Blood and Lymph Unit 2-2019 Flashcards Preview

Blood and Lymph class of 2019 > Blood and Lymph Unit 2-2019 > Flashcards

Flashcards in Blood and Lymph Unit 2-2019 Deck (221):
1

t cells have to be _______ at the site of interaction with antigen.

present. they do not secrete their receptors. the only see antigenic determinants shown to them by presenting molecules on other cells.

2

what happens if you neonatally thymectomize mice?

they grow up with wasting syndrome, cannot reject foreign skin grafts. If you give them a thyme transplant they are ok!

3

what are the 6 T cells?

5 helper T cells, 1 killer T cell

4

Th0

undecided precursor to helper T cells. found in paracortex. when DC brings them a correct antigen, they divide and become Th1, Th17, Th2, Tfh, or Treg cells.

5

what is the thing that helper T cells express on their surface?

surface marker CD4

6

what is the main determinant of Th0’s ultimate fate?

what the DC experienced: conditions in periphery when stimulated, what TLR is engaged, what cytokines/chemokines predominated.

7

Th1 Cells

delayed hypersensitivity T cells. after activated, daughters leave and circulate the body. when they find antigen, they secrete lymphokines.

8

what is the most important lymphokine secreted by Th1?

interferon gamma. IFNy. pro inflammatory. chemotactic for blood monocytes—>become tissue macrophages. move areas where Th1 recognizes antigen. activated IFNy, to become CLASSICALLY ACTIVATED M1 (angry) macrophages

9

what cytokines do macrophages release to intensify inflammation?

tumor necrosis factor alpha. TNFa. and IL-1

10

what is the main cause of fever and inflammation?

IL1. stimulates PGE2 which slows firing rate of temp. control neurons. activates heat generation and fever

11

Besides INFy, what else does a Th1 secrete?

IL-2. helps CTL (killer T cells) get activated post antigen recognition

12

Th17 cells

makes inflammatory lymphokine Il-17. resembles Th1, causes inflammation but it is also implicated in immune diseases.

13

cytokines

short range mediators made by any cell that affect behavior of the same or another cell

14

lymphokines

short range mediators made by lymphocytes, affect behavior of same or another cell. subset of cytokines

15

chemokines

small short range mediators made by any cell-primarily cause inflammation

16

list some cytokines

IL-1, TNFa, IL-12

17

list some lymphokines

IL-2, INFy, IL-4, IL-5, IL-10

18

list some chemokines

MIP-1 to 4, RANTES, CCL 28, CXCL16, Eotaxin, IL-8

19

Th2 cells

when activated leave the node, circulate until they encounter antigen. then they make IL4, IL5, and IL13 to attract ALTERNATIVELY ACTIVATED M2. these are more involved in healing (debris removal, scar, pathogen wall off).

20

IL-4 is chemotactic for what?

eosinophils (cells specialized for killing parasites)

21

Tfh (follicular helper T cells)

after DC presenting cell arrives in node, some activated Th migrate to follicles of cortex to find the B cells! These Th cells role is to help B cells that have recognized antigen, in order active and differentiate into plasma cells. Tfh secrete variety of cytokines, and stimulate B cells with direct contact to switch from secretion of IgM to IgG, A, or E.

22

Tfh cells tend to be________, the Tfh in the gut for example switch B cells to IgA, those in the spleen switch B cells to IgG.

heterogeneous!!!!

23

are Tfh of a separate lineage from Th1 and 2?

nah. its more likely that one of those buggers picked up a chemokine receptor like CXCR5 that lets them boogey over to the follicle.

24

Treg (regulatory cells)

a small number of Th cells suppress activation of all the other T cells. See, most regulatory T cells have CD4+/CD25+ and make TRANSCRIPTION FACTOR Foxp3. CD4=helper family. they also produce TGFbeta and IL10. they are super duper potent and one can suppress 1000 Th cells.

25

what happens if you don’t have Treg?

overactive immune response and often autoimmunity and self reactivity. (my stupid body is having a field day with this with the freaking Celiac)

26

Are Treg specific?

nah. they stop any nearby Th.

27

CTL (cytotoxic killer T cells)

these awesome doodads work by giving a “kiss of death”/lethal hit. signals the target to commit suicide by activating apoptosis. It dose this by engaging death receptor Fas (CD95) on the target or by secreting lytic granules (these bad boys have granzymes and perforins) to trigger apoptosis.

28

memory cells

once you’ve responded to an antigen, number of T cell clones declines rapidly. approx 5% stick around. These are the memory cells, and they act kinda like stem cells: replace themselves, and differentiate when re-exposed to low antigen concentrations

29

what are the most useful molecules on T cells for differentiation?

CD3, CD4, CD8.

30

what the heck does CD stand for?

cluster differentiation

31

CD3 is where?

on the surface of all T cells

32

CD4 is where?

on the surface of all T helpers

33

CD8 is where?

on CTL

34

MHC restriction, what does it mean?

