygen dependent myeloperoxidase dependent intracellular killing breaks down spontaneously?

yields singlet oxygen

853

what are the toxic species produced in oxygen dependent myeloperoxidase dependent intracellular killing?

OCl- • singlet oxygen

854

activated macrophages (via PRR or INFγ) express high levels of what enzyme?

nitric oxide synthase

855

is NO+O2- more or less toxic?

#NAME?

856

which TNF is associated with increased expression of iNOS by macrophages?

TNFα

857

how does TNFα affect production of Nitric Oxide?

TNF acts in an autocrine manner to induce the expression of the iNOS gene, resulting in the production of NO

858

what is the toxicity of NO in macrophages?

nitric oxide released is toxic and can kill microorganisms in the vicinity of the macrophage

859

what are the pro-inflammatory cytokines released by macrophages?

IL6 • TNF α • IL1β • CXCL8 • IL12

860

what are the systemic effects of IL6 released by macrophages?

1. fever • 2. induces acute phase protein production by hepatocytes

861

what are the local effects of TNFα released by macrophages?

activates vascular endothelium and increases vascular permeability, which leads to increased entry of complement and cells to tissues and increased fluid drainage into lymph nodes

862

what are the systemic effects of TNFα released by macrophages?

1. Fever • 2. Mobilization of metabolites • 3. Shock

863

what are the local effects of IL1β released by macrophages?

1. activates vascular endothelium • 2. activates lymphocytes • 3. local tissue destruction • 4. increases access of effector cells

864

what are the systemic effects of IL1β released by macrophages?

1. fever • 2. production of IL6

865

what are the local effects of CXCL8 released by macrophages?

chemotactic factor recruits neutrophils and basophils to site of infection

866

what are the local effects of IL12 released by macrophages?

activates NK cells

867

what was CXCL8 previously known as?

IL8

868

where does oxygen independent and dependent intracellular killing take place?

inside phagolysosome

869

where does nitric-oxide dependent killing take place?

inside phagolysosome and cytosol

870

what does a defect in NADPH oxidase cause?

chronic granulomatous disease

871

what are the 8 steps of phagocytosis of a bacterium by a phagocyte?

1. chemotaxis • 2. adherence through PAMP recognition • 3. membrane activation through danger signal • 4. initiation of phagocytosis • 5. phagosome formation • 6. fusion • 7. killing and digestion • 8. release of degradation products

872

at what step of phagocytosis does tissue damage known as bystander damage take place?

release of degradation products

873

what does the complement system consist of?

several proteins, about 30, circulating in blood plasma, lymph and extracellular fluids

874

how are complement proteins designated?

C#...C1, C2, C3 • factor ALPHA... factor B, factor H

875

what produces complement proteins?

liver cells • monocytes • macrophages • gut epithelial cells

876

are complement proteins heat stable or heat labile?

heat-labile

877

how are complement proteins activated?

most of these are proenzymes, inactive until they are cleaved (complement activation)

878

what triggers complement activation?

microbial substances • immune complex (antigen + antibody)

879

how are cleavage products of complement activation designated?

split products are distinguished from the parent pro-enzyme by suffix lower case letters: • C3--> C3a + C3b

880

what happens to complement proteins when they are cleaved?

they become active enzymes, proteases, "convertase" that act on other complement components

881

In what fashion does complement activation take place?

in a sequential fashion

882

describe the cascade fashion in which complement activation takes place

many components of the system serve as the substrate of a prior component and then as an enzyme to activate a subsequent component

883

what does C'-fixation mean?

utilization of C' by antigen-antibody complexes

884

what are the 3 activation pathways of the complement system?

1. classic • 2. alternative • 3. lectin/mannan pathway

885

in which type of immunity are the 3 activation pathways of the complement system involved?

innate and adaptive immunity

886

what are the major functions of the 3 activation pathways of the complement system?

