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Flashcards in Post-midterm Deck (164):
1

Sulfamethoxazole

Blocks Dihydropteroate synthetase (PABA --> Dihydrofolic acid)

2

Cyclines (Tetra)

Inhibitors of protein synthesis.
Bind 30s and prevent attachment of aminoacyl tRNA unable to bind
eg. Doxycycline, tetracycline, minocycline

3

Aminoglycosides

Interfere with formation of 30S initiation complex, IRREV.
eg. "Mean" (amino) GNATS caNNOT kill anaerobes.
Gentamicin, Neomycin, Amikacin, Tobramycin, Streptomycin
Bactericidal

4

Macrolides

Bind to 23 S component of 50S rRNA, blocking exit of peptide chain (translocation) (macroSLIDES). Bacteriostatic
eg. Azithromycin, clarithromycin, erythromycin

5

HLA haplotype associated with Graves, Addisions, and Sjogren's syndrome

DR3. Increases RR of having the disease

6

HLA haplotype associated with rheumatoid arthritis

DR4, increases RR By 6

7

HLA haplotype associated with Type I diabetes

DQ2+DQ8, DQ6, DQ8 - 1 and 8 together has RR of 20.

8

HLA haplotype associated with ankylosing spondylitis

B27 (Class I HLA associated). RR of 87.4

9

HLA haplotype associated with Myasthenia Gravis

B8 (Class I HLA asosciated). RR of 3.

10

MHC Restriction

T cells can only recognize antigens on MHC class I and II if originate from same person. Peptides on foreign MHC molecules are not recognized.

11

CD 1

Family has 5 known members, located on chromosome 1. Closely related (looks like) to MHC I. CD1a, CD1b, CD1c - expressed on APCs and present lipid antigens to CD-1 specific T cells.
CD1d is expressed on wide spectrum of cells, and presents to NK-T cells

12

What cytokine can induce expression of Class II MHC molecules?

IFN y - can induce expression of MCH II on other cell types.

13

Cross presentation

One type of cell, DC, can present antigens of other, infected or dying, cells or cell fragments, and prime (or activate) naïve T lymphocytes specific for these antigens. Present on MHC I, and once CD8 T cells to CTLs, they kill infected host cells tumour cells without need for DCs.

14

Virus Evasion of MHC class I presentation - EBV Mechanism

EBV: proteasomal process inhibitors, and inhibits TAP-mediated peptide transport (both in MHC I process)

15

Virus Evasion of MHC Class I Presentation (HCMV, Human Cytomegalovirus mechanism)

Binds TAP in ER and inhibits peptide translocation, Competes for B2m and peptide (B2m is a subunit on MHC I, that is just there to maintain the 3d structure), Delays MHC class I egress from the ER, Binds MHC class I in the ER and prevents its egress, Ejects MHC class I molecules into the cytoplasm.

16

Viral Evasion of MHC CLass I Presentation - Herpesvirus

Ibhibits TAP mediated peptide transport.

17

LFA-1

Leukocyte function associated antigen 1 (integrin on T cell) - ligand on APCs is ICAM 1.
Is the major T cell integrin involved in APC binding.

18

CD28

Receptor on T cells, recognizes co-stimulatory protiens B7-1 (CD80) and B7-2 (CD86). Binding generates signals that work together with signals from TCR recognition of antigen presented by MHC on same APCs.

19

ICOS (inducible costimulator)

Related to CD28, also expressed on T cells – important in development and function of follicular helper T cells in GC responses. Costimulator molecule in T cell activation

20

CD 40 L (CD 154)

CD40L on antigen stimulated T cells binds CD40 on APCs and activates APCs to express more B7 co-stimulators and to secrete cytokines --> IL-12 --> enhance T cell differentiation
Ie CD40L-CD40 interaction, promotes T cell activation by making APCs better at simulating cells.

21

CTLA-4

LIke CD28, recognizes B7-1 and B7-2 on APCs. Induced in activated T cells, functions to terminate responses of these cells. Also important in suppressive function of Treg.

22

PD-1

Induced on activated T cells, recognizes different but structurally related ligands on many cell types. Function to terminate processes of activated T cells.

23

Cyclosporine

Inhibits calcineurin's phosphatase activity, thus suppressing the NFAT-dependent production of cytokines by T cells. Widely used as an immunosuppressive drug to prevent graft rejection.