T cells are restricted in antigen recognition. They recognize antigen on surfaces of cells GENETICALLY IDENTICAL TO THEMSELVES. they don’t only see antigen, but antigen on an identical. So basically you have to be an individual with the same alleles at the same loci called MHC. T cells are antigen specific and MHC restricted.

35

Are MHCs variable?

heck yes. very.

36

will T cells interact with free antigen?

NO! it can only see it when complexed with cell-surface MHC. they have to focus on the cell surface, they have severe tunnel vision. B cells are more open and free-they totally will complex with free antigen

37

what’s the basic structure/layout of a Class 2 MHC?

it’s got an alpha and beta chain folded so that a cleft faces a T cell. the base of the cleft is a Beta sheet, with alpha helix sides. inside this cleft is the peptide (fruit bowl and fruit example).

38

T cell receptor for antigen (TCR)

structurally like an antibody. has 2 chains called alpha and beta (NOT the same as the one on Class 2 MHC). each has a constant, and variable portion. The receptors are made of V, (D), J regions, and each one has 3 CDRs.

39

what is “intimately” associated with TCR?

CD3! It’s got 5 chains and transducers TCR signals for the T cell. When a T cell bids that antigen+MHC, the signal to turn on is transmitted by CD3.

40

when a Th cell binds a good APC like a dendritic cell it receives_______ sorts of signals

Three!!!!

41

what is the first signal a Th cell get from it’s TCR? The second? The third?

1) TCR-pMHC interaction. 2) array of accessory molecule interactions provided by true APC (modify, enhance, diminish activation). 3) variety of cytokines APC may secrete.

42

What's an APC?

antigen presenting cells

43

Class 1 MHC genes

on all nucleated cells

44

Class 2 MHC genes

expressed on dendritic and macrophage cells, B cells, and a few others (all involved in presenting antigen peptides to Th cells

45

when an antigen is endocytose and presented by a DC, it associates with ______ MHC molecules in endocytic vesicle.

Class 2!!! these complexes are what DC presents to T cell. Th1, Th17, Tfh, Treg, and Th2 are selected to recognize peptides on Class 2 molecules

46

Class 1 MHC molecule associate best with peptides sampled from proteins synthesized ________ the cell itself.

within!!! not taken up by endocytosis (intrinsic path). finds internal pathogens (viruses). CTL are programmed to see antigen associated with MHC class 1 molecules

47

CTL are necessary for getting rid of virus, so by default they have to be able to see ____ infected cell.

any. they are restricted by Class 1 molecules.

48

which thing does DC express? Class 1 or 2?

Trick question! It expresses both! this way it can bring in stuff from the periphery to arrange for Th and CTL responses. this is called CROSS PRESENTATION.

49

What does CD4 bind to?

MCH class 2, to the unvarying “base” of the peptide. it helps increase the strength of the bond when Th is seeing antigen+class 2.

50

CD8 on CTL binds what?

base of Class1, increasing binding affinity of CTL to antigen+ Class1.

51

how do Tfh cells manage to help activate B cells?

T and B cell must have same MHC class2. they are not specific for the same epitope, but the epitope they are both programmed for CAN be on the same ANTIGEN. if you block a B cell from endocytosing, it can’t be helped or make antibody. the Tfh must contact the B cell.

52

give me a breakdown of the steps of B cell activation:

B cell binds epitope on an antigen, endocytosis the molecule, the molecule breaks down, fragments bind MHC class2, and the complex moves to the surface. B cell displays antigen+class2. Tfh wanders by, sees the epitope it has searched for and dreamed of all its life, and binds, focusing surface interactions and helper lymphokines on the B cell.

53

what does it mean if an antigen is T independent?

it's just so great and amazing it doesn’t need help from T cells. they tend to be molecules with a repeating epitope (like large carbs). This means even if people are T cell deficient, they can make antigens to carbs without help.

54

lectins

proteins made by many life forms. they have affinities for certain sugars, usually one that the organism it comes from doesn’t have. some bind and stimulate T and B cells.

55

phytohemagglutinin (PHA)

bean lectin. stimulates all T cells to divide by binding CD3. since it stimulates mitosis, it is a MITOGEN.

56

T cells originate in the thymus and come outs as _____ or ______.

CTL or Th0.

57

what pouches does the thymus originate from?

3 and 4

58

lymphoid precursors land where in the thymus after leaving the blood?

in the outer cortex.

59

what makes a T cell mature?

it is no longer double positive for 4 and 8, it is single positive.

60

how many T cells are exported from the thymus?

less than 2%

61

what are the 3 things a T cell must do:

1) not recognize self, 2) not recognize free antigen, 3) recognize antigenic peptide + self MHC

62

positive selection

affinity for self MHC but not self peptide in the periphery might turn out to be high affinity for self MHC+foreign peptide

63

Negative selection

immature T cell binds MCH with high affinity, enough to activate all T cells. Cell either dies or becomes a Treg.