1. inflammation- vasodilation • 2. chemotaxis- attraction of cells of the immune system • 3. killing of pathogen cells by lysis • 4. opsonization- enhancing phagocytosis

887

what is an opsonin?

any molecule that targets an antigen for an immune response

888

what happens in the alternative pathway of complement activation?

pathogen surface creates local environment conducive to complement activation

889

which of the pathways of complement activation is first to act?

alternative pathway

890

what happens in the lectin pathway of complement activation?

mannose binding lectin binds to pathogen surface

891

which of the pathways of complement activation is second to act?

lectin pathway

892

what happens in the classical pathway of complement activation?

C-reactive protein or antibody binds to specific antigen on pathogen surface

893

which of the pathways of complement activation is the 3rd to act?

Classical Pathway

894

what happens in complement activation as a result of all 3 pathways of complement activation?

cleavage of C3 to C3a and C3b • C3b covalently bound to surface components of pathogen

895

what 3 things happens as a result of C3 cleavage and C3b binding to surface components of pathogen?

1. recruitment of inflammatory cells • 2. opsonization of pathogens, facilitating uptake and killing by phagocytes • 3. perforation of pathogen cell membranes • ...which collectively cause the death of the pathogen

896

what are the key steps in all pathways of complement activation?

1. initiation • 2. formation of the C3 convertase • 3. formation of the C5 convertase • 4. all pathways feed into terminal or membrane attack complex formation

897

is the alternative pathway part of the innate or adaptive immune response?

part of the innate immune response

898

what happens in the initiation of the alternative pathway of complement activation?

spontaneous cleavage of C3 at low rate in plasma: • - C3b gets inactivated in plasma, but: • --if it binds human cells, it is inactivated by complement regulator proteins produced by host cells. • -- if it binds to the surface of foreign microorganisms, it gets stabilized

899

what are examples of specific molecules on the surface of microorganism required for the alternative pathway of complement activation?

1. peptidoglycan • 2. teichoic acids • 3. lipolysaccharides

900

what triggers the alternative pathway of complement activation?

C3 hydrolysis directly on the surface of a pathogen

901

what does the alternative pathway of complement activation not rely on, that the other pathways do rely on?

pathogen-binding protein

902

where is C3 produced and cleaved in the alternative pathway of complement activation?

protein C3 is produced in the liver and is then cleaved into C3a and C3b by enzymes in the blood

903

what happens to C3a and C3b if there is no pathogen in the blood?

the C3a and C3b protein fragments will be deactivated

904

what happens in the alternative pathway if there is a nearby pathogen?

1. some of the C3b is bound to the plasma membrane of the pathogen. • 2. it will bind factor B • 3. this complex will be cleaved by factor D into Ba and the alternative pathway C3-convertase, Bb

905

what does C3bBb do?

The C3bBb complex, which is 'hooked' onto the surface of the pathogen, will act like a chain saw, catalyzing the hydrolysis of C3 in the blood to C3a and C3b, which positively affects the number of C3bBb hooked onto a pathogen.

906

what happens after hydrolysis of C3 in the alternative pathway of complement activation/

C3b complexes to become C3bBbC3b, which cleaves C5 into C5a and C5b.

907

C5a and C3a are known to trigger what?

mast cell degranulation

908

what is a membrane attack complex and how is it formed?

C5b, with C6, C7, C8, C9 (C5b6789) complex to form the MAC, which is inserted into the cell membrane, punches a hole, and initiates cell lysis.

909

which pathway provides another means of protection against certain pathogens before an antibody response is mounted?

the alternative pathway of C activation

910

what does a deficiency of C3 cause?

increased susceptibility to the organisms that activate the alternative pathway

911

which is the most primitive of the complement activation pathways?

alternative pathway

912

what are the benefits of the alternative pathway of complement activation?

provides a means of non-specific resistance against infection without the participation of antibodies and hence provides a first line of defense against a number of infectious agents.