24

Rapamycin

Inhibits mTOR protein. mTOR stimulates protein translation, cell survival and growth of T cells. Related/similar to PI-3 kinase path. Used to treat graft rejection

25

L selectin

(CD62L)
Expressed on Naive T cells as a T cell homing receptor. Binds L selectin ligand on endothelial cell for initial weak adhesion of naive T cells to HEV in lymph node

26

LFA-1 (B2 integrin)

Is an integrin dîmer - CD18 + CD11a
T cell homing receptor expressed on naive T cells. Binds ICAM-1 ligand on endothelial cells. Induces stable arrest on HEV.

CD18 deficiency --> linked to LAD type I syndrome.

27

CCR7

T cell homing receptor on naive T cells. Binds CCL19 or CCL21 on endothelial cells. Functions to activate integrins and chemotaxis.

28

E and P selectin

Expressed on endothelial Cell, bind E and P selectin ligand on activated (elector and memory) T cells. Initial weak adhesion of effector and memory T cells to cytokine-activated endothelium at peripheral site of infection

29

LFA-1 (B2 integrin) or VLA-4 (B1 integrin)

Expressed on activated (effector and memory) T cells. Bind ICAM-1 or VCAM-1 on endothelial cells. Stable arrest on cytokine-activated endothelium at peripheral site of infection

30

Cytokines that activate Th0 to Th1, and result of Th1 activation

IL-12, IFNy stimulate differentiation to Th1.
Th1 cells then produce IFNy, IL-2, TNFalpha
In response to intracellular bacteria.
Activates macrophages and CTLs.

31

Cytokines activating Th2 cells, and Th2 response

IL-4 (and IL2, first aid) activates differentiation to TH2. Th2 then generates IL-4, IL5, and IL 13 (Also 6 and 10, from first aid)
Recruit eosinophils for parasite defence, IgE production.
Inhibited by IFNy.

32

Cytokines that stimulate production of Th17 cells

IL-6, Il 21, and TGFB, stimulate formation of Th 17 from Th0.
Th17 then produces IL-17, IL-22, to act on PMN, monocytes, and cytokines.
(Also produces IL-4 which activates Th2?)

33

Cytokines stimulating formation of Treg cells from T0

IL-2, TGFB stimulate production of Treg cells, which then produce TGFB, and IL-10.

34

Cytokines stimulating production of Tfh cells from T-

IL-21, and IL 6.
T follicular helper cell s- produce IL-21, Il-4, CD40L, ICOS - help B cells,.

35

LFA-2 (CD2) (is an IgCAM)

Expressed on Th cell, is a cell adhesion molecule, binds LFA--3 (CD58) on APCs.

36

VLA-4

Expressed on Th cell. Binds VCAM-1 on endothelial cells.

37

Five groups of cell adhesion molecules

1. Immunoglobulin superfamily CAMs (IgCAMs0 - bind either integrins, or other IgCAMs(ie ICAM-1)
2. Integrins - heterophilic dimers that bind either IgCAMs or the ECM (ie CD18/LFA-1)
3. Lymphocyte homing receptors - targets = addressins
4. CAlcium dependent Cadherins (homophilic CAMs)
- E cadherins (epithelial), P cadherins (placental) N cadherins (neural)
5. Calcium dependent selectins - heterophilic CAMs that bind fucosylated carbs such as mutins. Ie E-selectin (endothelial) P selectin (platelet), L selectin (leukocyte)

38

Cytokines produced by activated CTLs (limited spectrum, but still produce)

IFN y - macrophage activating, autoimmunity and inflammation
TNFa - pro-inflammatory, induces apoptosis death, inhibits tumorigenesis, and viral replication
TNFB (ie lymphotoxin) - cytotoxic and other effects similar to TNF a, enhances phagocytosis

39

CTLA-4 (CD152)

Initially absent on naive T cells. After initial activation and proliferation, clones turn on transcription of CTLA-4.
Replaces CD28 and binds to B7 on APC (higher affinity for B7)
Downregulates IL-2 synthesis and thus downregulates activation of T cell. (involved in peripheral tolerance)

--> mutations linked to autoimmunity. Ie insulin-dependent diabetes mellitus, Graves disease, Hashimoto thryoiditis, others.

40

Type 1 Thymus-Independent Antigens

Do NOT require Th cells. They are polyclonal activators/mitoyens. They have the ability to activate substantial portions of B cells, without reference to the antigen specificity of the surface. Ie LPS.

41

Type 2 thymus independent antigens

Bind specifically to Ig surface receptors. Represented by appropriately spaced highly repeating epitope ie Pneumococcus polysaccharide capsule. Cross linke Ig surface receptors, and activate B cell but only trigger production of IgM low specificity antibodies..
Leads to memory generation

42

Thymus dependent antigens

Degradable proteins which may possess any non-repetitive epitope
B cells require collaboration from Th cells for these antigens.