64

Non selection

most of TCR have no affinity for MHC molecules expressed in thymus. No stimulation=death.

65

histocompatability

describes the outcome of grafts of living tissue btw. 2 individuals, if the graft is accepted for a long time they are compatible

66

what is the most important region in histocompatibility?

H2 region. not a single locus, but many loci close to gather on 17th chromosome. codes for histocompatibility antigens, some of which are expressed on surfaces of all nucleated cells

67

what is the strongest histocompatibility antigen?

the Major Histocompatibility Complex! (MHC). Mice=H2, in humans it’s the HLA (human leukocyte antigen)

68

what are the most important loci in the HLA?

HLA-A, HLA-B, HLA-D group (here, DR is the most concert to transplanters

69

Map the MHC! tell me the order the classes go from L to R!

Class 2, Class 3, Class 1

70

what are the loci in MHC Class 2:

centromere/DP/DQ/DR

71

what are the loci in MHC Class 3:

C4/Bf/C2/TNF

72

what are the loci in MHC Class 1:

B/C/A

73

are the loci expressed dominantly or codominantly in the HLA loci?

codominantly! this means at the HLA-A locus you have patternal and maternal alleles expresesed

74

what is a haplotype?

the MHC gene set you inherited from one parent

75

How do you type someone’s HLA loci?

you treat the patient’s leukocytes with a panel of antisera specific to HLA alleles and complement. if the allele is expressed, that antibody gets recognized, complement lyses with them, and you can observe it. Or if you want it to be easier you could just sequence them, it kinda has more info and is just better

76

what do you run the risk of missing if you only use antisera to type someone’s HLA?

you run the risk of missing that different alleles make up the HLA you are looking at. antisera shows multiple types as one thing (eg: HLA-B27), but sequencing shows the specific alleles for each

77

can offspring accept grafts from parents in mice?

YES! it is not unfamiliar to the child, but you can’t go the other direction!

78

can humans accept grafts from parents?

Hahaha! No. best bet is a sibling or someone with the same HLA genotype

79

what are Class 1 MHC loci?

the original transplantation antigens. they are on all nucleated cells. HLA A, B, (and C).

80

is matching HLA A, B enough for a graft to not be rejected?

NOPE! if you mix in cell culture, T cells will recognized antigens on the foreign white cells.

81

what is the Mixed Leukocyte Reaction (MLR)

what happens when T cells recognize foreign antigen on white cells that aren’t the host bodies. These antigens are CLASS 2 MHC!

82

describe reaction between MLR and Class 2 MHC for me:

recognition is bidirectional, so it’s hard to tell how strongly T cells respond against donor Class 2

83

what test do you have to do to see if a donor tissue will be rejected or not?

you have to do a “one-way” MLR. here, cells from the donor are treated to prevent division. then you watch the recipient’t Th cells dividing in response to the donor’s class2 MHC. Strong reaction=no transplant

84

Let’s talk about MHC antigen structure. Class 1 and 2 antigens are ______ composed of (#?) polypeptide chains.

glycoproteins, 2. Class 1 have an allelically variable chain associated with invariant chain called beta2-microglobulin. both class2 chains are variable.

85

which class loci have humans triplicated?

class 2! we have DR, DP, DQ. To simplify-say HLA-D when discussing Class 2. note-HLA-DR is the most significant in solid organ transplant

86

minor histocompatiblity antigens-give me the rundown!

there are about 30 of these bad boys. if you mismatch (even just 1!!!) you may cause slow/chronic rejection. for example, H-Y is an internal protein with peptides displayed on MHC Class 1, and because of it Male skin grafts are rejected by females. Males accept female grafts no problem

87

what are grafts btw. identical individuals called?

syngeneic or isografts

88

what are grafts btw. non-identical members of same species?

allogenic, allografts

89

what are grafts btw. members of diff species called?

xenogenic, xenografts

90

what are grafts between 1 person called

autografts (hahahaha.)

91

what's the most important T cell involved in graft rejection?

Th1 (via lymphokines and monocyte/macrophage respones) and CTL.

92

hyperacute rejection

a graft is given to a person who has a pre-existing antibody (IgG or IgM) to it. (from HLA, transfusion,mismatch, ABO blood group). antibody immediately binds to the endothelial cells of graft’s blood vessels. Complement is activated, vasospasm, organ may never even get blood.

93

tell me what happens in rejection:

Th1 cells recognize foreign HLA-DR on graft cells (not all cells express these, cells that dare primarily macrophages and dendritic cells). Th1 proliferate, secrete lymphokines (IFNy) to attract macrophages. CTL recognize foreign HLA-A and B (on all graft cells), and wait for a secondary signal (Th1 derived IL-2) to be activated. once they are activated they are cytotoxic, they proliferate and kill kill kill!!!!!!

94

normal response to virus vs. tissue rejection:

normal response is peptide + self MHC recognized, in rejection is foreign MHC.

95

what is the most important thing to match in transplant? Why (tell me the differences in matching the two?)