913

which protein has been extensively studied for its ability to activate the alternative pathway ?

cobra venom factor (CVF)

914

what happens when C3b associates with C3bBb?

C3BbCBb is formed

915

what is C3bBbCBb?

a C5 convertase

916

what kind of organisms activate the alternative pathway?

1. many Gram-negative bacteria (most significantly, Neisseria meningitidis and N. gonorrhoea) • 2. some Gram-positive • 3. certain viruses and parasites

917

In serum there is a low level of spontaneous hydrolysis of C3 to produce what?

iC3

918

Factor B binds to iC3 and becomes what?

susceptible to Factor D

919

what does factor D cleave factor B into?

Bb

920

what does the iC3Bb complex do?

acts as a convertase and cleaves C3 into C3a and C3b

921

What does factor B do once Cb is formed by cleavage of C3?

Factor B will bind to C3b and becomes susceptible to cleavage by factor D, resulting in a C3bBb complex.

922

what does the C3bBb complex generate?

more C3b, thus amplifying C3b production

923

what happens if C3 activation continues unchecked?

consumption of all C3 in the serum

924

what role does properdin play in alternative pathway control?

properdin stabilizes C3 convertase C3bBb

925

what are the roles of factors H and I in the control of the alternative pathway?

destabilization/destruction: • inactivation of C3b by factor H and I to give fragment iC3b

926

what does deficiency of factor H and I lead to?

depletion of C • fail to control infections

927

what role does DAF, MCP play in control of the alternative pathway

destabilization/destruction: • DAF and MCP disrupt C3 convertase C3bBb on a human cell surface

928

what does deficiency of DAF, MCP lead to?

destruction of self cells

929

What is DAF?

decay accelerating factor

930

What is MCP?

membrane co-factor protein

931

how do factor H and I avoid excessive usage and depletion of C3 from the plasma?

by inactivating C3b and preventing further cleavage of C3

932

when faced with bacterial infection, patients with factor H/I deficiency run out of C3 and fail to control infections, especially with WHICH TYPE of bacteria?

capsulated bacteria which require opsonization for elimination by phagocytic cells

933

what is the role of i3Cb?

deposited on surface of pathogens • serves as opsonin • facilitate phagocytosis by binding to CR3 and CR4 (complement receptors) on phagocytic cells.

934

what are the 2 main features of membrane attack complex formation (pathway)?

1. initiated by the formation of C5 convertase • 2. requires the presence of an accessible phospholipid membrane on the target cell on which to build the pore complex

935

what does formation of the c5 convertase trigger in the MAC formation (pathway)?

the association of a group of complement proteins which do not undergo cleavage but are active as intact proteins which build a transmembrane pore (MAC) in the target cell, resulting in leakage of cytoplasmic contents

936

what are examples of microbes resistant to MAC?

1. encapsulated bacteria • 2. gram positive bacteria • 3. un-enveloped viruses

937

what happens in the Membrane Attack (lytic) Pathway?

1. C5 convertase from the alternative (C3bBb3b) pathway cleaves C5 into C5a and C5b. • 2. C5a remains in the fluid phase and the C5b rapidly associates with C6 and C7 and inserts into the membrane. • 3. C8 binds, followed by several molecules of C9. • 4. The C9 molecules form a pore in the membrane through which the cellular contents leak and lysis occurs.

938

is membrane attack pathway lysis an enzymatic process?

no: • it is thought to be due to physical damage to the membrane

939

what is the complex consisting of C5bC6C7C8C9 referred to as?

the membrane attack complex

940

what are some of the potent biological activities of C5 generated in the lytic pathway?

1. it is the most potent anaphylotoxin • 2. it is a chemotactic factor for neutrophils and stimulates the respiratory burst in them • 3. it stimulates inflammatory cytokine production by macrophages

941

the activities of C5 generated in the lytic pathway are controlled by what?

carboxypeptidase B (C3-INA)

942

what intermediate of the lytic pathway can dissociate from the membrane and enter the fluid phase?