43

CD40 L or CD 40 deficiencies

CD 40 L - on T cell, X linked gene --> hyper IgM syndrome
CD 40 - on B cells (and APCs.. etc?) iautosomal - Hyper IgM syndrome as well.

44

Hapten

Small chemical recognised by B cells, but stimulates strong antibody responses only if attached to a carrier protein. Without support from Th cells, happen will be destroyed in B cell, but no immune response will be initiated, no hypersensitivity.
If attached to carrier protein molecule, generates a strong immune reaction and immuno memory. B cells present the carrier proteins (NOT THE HAPTEN) on MHC II to Th cells. Th cells activate the B cells (CD40/L, CD28/B7, Type 2 cytokines ), plasma cells and Abs produced against initial specificity which is against the hapten.
Class switch
cytokines are released, Ig's (E A G) are made, strong reaction.
Basis for some conjugate vaccines.

45

AIRE (autoimmune regultor) transcription factor

Expressed in the thymus. Responsible for turning on peripheral and tissue specific antigen expression, not functionally needed in the thymus, so that T cells can see this and those that self-recognize these antigens are ngatively selected.
Defects in AIRE --> autoimmune polyendocrine system, diabetes?

46

Autoimmune polyendocrine syndrome

Mutation in AIRE gene - several tissue antigens not expressed in thymus, so immature T cells specific for these antigens are not eliminated and do not develop into regulatory cells, remaining capable of reacting harmfully against the self antigens.

47

Causes of clonal Anergy in T cells

Failure of APC to deliver second costimulatory signal during antigen presentation (ie B7-D28) - because self antigens don't generally have costimulators.
Or engagement of inhibitory signal (i B7-CTLA4/CD152)

48

IPEX Syndrome

Mutations in FoxP3 (responsible for development of Tregs) --> systemic, multi-organ autoimmune disease : IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome)
Massive lymphoproliferation, diabetes, thyroiditis and enteropathy, exfoliative dermatitis.

Defective Treg also linked to Wiskott-aldrich (eczema part), autoimmune polyglandulr syndrome type 2, autoimmune lymphoproliferative syndrome.

49

FCyRIIB

Inhibitory receptor, antibody based B cell clonal suppression. Feedback inhibition of B cell activation.
Also inhibits activation of macrophages and DCs, and thus serve an anti-inflamm function as well.
IvIG binds FcyRIIB.
Cytoplasmic domain of FcyRIIB contains an ITIM that binds enzymes inhibiting an antigen receptor-mediated B cell activation.

50

Burnet's Hypothesis

During development of immune system in neonatal stage, the antigens are recognized as self. Immune system becomes tolerance to these antigens by clonal deletion

51

Superantigens

Bind to invariant parts of TCR, on many clones regardless of antigen specificity. Stimulate large numbers of T cells, excessive polyclonal T cell activation. Certain microbial toxins produced by some bacteria and viruses - causes large amounts of inflamm. cytokine release and a syndrome similar to septic shock . Are NOT processed and presented by APCs - instead crosslink CD4 on T cell with MHC class II by binding outside.

52

Lepromatous Leprosy

Destructive form of infection with mycobacterium leprae - when patients do not have adequate Th1 cellular response to the bacteria, and sometimes have strong Th2 response.

53

Tuberculoid Leprosy

Less serious form of infection with mycobacterium leprae - activation of m. leprae specific Th1 cells.

54

AID

Activation-Induced Cytidine deaminase. Works on light and heavy chain variable regions. Somatic hypermutation, and class switching.

55

Two types of TCR

A single T cell can only express on of the known types of TCRs ; alpha Beta chains, or gamma delta chains.

56

Alpha Beta TCR

Can only recognize antigen when presented by MHC on APCs. B chain: one variable, one constant region
Alpha: one variable, one constant region
Are the majority of blood born T cells (85%)

57

Gamma Delta TCR

Rarely in peripheral blood (15%). Mostly in periphery ie intestinal mucosa, skin epithelium, and within intraepithelial lymphocytes (IELs). Divided into sub-populations - identified by their invariant TCR receptors
Recognize NON CANONICAL antigens - ie lipids, stress molecules, non peptide metabolites, microbial patterns. are in INNATE immunity domain (but also adaptive)
Some can still see antigen presentation on MHC Ib.
Resemble NKTs

58

NKT CElls

Have NK markers, but alpha Beta TCR. See antigens through CD1 (MHC). Rapid responses to foreign antigens.