Class 2!!!! if donor and recipient are identical at class 1 but different at class2, Th1 will be activated, but not CTL will be activated (no difference to see). Graft will be rejected slowly. if the donor and recipient are different at class1 but same at class 2, there is no Th1 activation, no IL-2 generation

96

if Th cells normally see MHC Class2 + peptide, they also see foreign _______.

MHC class 2. CTL normally see peptide + class 1 and also see foreign class 1.

97

recognition of foreign MHC is a a chance _____, the receptors are actually selected to recognize SELF MHC + antigen.

cross reaction.

98

if when we have an immune response to someone else’s material we are acting like what?

like we are immunized against that other person. 5% of your T cells bind my MHC strongly enough to activate (which is a TON!). Why we can’t give T cells to another person

99

ankylosing spodylitis

arthritic condition of inflammation at insertion of tendon into bone, fibrous spinal joints an pelvis, and calcification. 92% with it are HLA-B27. B27 is prone to misfiling, and it may cause the inflammation. ERAP1 gene that codes for endopeptidase affects how HLA27 loads with endogenous peptides

100

linkage disequelibrium

the non-random association of alleles at different loci i.e. the presence of statistical associations between alleles at different loci that are different from what would be expected if alleles were independently, randomly sampled based on their individual allele frequencies

101

modifications of proteins may cause ____ _____ associated strongly with certain MHC alleles

novel epitopes. the cells that respond to these neoantigens cross react with normal protein. modifications are likely more environmental than genetic

102

cells that provide immune defense are organized into what organs? (3 things)

encapsulated lymphoid, unencapsulated cell aggregates, individual free cells in blood

103

what are the primary lymph organs?

bone marrow and thymus

104

what are the secondary lymph organs

areas where aggregates of lymphocytes are found in close proximity to antigen presenting cells, can also furnish an adaptive immune response.

105

what are the encapsulated lymph organs?

lymph nodes, thymus, spleen

106

where are diffuse, non-encapsulated lymph cells harbored in the body?

aggregates or nodules of cells are harbored throughout the body, often in underlying mucosal epithelia, esp in areas where bacteria infection tend occur (GI)

107

what's a lymph node?

a small organ found throughout the body alone or in clusters. they are filters for debris, microorganism, etc. they are the key areas of antigen presentation in adaptive immunity.

108

what is afferent lymph?

small spaces in tissues lined by squamous epithelium, and they connect to a local lymph node

109

what's the sub capsular space?

a connective tissue capsule (duh) where lymphocytes enter the node.

110

where does lymph fluid leave the node from?

the efferent lymphatic vessel along with lymphocytes

111

describe the layers of the lymph node to me briefly.

outer cortex, loosely defined paracortical region, medulla. the outer capsule connects to a connective tissue called trabecular that extends into and divides up the cortex. Inside there are reticular fibers that allow things to hang on despite the fluid flow.

112

where are lymphoid follicles found?

high in the cortex

113

what are germinal centers?

regions of active cell proliferation and apoptosis. mostly made of B cells and dividing activated B cells and macrophages.

114

what makes up the paracortical region?

mostly T cells and some B cells. no sharp demarcation between the regions

115

where does blood enter the lymph node?

would that be at the small artery at the hilus? And would it possibly leave at the hilum? Yeah I think so.

116

what is the medulla?

region of loosely arranged cords of cells. B and T cells and plasma cells

117

what is the endothelium lining the lymph node vessels?

a special endothelium called HIGH ENDOTHELIAL VENULE. sites of recognition and diapedesis of lymphocytes. Have “docking receptors” that initiate passage through the epithelium. These are round cells and they protrude into the vessel lumen

118

the thymus is where _______ ________ cells undergo the processes that make them immunocompetent T cells!

thymocytic precursor. here they proliferate, differentiate, and select.

119

tell me about the thymus lobes; how many are there and what are they like?

there are 2. it is sheathed by a connective tissue capsule that a septa divides the organ with (trabeculae). in the lobes there is a cortex that has lots of developing thymocytes with dark nuclei. more mature thymocytes are in the medulla and are a little more loosey-goosey. the cells beneath the capsule are blasts, and they divide and create immature thymocytes

120

what are epithelioreticular cells?

aka, stromal cells. they are epithelial like cells, dendritic cells, macrophages. they provide a matrix and envelop thymocytes in cortex and medulla. stream cells are important in the (-) and (+) selection of thymocytes.

121

does the thymus have reticular fibers? why or why not?

Nope! there is not fluid flow through it. Streams cells instead provide support

122

what are Hassal’s corpuscles?

in the medullary region you can see circular bodies made of concentric layers of reticular cells. they produce thymus and stream lymphoprotein that suppresses autoimmune events.

123

how does blood flow through the thymus?

small arteries enter it through outer capsule and penetrate into it, and bifurcate in the septa. the endothelial cells have tight junctions, and form the blood thymus barrier. cells are therefore not exposed to molecules in the blood (they are protected in a bubble).