C5b67, the dissociation of which could cause damage to bystander cells

943

damage to bystander cells by C5b67 from the lytic pathway which has dissociated from the membrane is prevented by what?

Protein S (vitronectin): • Protein S binds to soluble C5b67 and prevents it from binding other cells

944

what binds to the C5b678 complex on human cells and prevents recruitment of C9 to form the pore?

CD59

945

what are the main features of the lectin (mannan) pathway?

1. part of the innate immune response • 2. nonspecific • 3. initiated when MBL binds to mannose or GlcNAc residues on microorganisms

946

what does initiation of the lectin (mannan) pathway activate?

MBL-associated serine proteases (MASPs) which split C4 and C2 to form C3 convertase

947

what happens after the initiation of the lectin (mannan) pathway creates the C3 convertase?

1. C3b is produced • 2. the C5 convertase (C4b, C2a, C3b) is formed and the MAC complex begins

948

To which other complement activation pathway is the Lectin pathway most similar?

the classical pathway

949

how is the Lectin pathway initiated?

by the binding of MBL to bacterial surfaces with mannose containing polysaccharides.

950

what are mannans?

mannose containing polysaccharides

951

binding of MBL to a pathogen results in what?

association of 2 serine proteases: • 1. MASP-1 • 2. MASP-2

952

what other proteins are MASP-1 and MASP-2 similar to?

C1r and C1s

953

what protein is MBL similar to?

C1q

954

formation of the MBL/MASP-1/MASP-2 trimolecular complex results in what?

the activation of the MASP's and subsequent cleavage of C4 into C4a and C4b

955

what happens to the C4a/b fragments formed by cleavage of C4 in the Lectin pathway?

1. the C4b fragment binds to the membrane • 2. C4a fragment is released into the microenvironment

956

in addition to cleaving C4 in the Lectin pathway, MASP's also cleave what?

C2 into C2a and C2b

957

what do C2a and C2b cleaved by the MASP's in the Lectin pathway do?

1. C2a binds to the membrane in association with C4b. • 2. C2b is released into the microenvironment

958

what is the function of the C4bC2a complex in the Lectin pathway?

it is a C3 convertase which cleaves C3 into C3a and C3b

959

what happens to C3a and C3b formed from cleavage by C4bC2a in the Lectin pathway?

1. C3b binds to the membrane in association with C4b and C2a. • 2. C3a is released into the microenvironment

960

what is the function of C4bC2aC3b complex in the Lectin pathway?

C5 convertase

961

what is the end of the Lectin pathway?

generation of the C5 convertase

962

What are Ficolins?

a group of oligomeric lectins with subunits consisting of both collagen (Col)-like long thin stretches and fibrinogen (Fi)-like globular domains with lectin (Lin) activity usually specific for N-acetylglucosamine (GlcNAc)

963

what are Ficolins similar to?

ficolins are homologous to MBL and function via MASP in a similar way

964

what do ficolins do in non-vertebrates without an adaptive immune system?

ficolins are expanded and their binding specificities diversified to compensate for the lack of pathogen-specific recognition molecules

965

the biological activities and the regulatory proteins of the Lectin pathway are the same as those of what pathway?

the classical pathway

966

Is the classical pathway part of innate or adaptive immunity?

both

967

why is the classical pathway 'specific'?

due to the requirement of antibodies bound to the surface of particulate antigen

968

the classical pathway is activated by what?

Antigen-Antibody

969

the 'innate' classical pathway is activated by what?

C-reactive protein bound to pathogens

970

what complement protein does the classical pathway require?

C1

971

what is C1 composed of?

C1q • C1r • C1s

972

what is the best activator of the classical pathway?

IgM

973

what are the weaker activators of the classical pathway?

some classes of bound IgG: • IgG3,1,2

974

What does the C1-complex consist of?

one molecule of C1q and two molecules of C1r and C1s

975

how is the classical pathway triggered?

by activation of the C1 complex

976

how is the C1-complex activated?