59

DETC (dendritic epidermal gammadelta T cells)

Subtype of gammadelta T cells. CApable of presenting antigens on MHC II to alpha Beta T cells - link between innate and adaptive imunity.

60

Variable alpha chain of alpha beta TCR

Coded by one Variable alpha gene and many Jalpha N segments (junctional)

61

B chain of alpha beta TCR

One variable domain coded by one set of Variablabe genes, and two sets of Dbeta and Jbeta genes (diversity and junctional)
Single constant domain: present in two versions

62

Which two TCR chains are on the same chromosome?

Alpha genes and delta TCR gene segments. Chromosome 14 - delta genes are inside alpha Genes
Gamma and B are on the same chromosome (7) - but are far away

63

Variable Beta genes of TCR

One set of variable beta genes, two sets of diversity and junctional beta genes.

64

Variable alpha genes of alpha beta TCR

One Variable gene, many Junctional genes.

65

Gamma chains of gamma delta TCR genes

One variable gamma, two sets of junctional gamma genes

66

Number of V D and H gene segments of heavy chain Ig

V: 100 variants
D: 50 variants
J: 6 variants

67

Class Switching

Occurs in the light zone of the Germinal Center. The antigenic specificity (V protein domain) is preserved, ONLY constant domain changes.

68

At what stage of B cell development does Somatic recombination occur?

VDJ recombination/somatic recombination occurs at the PRE-B cell stage in the bone marrow, with help from RAG1/RAG 2 etc.

69

Mechanisms of junctional diversity

Addition of random nucleotides by Tdt. Combinatorial mistakes ie adding two Ds, ORF inaccuracies, and opening of P palindrome sequence.

70

AID (Activation Induced Deaminase)

Involved in processes of somatic hypermutation and class switch of antibodies.

71

SCID defects

IL-7R, JAK 3, Common gamma chain (affects IL-2), RAG1/RAG2

72

CVID (common variable immunodeficiency) defects

ICOS, defects in CD19 or CD20, BAFF-R

73

Hyper IgM Type II and IV

Autosomal recessive defects in AID (no class switch or somatic hypermuation ie affinity maturation)

74

Hyper IgM Type I

X linked defect in CD40L on T cells (activate AID for class switch)

75

Hyper IgM Type 3

Autosomal defect in CD40 on B cells

76

Rituximab

Monoclonal Antibody to CD20, chimeric IgG1. Indicated in Non-hodgins lymphoma )we also saw in Duncan's syndrome...)

77

MHC Class III

Between class I and II genes on chromosome 6. Non-polymorphic genes linked to immune system ie complement proteins C4, Factor B, C2 and Cytokines LTB, TNF a, LTa

78

MHC Class Ib features

More restricted pattern of expression, either recognized by subsets of TCR or innate immune receptors. Elicit rapid response from immune cells due to ability to be recognized by more restricted sets of receptors, regarded part of INNATE immunity. Some are APCs, others are direct ligands.

79

Antigen Cross Presentation

Ability of APC to present exogenous antigens (ie tumor markers) on MHC CLass I in addition to MHC Class II.

80

CD8 binding site on MHC Class I

Alpha 3 invariant chain

81

CD4 binding site on MHC Class II

Beta 2 invariant chain.

82

Minor MHCs

Class Ib, Class II DM or DO - low polymorphism. Some bind antigens involved in NK cell recognition (Class Ib E G)

83

Goodpasture Syndrome

Type II Cytotoxic HS. Antibodies against glomerular basement membrane antigen (collagen alpha 3), present in lung and kidney. Coughing blood and burning during urination, lung and kidney failure. Treatment : immunosuppressant

84

Rheumatic Fever

Antigens from Streptococcus can induce cross-reactinc antibodies against myocardial antigns. Myocarditis, arthritis, chorea, erythema marginatum, inflammation. Type II cytotoxic HS.

85

Cold (hem) agglutinin disease

Type II cytotoxic HS. Mycoplasma pneum, EVC, CMV are triggers. Autoantibodies target RBC at low temps, destruction of RBC noted in arms and legs. Anemia. Cold agglutinins - cross reacting IgM antibodies against RBC. . Coombs test could be false negative if not properly performed ,

86

Glomerulonephritis

Type III HS - circulating immune complex deposits. Inflammation of glomeruli. Usually follows infection by group A streptococci, appears 10 days after infection. Post streptococcal acute glomerulonephritis. Inflammatory process damages basement membrane, causing linkage of serum proteins - proteinuria.