124

“what does the spleen do????” (ring ding ding ding dingdeding)

I don’t know, maybe it filters blood? it’s an organ the serves multiple purposes, including adaptive immunity. has open blood circulation through porous splenic sinuses.

125

how does the spleen get blood?

via the splenic artery and vein. artery branches into arterioles that run into the pulp of the spleen, lined with discontinuous endothelial cells so platelets, RBC, and leukocytes leave vessels and enter sinuses.

126

how is the bulk of the lymphoid tissue in the spleen arranged?

in prearteriolar lymphoid sheath (PALS. Hey! lymph is a “pal” to the blood vessels in the spleen!) germinal centers are arranged in these.

127

what is red pulp?

area where blood flows through loosely rearranged channels/sinuses

128

what is white pulp?

more organized lymphoid tissue in the spleen.

129

does the spleen have reticular fibers?

you betcha. primarily in the red pulp

130

what do macrophages in the spleen do?

remove senescent RBC and platelets, recycle iron, convert it to bilirubin and Hg. also remove debris and bacteria. they predominate in red pulp

131

since your gut is associated with lots of targets of bacterial infection, how does it deal?

uses mucosal protection. unencapsulated collections of lymphoid cells and support cells and macrophages. Eg; tonsils, pharyngeal adenoids, appendix, bronchial nodules, large numbers aggregates in intestine. basically Mucosal-Associated Lymphoid Tissue (MALT)

132

what type of immune responses can occur in MALT?

a full repertoire! small intestine/respiratory tract: M cells deliver antigen to underlying lymph. lymphocytes in MALT enter lymph and general circulation. Antibodies of IgA class are secreted across mucosal epithelia

133

list the 4 kinds of immunity:

natural, passive. natural, active. artificial, active. artificial, passive.

134

natural, active immunity

usual immunity from real life exposure to pathogen. most long lasting.

135

natural, passive immunity

products of someone else’s immune response. Fetus getting IgG from mom, and IgA in milk.

136

artificial, active immunity

results from intentional immunization with vaccines, toxoids, antigenic preparations. whole killed bacteria are more complex=more side effects. pure toxins are more innocuous. live vaccinations=better protection than killed

137

artificial, passive immunity

use of immune serum or purified antibodies to protect patient at risk from a particular disease. risk of serum sickness. we try to use human antiserum. unless formulated for IV use, IgG will aggregate in bottle, activate complement, and become anaphylatoxic. ALWAYS READ PACKAGE INSERT!

138

tetanus immunization

offers close to 100% protection. only 1 form of toxin, and the bacterium is the solo virulence factor. immunogen made of inactivated toxin (TOXOID) will almost always be effective. protection is 10-20 years.

139

smallpox…. (dun-dun dun!!!!)

no good treatment, has been eliminated by vaccination

140

rabies vaccine

immunization possible with vaccine grown on human diploid cells (HDCV). few side effects. you must immunize someone who has been exposed, and hope that you got it in time!!!

141

diptheria vaccine

toxoid. immunity lasts years.

142

pertussis vaccine

acellular pertussis (aP) vaccine, very safe. no heard immunity for unimmunized children. incidence is rising. New strain is important to remember-vaccine is based on 50’s strain

143

measles vaccine

almost gone when we were immunized to 90%. number is rising. 250,000 people die each year, mostly children.

144

major immunogens for Hemophilus, Strep, and Neisseria found?

in their capsular carbohydrates. carbs are T independent, mostly IgM. to make the vaccine for Hib more effective, it was paired with a protein carrier so Tfh cels could respond and focus help on B cells.

145

conjugate vaccines

effective since they are protein carriers with the vaccine so that the result is more strong. useful in elderly, children

146

rotashield causes what severe side effect?

diarrhea. kills 500,000 children worldwide annually. Intusussception was reported in children getting the live vaccine, so it was withdrawn. possible that it caused hypertrophy of Peyer’s patches and peristaltic traction pulled the bowel onto itself. was replaced with RotaTeq and RotaRix.

147

what is intussusception?

telescoping of a segment of bowel. risk is that will lose blood supply due to compression and become necrotic, leading to peritonitis.

148

influenza is rarely associated with what syndrome?

Guillain-Barre syndrome-may be coincidental

149

adjuvants

substances added to a vaccine to make them more immunogenic. work by causing an innate immune response, leading to adaptive response. Usually is alum (hydrated potassium aluminum sulfate) that mimics PAMPs. stimulates effective antibody response, but not so great T cell response. only other approved one is lipid A (added to HPV vaccine)

150

herd effect is what?

the decrease in infection rate in non-immune part of the herd. there is a chance a non-immune member will come in contact with an infectious member, and disease will transmit.

151

bacterial immunity

bacteria that live extracellularly are fought by antibody. block from attachment by IgA, and opsonized by plasma antibody. Some can be lysed by C9 (gonorrhoae). Intracellular bacteria are killed if macrophage activated by Th1 cells.