1. C1q'a binding to antibodies from classes M and G complexed with antigens • or • 2. binding of C1q to the surface of the pathogen

977

the binding of C1q to the antibodies or the surface of the pathogen leads to what?

1. conformational changes in C1q molecule, which leads to the activation of two C1r molecules. • 2. then C1r cleaves C1s

978

what does the C1-complex do after 2 C1r's cleave 2 C1s's in the classical pathway?

the complex now binds to and splits C2 and C4, producing C2a and C4b

979

the inhibition of C1r and C1s is controlled by what?

C1-inhibitor

980

in the classical pathway, what molecules bind to form the C3 convertase?

C4b and C2a

981

which protein is larger, C2a or C2b?

C2a

982

what signals the end of the classical pathway?

production of the C3 convertase, but cleavage of C3 by this enzyme brings us to the start of the Alternative pathway

983

to what 2 things does C1 bind in the same way?

IgM and C-reactive protein

984

what are the 2 types of C3 convertase?

1. Lectin and Classical- C4bC2a • 2. Alternative- C3bBb

985

what are the types of C5 convertase?

1. Lectin and Classical- C2a4b3b • 2. Alternative- C3bBb3b

986

what does C4-BP inhibit?

C4b

987

What are the components of the Alternative pathway?

C3 • Factor B • Factor D • Properdin

988

what are the components of the Classical Pathway?

C1 • C4 • C2 • C3

989

what are the components of the Lectin pathway?

MBL • MASP-1 • MASP-2 • C4 • C2 • C3

990

is the Alternative pathway antibody initiated?

NO

991

is the Classical Pathway Antibody initiated?

YES

992

is the Lectin Pathway Antibody Initiated?

NO

993

is the alternative pathway initiated by pathogen surfaces?

yes

994

is the classical pathway initiated by pathogen surfaces?

Yes via antibody attachment or CRP

995

is the Lectin pathway initiated by pathogen surfaces?

yes

996

is there anaphylotoxin generation in the alternative pathway?

yes

997

is there anaphylotoxin generation in the classical pathway?

yes

998

is there anaphylotoxin generation in the lectin pathway?

yes

999

what is anaphylotoxin?

C3a • C5a

1000

does the alternative pathway feed into the MAC?

yes

1001

does the classical pathway feed into the MAC?

yes

1002

does the Lectin pathway feed into the MAC?

yes

1003

what are the regulatory components of the alternative pathway?

Factor H • Factor I • DAF • CR1

1004

what are the regulatory factors of the classical pathway?

C1-INH • C4-BP • Factor I

1005

what are the regulatory components of the Lectin pathway?

C1-INH • C4-BP • Factor I

1006

what type of pathogens do opsonization and MAC lysis target?

extracellular pathogens

1007

what are anaphylotoxins?

inflammatory mediators

1008

what type of anaphylotoxin is C4a?

a weak anaphylotoxin

1009

what do anaphylotoxins do?

1. mediate degranulation of mast cells, basophils, eosinophils- release of biologically active mediator (eg histamine) • 2. promote smooth muscle contraction- increase vasodilation and vascular permeability (edema, low BP) • 3. mediate chemotaxis of leukocytes to sites of infection- activate macrophages and neutrophils • 4. promote platelet aggregation

1010

what does C5a do to C' receptors?

increases expression of CR's on inflammatory cells (neutrophils, monocytes, macrophages, B cells)

1011

describe the dose dependent action of anaphylotoxins

beneficial in low doses, cause anaphylaxis at high doses

1012

What types of cells have C3a and C5a receptors?

1. smooth muscle cells • 2. Mast cells • 3. basophils • 4. eosinophils • 5. endothelial cells • 6. phagocytic cells • 7. platelets

1013

what is the effect of anaphylotoxins increasing vascular permeability?