87

SLE Lupus

Type III Hypersensitivity. Auto antibodies against dsDNA and other parts of cell nucleus - histones, nuclear protein. Anti=cardiolipid et. Systemic, multi organ inflamm - Immune complexes trapped iN BM of glomeruli skin, joints, and kidney.
Flares - patients will have LOW C3 and C4 proteins, and LOW CH50 activity.
Associated with HLA DR2/DR3

88

Rheumatoid Arthritis

TYPE III HS (and type IV). Active phases: High level of rheumatoid factor, low level of complement. RF - IgM and IgG antibodies against Fc isotype region of normal antibodies.
ACPAs - anti-citrullinated protein antibodies sensitive, specific markers for predicting disease progression.
Inflamed joint infiltrated with T cells, plasma, macrophages, synovial fluid with high cytokines TNF and IL-1 (Type IV)
Deposition of immune complex in blood vessels and synovial fluid activates complement (Type III)

89

Diabetes Type I/Juvenile diabetes/Insuline dependent DM

Type IV: Destruction of pancreatic B cells in islets due to auto reactive T cell mediated cytotoxicity.

90

Multiple Sclerosis

Type IV HS, Cell mediated. CNS demyelination - mediatd by auto-reactive T cells and activated macrophages. Anti-myelin basic protein (important in myelination).
And anti measles and EBV Abs (potential viral infections)

91

Autoimmune Polyendocrinopathy syndrome (APS-1)

TYPE IV HS. AR. Chromosome 21. Multiple autoimmune diseases linked. Hypothyroid, hypogonad, infertility. Candidiasis, vitiligo, alopecia. Addisons, pernicious anemia.
Absence of AIRE TF - lack of self tolerance

92

Graves Disease;

Type V (or II), Associated HLA-DR3. Stimulating auto-antibodies against TSH receptor on thyroid cells - hyperthyroidism. . Bulging eyes, goiter. TSH reduced, Free T4 elevated.

93

Myasthenia Gravis

Type V HS (or t II). Auto-antibodies against AChR block binding of ACh at NMJ.

94

Bruton's Agammaglobulinemia (X linked)

Defect in BTK (bruton's tyrosine kinase). Cell mediated immunity is NORMAL. Pre b cells are present, but fail to mature --> realtively no detectable B cell in blood. Low levels of all Ig. First sx in childhood >6 mo, with clearnace of maternal Ab.s.
Associated pathogens: haemophilus influence, strep pneumonia.
Btk are reg genes needed for pre B cell diffn, diagnosis based on absence of CD19 or CD20 cells by Fluro cytometric assays (FACs). Treat with IvIG.

95

Transient Hypogammaglobulinemia

Delayed onset of IgG production - transient deficiency up to two yeras. All other Ig normal. Deficiency in Th functions, diminished class switch to IgG.

96

CVID (Common variable immune deficiency)

High variability of Ig production - either low or high levels.
Usually during adulthood, slow onset. B cell defects range: absence of B cell prolif in response to antigen, normal prolif of B cells but only IgM production. Increased pyogenic infections, risk of autoimmune disease. treat with IvIG. Can live until 80 yo with disease.

97

Selective Immunoglobulin deficiencies

IgA deficiency most common - unclear cause.
IgA def: recurrent sinus and lung infections, allergies.
Absence of selected antibodies deprive from defence.
IgM and IgG much more rare and more severe
Treat with antibiotics.
Passive immunity DNE because Ab required in mucosal membrane.

98

DiGeorge Syndrome (Congenital Thymic Aplasia)

Deletion on chrom 22 - embryological development of 3rd and 4th pharyngeal pouches --> failure of thymus and parathyroids to develop. Hypoparathyroidism leads to cardiovascular anomalies. Thymic aplasia - T cells completely absent or presence of a few abnormal T cells.
B cells, plasma cells, serum Ig detected but subnormal levels.
Commonly intracellular infections such as viruses and yeast ie c. albicans and pneumocystics.
NEVER immunize with live attenuated vaccines
treat: antibiotic for infections , thymic transplantaions (before 6 months to avoid GVHD) for T cells but doesn't restore other defects --> but provides sufficient thymic epithelial cells.