152

what is the important general principle about viral immunity?

humoral immunity may prevent a viral illness, but once ill T cell immunity is required for recovery.

153

virus immunity

viruses enter typically through mucous membrane, establish site of infection. there it multiplies, spreads via blood, finds target, produces disease. local immunity can prevent invasion-secretory IgA. then can be stopped in plasma phase by IgG. if no antibody, virus infects cells, so T cells respond (many have TLR for viral RNA and make cytokines and chemokine in response)

154

viruses in infected body cells make early products like_______, and peptides from them are shown on cell surface Class 1 before the complete viral particle is assembled.

glycoprotein. these are recognized by CTL (specific for foreign antigen+MHC Class 1). Infected cell is killed in viral eclipse phase.

155

Titer

reciprocal of maximal dilution of a patient serum that is positive in a defined test. Rubella titers are good example.

156

Rubella titer

if mother has rubella in first 8 weeks, fetal infection rate is 50%. 3/4 of those infected have congenital malformations. Babies infected in utero make IgM anti-rubella. Titers of umbilical cord blood give IgM measure indicative of congenital infection. Most babies have IgG anti-rubella since mom immunized.

157

IgM detection in Rubella indicates what?

recent infection. IgM rises shortly after the rubella rash, peaks 10 days later, as gone in 50 days.

158

DNA vaccines

possible new field of therapy. DNA would be isolated from organism, cloned into vector, injected into muscle/skin. would get into cells then would have your own antigen. very stable, would be live, active immunity. Possibility of CTL just killing the cells though which would be bad.

159

how long does it take under non-stressed and stressed conditions to move from pluripotent stem cells to mature neutrophils?

10 days to 2 weeks, and can be shortened to 5 days.

160

what forms the mitotic pool?

earliest recognized myeloid cells. they divide, and mature (get azurophilic and specific granules)

161

what does the storage compartment contain?

metamyelocytes, bands, segs. these can’t divide but they can mature granules and their contents and cytosolic proteins to help give mature cells functional activity.

162

what does the storage pool contain?

bands and segs. gives a reserve of 1st responding phagocytic cells that can be mobilized into peripheral blood to fight infections.

163

neutropenia

decrease in absolute neutrophil count (bands and segs) below accepted norms. vary with age:

164

what should you include in a neutropenia workup?

a history to find duration or periodicity of low counts and associated symptoms and signs. a physical exam (pay close attention to infected sites: TEETH AND GUMS, lymph nodes, liver, spleen, other). lab investigations including CBC and WBC differential and review of leukocyte morphology.

165

what do you test for chronic neutropenia?

counts 2x’s weekly for 6 weeks, blood chemistries, neutrophils unibodies and bone marrow aspirate and biopsy. other tests as necessry

166

how can you (generally) classify neutropenia after initial evaluation?

those with decreased bone marrow production (primary or secondary), normal or near normal reserve and high turnover (usually secondary).

167

what can cause neutropenia? (disorders, other)

kostmann syndrome, Shwachman-Diamond syndrome, cyclic and idiopathic neutropenia, drugs, antibody associated neutropenia, hypersplenism.

168

chemotherapy drugs used for ______ conditions are a major cause of neutropenia related to direct effects on ______ cells and myeloid precursors.

malignant, stem. exposure to these drugs reduces production and may leave patient at high risk for severe infection

169

what's a (the most) common cause of acute neutropenia?

viral INFECTION. (EBV, varicella, measles, CMV, hepatitis, HIV). may suppress marrow production and cause increase in peripheral turnover. can resolve in days to months.

170

secondary vs. primary neutropenia

AINs are classified as primary (i.e. not associated with other detectable pathology) or secondary, in cases in which there is another pathology, usually rheumatological (particularly Felty’s syndrome and systemic lupus erythematosus [SLE]) or haematological (large granular lymphocyte [LGL] syndrome)

171

secondary causes of neutropenia drugs/toxins: mechanism, example drugs, clinical charachteristics

mechanism:immune. example drugs: penicillin, antibiotics. Characteristics: onset=days to weeks, acute symptoms, recurrence even with small dose, antibody test positive

172

_____ deficiencies such as folate, B12, copper, or protein/calorie malnutrition can cause ineffective myelopoeisis and neutropenia.

nutritional.

173

what are some congenital/inherited disorders characterized by decreased production and decrease in myeloid production?

Kostmann syndrome, Shwachman-Diamond syndrome, cyclic neutropenia. PRIMARY neutropenias.

174

Kostmann syndrome

severe peripheral neutropenia, apoptosis in early precursors. decrease in myeloid production beyond promyelocytes. high risk infection and death before 2 yo. some patients survive to develop ML or MDS. related to elastase gene defects. nothing in storage pool. Treat infections, start on G-CSF, consider BMT if no response.