1. increased permeability allows increased fluid leakage from blood vessels and extravasation of complement and other plasma proteins at the site of infection • 2. Migration of monocytes and neutrophils from blood into tissue is increased

1014

what is the binding action of the complement receptors on phagocytic cells?

CR1 binds to C3b • CR3 and CR4 binds to iC3b

1015

what are the steps of opsonization and phagocytosis of bacteria?

1. complement activation leads to deposition of C3b on the bacterial cell surface • 2. CR1 on macrophage binds C3b on bacterium • 3. endocytosis of the bacterium by the macrophage • 4. macrophage membranes fuse, creating a membrane-bounded vesicle, the phagosome • 5. Lysosomes fuse with the phagosomes forming the phagolysosome

1016

Describe step-wise the role of complement in clearing immune complexes from the circulation

1. circulating immune complexes become substrates for the activation of the classical pathway • 2. complement fragment C3b attaches to these immune complexes, mediating attachment of the complexes to RBCs via CR1. • 3. The RBC circulates the liver where CR1 acts as a cofactor for Factor I mediated cleavage of fragment C3b, forming the 2 products iC3b and C3f. • 4. iC3b is not bound by CR1, and so the RBC releases the immune complex, which is immediately bound by macrophages via CR3 or CR4. • 5. The macrophage ingests the immune complex

1017

in the liver, CR1 acts as a cofactor for what cleavage reaction?

Factor I mediated cleavage of C3b

1018

what are the products of factor I mediated cleavage of C3b in the liver?

iC3b • C3f

1019

what happens to the complement level in the blood of patients with immune complex diseases?

patients with immune complex diseases will deplete their complement level in the blood

1020

what is used in diagnosis of immune complex disease?

measurement of C2 and C4

1021

What is the activity of C2b?

prokinin, accumulation of fluids

1022

what is the effect of C2b?

edema

1023

what are the control factors for C2b?

C1-INH

1024

what is the activity of C3a?

1. basophil and mast cell degranulation • 2. ennhanced vascular permeability • 3. enhanced smooth muscle contraction

1025

what is the effect of C3a?

anaphylaxis

1026

what are the control factors of C3a?

C3a-INA

1027

what is the activity of C3b?

opsonin, phagocyte activation

1028

what is the effect of C3b?

phagocytosis

1029

what are the control factors of C3b?

Factors H and I

1030

what is the activity of C4a?

1. Basophil and mast cell degranulation • 2. enhanced vascular permeability • 3. enhanced smooth muscle contraction

1031

what is the effect of C4a?

anaphylaxis (least potent)

1032

what are the control factors of C4a?

C4-BP and Factor I

1033

what is the activity of C5a?

1. basophil and mast cell degranulation • 2. enhanced vascular permeability • 3. enhanced smooth muscle contraction • 4. chemotaxis • 5. stimulation of respiratory burst • 6. activation of phagocytes • 7. stimulation of inflammatory cytokines

1034

what are the effects of C5a?

anaphylaxis (most potent) • inflammation

1035

what are the anaphylactic activities of C5a?

1. basophil and mast cell degranulation • 2. enhanced vascular permeability • 3. enhanced smooth muscle contraction

1036

what are the inflammatory activities of C5a?

4. chemotaxis • 5. stimulation of respiratory burst • 6. activation of phagocytes • 7. stimulation of inflammatory cytokines

1037

what are the control factors of C5a?

C3a-INA

1038

what happens to prokinin?

cleaved by plasmin to yield kinin, which results in edema

1039

Which has a higher plasma concentration, complement control proteins or complement proteins?

complement control proteins

1040

what is an example of a control protein present on the membrane of self-cells preventing them from being targeted by complement?

CD59, which inhibits C9 polymerization during formation of the MAC

1041

What syndromes/disease states are caused by deficiency of Factors B or D in the alternative pathway?

susceptibility to pyogenic bacterial infections