99

Duncan Syndrome (X-linked lymphoproliferative syndrome)

T cells deficiency. No presentation of symptoms until infected with EBV.
Two genes, two forms XLP1 and XLP2
XLP1: Mutation of SH2 domain on SAP signaling protein, impairing activation of T and NK cells --> incapable of killing EBCV infected B cells
T cells prolif. as a result, increased risk of lymphoma etc.
Sx: fulminant infectious mononucleosis, hypogammaglobulinemia, lymphoma, hemophagocytic lymphohistiocytosis (too many active immune cells).
Treat: allogenic stem cell transplantation. Pre-emptive treatment to block B cells with anti Cd20 (rituximab) until EBV is reduced

100

Chronic Mucocutaneous candidiasis

Heterogenous group of disorders - recurrent, persistent superficial skin infections usually candida albicans. Skin, mucous membranes, nails. Defect in functioning of Th1 and Th17 cells against C albicans. Normal cellular response toward other pathogens, normal C cell functions.

101

X linked SCID

Deficiency in Common gamma (CD132) chain which affects cytokine receptors: IL-2R, IL-4R, IL-7R, IL-9R, IL-15R, IL-21R
T - NK - B+
Failure to thrive, recurrent and persistent infections (bacterial, viral, fungal)

102

Bare Lymphocyte Syndrome (Type 1 or 2)

Defect in MHC Class I (Type I) or II (Type 2). Normal T cells but lack of MHC Presentation.

103

RAG 1 and RAG 2 deficiency

T - B - NK +. Absence of proper TCR and BCR arrangements.

104

Ataxia-Telangiectasia

Combined T and B cell defect. ATM gene codes for serine/threonine protein kinase involved in DNA repair. Defect in repair of dsDNA breaks during V(D)J recombination --> T cells and functions, B cell numbers with normal IgM, Reduced IgG E and A, low blood lymphocytes. AR (chrom 11) - various mutations, nonsense misense --> variability in severity.
Neurodegenerative - ataxia
Telangiectasia - dilatino of small blood vessels (esp facial area) ie spider veins.
High incidence of malignancy(leukemia), chrom instability, raised AFP.

105

Wiskott-Aldrich Syndrome

Triad: pyogenic infection, eczema, thrombocytopenia (petechia and bleeding, defective plateleys). Poor response to POLYSACCHAIDE antigen, increased risk of severe autoimmune disease and malignancy. Mutations mapped to WASp X linked gene expressed on HSc.s -- actin cytoskeleton rearrangement for signaling in lymphocytes and platelets. INability of T cells to become polarized - reduced IgM, IgA and IgE might be elevated. variable IgG. Anti-inflamm drugs, IvIg, bone marrow transplant.

106

Chronic Granulomatous Disease (CGD)

Impaired NADPH oxidase function - required for generatino of peroxidase and superoxides in phagosomal microbicidal killing by neutrophils and moncytes.
Many mutations- intracellular survival of pathogens --> formation of granuloma.
Susceptivle to opportunistic infection - most are staph aureas, some gram - bacilli, , aspergillus fumigatus, candida
Diagnose: NBT - defective phagocytes take up salt but cannot oxidise.
Treat: chemo, IFN-y to stimulate production of superoxide, bone marrow transpant

107

LAD-1

AR, mutation in B2 integrin (CD18), part of LFA-1 and other integrins. LFA-1 mediates adhesion of T cell, B cells, macrophages, neutrophils to endothelial cells.
Highly susceptible to pyogenic infections, variable severity. Delayed separation of the umbilical cord - earliest sign. Treat: bone marrow transplant, stem cell, gene therapy for CD18.

108

IFN y receptor deficiency

Receptor gene encoding ligand binding or signal transducing part of receptor. Increaed infections, esp mycobacterial due to macrophage failure.
should NOT be immunized with live attenuated vaccine (ie. BCG)
Chemotherapy, immunotherapy (admin IFN-y),

109

Chediak Higashi Syndrome

Mutation in LYST (lysosomal trafficking gene regulator) - accumulation of large cytoplasmic granules that cannot fuse with lysosomes, affects phagocytes, Tc and NK cells. Inability to destroy targets --> bacterial, viral, fungal infections. Reduced pigmentation: silver hair, partial albinism, photophobia. Treat: antibac and antifungal drugs, bone marrow transplant.

110

Job's Syndrome (AD Hyper IgE)

Eczema, elevated IgE and eosinophilia, recurrent skin and pulmonary infections - avg survival 27 yo. Sxs staph aureus, strep pneumonia, haemophilus influenzae. Skin absecesses with staph. Pharmacotherapy.