175

shwachman-diamond syndrome

neutropenia, pancreatic insufficiency with fat malabsorption, bony abnormalities, growth delay. half develop aplastic anemia or MDS/lukemia. Autosomal recessive inheritance. abnormalities= apoptosis in precursors, defect in nurse cells in marrow stroma. 25% will develop aplastic anemia, other 25% develop acute lukemia, aplasia. give GCSF, antibiotics, BMT for severe.

176

cyclic neutropenia

severe peripheral neutropenia for 5-7 days with periodicity in 15-25 day cycles. recurrent fevers, mouth ulcers. linked to apoptosis in marrow precursors and mutations in elastase. manage with antibiotics, some need G-CSF daily or on alternate days

177

(chronic) idiopathic neutropenia

group of disorders with decreased production and maturation arrest at myelocyte level

178

chronic benign neutropenia of childhood

results from antibody production that cross react with neutrophils. children have low ANC chronically but may increase counts associated with infection. no increased risk of severe infection, resolves after 20 months

179

immune neutropenias

antibodies to neutrophils. marrow production is normal to increased, storage pool decreased. neutrophil turnover is high, vascular compartment decreased

180

autoimmune neutropenia

caused by antibodies to specific determinants on neutrophil. seen in systemic lupus erythematosus, evans syndrome, felty’s syndrome. antibodies to red cells, platelets or coat proteins may be seen. marrow shows normal cellularity, late maturation arrest. treat autoimmune disorder/hematologic antibodies. sometimes treat with G-CSF fi pool depleted

181

alloimmune neutropenia

passive transfer of antibodies from mom to baby. common pathophysiology with Rh hemolytic disease and illumine thrombocytopenia of newborn. passage of neonatal cells with antigens mom doesn’t have causes mom to make antibodies against babies antigens. accumulation of IgG class antibodies by fetus makes a pool of antibodies that bind neutrophils, resulting in neutropenia. marrow has myeloid hyperplasia with maturation arrest at mature precursors. mostly asymptomatic, can be skin infections. treat with antibiotics, G-CSF in severe infection. goes away shortly after birth.

182

______ and _____ cause neutropenia related to excessive sequestration of neutrophils in speed, and may be associated with sequestration of red cells and platelets.

spenomegaly, hypersplenism

183

patients with severe neutropenia and production defects are predisposed to what infections?

bacterial and fungal.

184

how do you treat neutropenia?

you must diagnose the type first. take cultures. identify the infected site and involved organisms. when you ID the organisms, change antibiotics. G-CSF given at 3-5 ug/kg will help normalize production, increase neutrophils, and prevent infection. some may respond to IVIG (intra venous gamma globulin)

185

neutrophilia

ANC >7500 cell/ul outside the normal range (7-13000/ul). may be caused by increased production, increased release from storage pool, decreased egress from circulation, reduced margination

186

leukocytosis

increase in total number of WBC beyond normal values. Infection, inflammation, non-specific physiologic stress, malignancy. Left shift-changes in white cell differential with increase in segs and bands and immature myeloid precursors only found in marrow.

187

basophilia

seen primarily in drug or food hypersensitivity or urticaria. may be seen in infection/inflammation as well as myeloproliferative diseases

188

eosinophilia

absolute count >350/ul is abnormal. could be due to allergies, parasitic infections, drug reactions (allergic). rarely caused by pemphigus, tumors/malignancies, infections (chronic).

189

monocytosis

>1000/ul newborns and >500/ul in children/adults. found in hematologic malignancies, collagen vascular diseases, granulomatous diseases, infections, carcinoma.

190

infection or tissue damage results in activation of what receptors and release of what inflammatory mediators?

TLRs; lipids (PAF, LTB4), cytokines and interleukins, chemokines, complement, kinins, coagulation factors. movement of neutrophils and monocytes into the area results in release of innate immune response

191

how do neutrophils move?

with the laminar flow of the blood. pulled to areas of infection by interacting with endothelial cells in rolling motion. adhesion then diapedesis, move towards offending organism (chemotaxis) following chemoattractants to engage the invader

192

when a microbe is opsonized with C3b or antibody, it is enveloped by what? then what happens?

pseudopods! with fusion of pseudopods, a phagosome forms to encase the ingested particle. Granules fuse with with the phagolysosome and oxidase enzyme system is assembled. O2-, H2O2, HClO, OH radical; all ROS; destroy the microbe

193

what are the 4 phases of the function of neutrophils and other phagocytic cells?

adherence, chemotaxis, ingestion, degranulation/microbial activity.

194

how are the 4 phases induced?

through engagement of specific receptors that activate the function of sub cellular organelles through physiologic and biochemical processes

195

adherence dysfunction

abnormalities=leukocyte adhesion deficiencies. loss of firm adherence/rolling leads to inability to accumulate neutrophils at infection site. recurrent infections, poor healing result

196

chemotaxis and ingestion disorders

defects in motility (caused by small group of cytoskeleton disorders and directed migration). some bad enough to cause ingestion abnormalities. FC receptor issues cause primary ingestion defects

197

granule defects

defects may be associated with deficient neutrophil function (specific and azurophilic granules). altered cell morphology

198

defects in bactericidal activity

microbes are ingested but can’t be killed. Chronic granulomatous disease (CGD) is abnormalities inoxidase components. if you are deficient in gp91phox, p22phox, p47phox, p67phox, you have no respiratory burst or ROS. recurrent infections, MPO deficiency, HClO production decrease, limited killing of Candida

199

leukocyte adhesion deficiency 1: clinical presentation

recurrent soft tissue infections, gingivitis, mucositis, peridontitis, cellist, abscesses, delayed separation of umbilical cord/omphalitis, poor wound healing

200

leukocyte adhesion deficiency 1: functional Defect

neutrophilia. decreased adhesion to endothelial surface leading to defect in movement neutrophils to infected site

201

leukocyte adhesion deficiency 1: molecular defect

complete or partial deficiency of CD18 resulting in lack of CD11b/CD18. autosomal recessive

202

chronic granulomatus disease: clinical presentation

recurrent purulent infections with catalase positive bacteria and fungi involving skin and mucous membranes. deep infections of lung, liver, spleen, lymph nodes, bones

203

chronic granulomatus disease: functional defect

neutrophilia. normal adherence, chemotaxis, ingestion, degranulation. defect in oxidase enzyme system. no toxic oxygen metabolites produced

204

chronic granulomatus disease: molecular defect

defects in 1 of 4 oxidase components. absent cytochrome b558 associated with gp91phox, p22phox, or absent p47phox and p67phox

205

chediak higashi syndrome: clinical presentation

Oculocutaneous albanism, nystagmus photophobia. Recurrent infections of skin, mucous membranes and respiratory tract by bacteria. Lymphoproliferative phase associated with EBV infection, fever, hepatosplenomegaly and hemophagocytic disorder. Neurodegenerative syndrome.

206

chediak higashi syndrome: functional defect

Neutropenia. Giant granules in all leukocytes. Abnormal degranulation. Major defect in movement, also decreased degranulation and microbicidal activity.

207

chediak higashi syndrome: molecular defect

Alterations in membrane fusion with formation of giant, leaky granules. Other metabolic abnormalities in microtubule assembly. CHS gene identified, autosomal recessive.

208

myeloperoxidase deficiency: clinical presentation

Generally healthy. Increase fungal infections when associated with diabetes.

209

myeloperoxidase deficiency: functional defect

Partial or complete deficiency of myeloperoxidase. Mild defect in killing bacteria, significant defect in killing candida.

210

myeloperoxidase deficiency: molecular defect

Post-translational modification defect in processing protein. Autosomal recessive.

211

what is the complement system?

a group of plasma proteins that are activated by lectins, bacterial proteins or surface bound IgG. they are bound through 2 paths: classical or alternative

212

sequential proteolytic interactions of complement proteins in a cascade leads to what?

activated fragments which attach to membranes opsonizing target cells for phagocytosis, or serve as chemotactic stimulants.

213

activation of terminal components C5-9 leads to what structure?

amphiphilic cylinder that inserts into the plasma membrane of the bacterium.

214

deficiency of what factors is associated with risk of systemic lupus erythematosus or other autoimmune/inflammatory vascular diseases?

factors 1q, 4, 2. primary deficiency in C3 is inefficient opsonization of bacteria (recurrent infections), defects in C5-9 are risk of Neisseria bacteria.

215

infections of phagocyte function result in what?

high rates bacterial and fungal infections. Atypical/unusual microorganism infection. catalase positive organisms (patients with CGD). severe infections. periodontal childhood disease. recurrent infections in areas that interact with the microbial world

216

complement disorders result in what?

bacterial infections that may be seen with antibody deficiency. terminal complement deficiencies=problems with Neisseria.

217

how do you screen for phagocyte disorder?

CBC, differential. morphology review. bactericidal activity, chemotaxis assay. expression of CD11b/CD18. NBT dye reduction or DHR oxidation

218

how do you screen for complement disorder?

C3, CH50. Quantitative Ig’s. Lymphocyte numbers

219

what are confirmatory/detailed tests for phagocytic disorders?

adherence to inert surface/endothelial cells. Measurement of CD11b/18, L-selection, Sialyl LeX. response to chemoattractants: shape change, direction change, movement rate change. Actin assembly. Ingestion labeled particles, degranulation specific components. bactericidal/candidicidal activity. ROS and oxidant production. studies for molecular deficits oxidase or other cell constituents

220

what are confirmatory/detailed tests for complement disorders?

measure specific complement components; alternative and classical paths. detailed evaluation of adaptive immune response

221

how do you manage an innate immune disorder?

anticipate infection and aggressively try to find causative agents. Surgical procedures if necessary. broad spectrum antibiotics. GCSF usage at 3ug/kg/day for neutropneia. prophylactic antibiotics or cytokine therapy. transplantation w/ hematopoietic stem cells. gene therapy.