111

Hereditary Angioedema C1 inhibitor deficiency

AD deficiency of C1 esterase inhibitor. Dysregulation of three cascades. Complement (classic C1 and MBL (MASP-2), coagulation (factor XI and XII, fibrin bulidup), contact cascade (increased bradykinin). Recurrent angioedema of skin, mucosa of GI. Absence of urticaria or rash, distinguishing from allergic reaction
Treatment: purified C1 inhibitor, FFP, kallikrein inhibitor

112

Paroxysmal Nocturnal Hemoglobinuria

HScs have GPI anchor - mounts regulatory proteins on surface to protect from unwanted attack. Ie DAF (CD55), Membrane inhibitor of reactive lysis (MIRL,CD59). Main defect, mutation in X linked PIGA enzyme, taking part in formation of GPI.

113

Classical Pathway deficiencies (C1, C4, C2)

Recurrent bacterial infections - C2 deficiency
Autoimmune disease (SLE, atherosclerosis) - inability to clear immune complexes after antibody formation linked to C2 and C4 deficiency.

114

MBL pathway deficiency

Includes C2 and C4, linked to recurrent severe bacterial infection in childhood, but NOT immune complex disease.

115

Alternative pathway deficiency (properdin, factor B, factor D)

Severe pyogenic and Neisseria spp. infections, but NOT immune complex disease

116

C3 deficiency

Infection with pyogenic bacteria (S. Aureas) increased chance of sepsis, and neisseria sp. SOMETIMES immune complex disease.

117

MAC deficiences (C5-C9)

Mostly Neisseria sp. (gonorrhoeae and meningitidis infections) Due to thickness of MAC complex.

118

Leiner's disease

Early infancy systemic disorder - deficiency of C5 (also reported with C3 and 4), chronic diarrhea, seborrhoeic dermatitis, recurrent infections.

119

Down Syndrome Patients - Immunological phenotype

Possibly in relation to immunodeficiency (AIRE expression significantly reduced). Many developed thyroid dysfunction.
ENT and airway infections in early years, increasing frequency of autoimmune diseases and lymph proliferation thereafter.

120

APS-1 (autoimmune polyendocrine syndrome type I

AR. Autoimmune multiorgan attack. Mutations in AIRE gene, defective AIRE protein. Classical clinical triad: mucocutaneous candidiasis, hypoparathyroidism, adrenal failure (addison's disease). Defined by presence of at least two of the triad.

121

APS-2

Autoimmune adrenal insufficiency (must always be present) and autoimmune thyroid disease and/or type I diabetes mellitus

122

APS-3

Autoimmune thyroid disease and other autoimmune diseases (excluding adrenal insuff, hypoparathyroidism, chronic candidiasis)

123

APS-4

Two or more organ-specific autoimmune diseases (which do not fall into type 1, 2, or 3)

124

Type I Diabetes

Anti-insulin and anti-glutamic acid decarboxylase antibodies; T cells attack pancreatic Beta cells. Type IV HS.

125

Multiple Sclerosis

Anti myelin oligodendrocytes glycoprotein antibodies (anti mylein-basic protein antibodies). Type IV HS. Related to DR3.4, DQ2/6/8.

126

Pelizaeus-merzbacher Disease

Anti-proteolipid protein antibodies.

127

Guillan Barre

Inflammatory neuropathy, cross reactivity between neural antigens and antibodies induced by infections eg. c jejuni, dengu, zika, vaccines.
Ie. c jejuni - express lipooligosaccharides in bacterial wall similar to gangliosides. Creats antiganglioside Abs. TYPE II cytotoxic HS. 0 Ab activate complement, damage cell membranes and NS. Complement mediated lysis.
Treat: plasmaphoresis, followed by Ig infusion.

128

Autoimmune Lymphoproliferative syndrome (ALPS) (Canale Smith Syndrome)

Mutation in FAS, Fas Ligand. Defective apoptosis of lymphocytes through Fas/FasL. Expansion of lymphocytes including self specific populations, and subsequent autoimmunity.
Characteristic chronic multi lineage cytopenias (ie reduced RBC, low WBC, low platelet, granulocyte, etc). from autoimmunity, non malignant lymphadenopathy and splenomegaly. Anemia, bleeding, increased infection (neutropenia). Diagnostic elevated peripheral blood double negative T cells (Have TCR but no CD4 or 8).
Treat: corticosteroids, IvIG.
Mycophenolate mofetil: drug to treat autoimmune cytopenias. Inhibitor of IMP dehydrogenase - rate limiting enzyme in denovo synth of G nucleotides. T and B lymphs dependent on this path - acts as an immunosuppresant

129

Th1

Stimulated by IL-12 and IFNy. Produces IFNy, Il-2, and TNF alpha. Inhibited by IL-4, IL-10.

130

Hapten

Small molecule, destroyed by B cells when alone. But without support from Th, no immune reaction is initiated and no hypersensitivity.
However if it binds to a carrier protein molecule --> generates a strong immune reaction and immunological memory
Hapten itself is NOT presented (and does not need to be a protein). It is the carrier protein that is presented.
Th cells activate B cells through co stim molecules, B cells produce antibodies against initially specificity ie against the hapten.

131

Peripheral Tolerance Mechanismss

Antigen sequestration - sequestered, recognized as non-self if ever exposed to immune system ie lens protein
Clonal deletion/apoptosis - PD-1
Fas/FasL trigger some apoptitic caspases
Anergy - failure of APC to deliver secondary costim signal, or engagemtn of inhibitory signals

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Trans-endocytosis

Form of clonal suppresion by Tregs - CTLA-4 inhibitory receptor competitively binds CD80/86, pulls away from APC surface by transendocytosis.

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Mechanisms of Treg cells clonal suppression

Through CTLA-4 transednocytosis, CTLA-4 inhibitory signal, or release of immunosuppresive cytokines TGFB, IL-10

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FoxP3

Gene crucial in differntiation of natural T reg (nTreg) cells developing in Thymus. Most are CD4+ CD35+ FoxP3. Mutations lead to IPEX (Immune dysfunction, polyendocrinopathy, enteropathy, X linked disorder) massive lymphoproliferation, diabetes, thyroiditis, exfoliative dermatitis

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Defective T regs linked diseases

IPEX, Wiskott-Aldrich, autoimmune polyglandular syndrome type II, autoimmune lymphoproliferative syndrome

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IgG in peripheral tolerance - Feedback control

IgG molecules compete with B cell receptors. So if administration of IgG and antigen, no immune resposnse. Ie dont give mumps and measles to infants before one year old bc maternally derived IgG still high. for 6 months

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Examples of superantigens

Staph enterotoxin, staph toxic shock toxin, staph exfoliating, streptococcus pyogenes.

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Examples of mitogens and their targets

Phytohaemagglutinin (PHA) : Acts on T cells, not B
Concanavalin A: Acts on T cells, not B
LPS: Acts on B cells, not T
Pokeweed mitogen: Acts on B cells, not T.

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Conjugation

F factor plasmid encodes for sex pills. Brings donor F+ close to F- cell. F- becomes F + , and other genes ie antibiotic resistance can be on the F plasmid that is transferred. ONLY IN GRAM NEGATIVE BACTERIA.

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Transduction

Bacteriophages (bacterial viruses)
Generalised transduction - lytic bacteriphages, transfer random parts of genome
Specialised transduction - lysogenic, integrates into chromosome and specific parts of genome from immediate vicinity of the prophage are transferred.

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Farmer's Lung

Type III HS: Alveolar inflammation. Inhalation of antigen ie mould from actinomyces, or various aspergillus species, mouldy hay grain. Causes hypersensitive pneumonia.

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Arthus reaction

Type III HS: Cutaneous vasculitis.
Localized cutaneous and subcutaneous inflamm response triggered by injection and deposition of antigen. Localized inflamm starts with complmenet activation, ie on blood vessel, vasodilation and rupture of bvs, edema, induration, and hemorrhagic necrosis of local tissue.

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Direct Coombs Test

Use for Type II Hypersensitivity, ie Rhesus disease, Cold (hem) agglutinin disease
Direct: Have fetal RBC's with maternal IgG bound. Then add rabbit anti-human Ab (Coombs reagent), binds and agglutinates.

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Indirect Coombs Test

Type II HS, ie Rhesus or cold hemagglutinin disease
Indirect: Only antibodies present in patient (maternal) serum, THEN add RBCs (RH+) (ie seeing if the antibody in the serum will bind these RBCs, if you were testing before the second child). Then add anti human IgG antibodies (Coombs reagent) and observe agglutination

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Serum Sickness

Type III HS
Originally observed as reaction against treatment with horse serum as passive immunization
Type III systemic inflamm response to the presence of immune complexes - few days post exposure - fever, urticaria, arthralgia, lymphadenopathy, splenomegaly

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Hypersensitivity Reactions to certain Drugs

Antibody-mediated destruction of red blood cells (hemolytic anemia) or platelets (thrombocytopenia) is an uncommon side-effect associated with the intake of certain drugs such as the antibiotic penicillin, the anti-cardiac arrhythmia drug quinidine, or the antihypertensive agent methyldopa. These are examples of type II hypersensitivity reactions in which the drug binds to the cell surface and serves as a target for anti-drug IgG antibodies that cause destruction of the cell (see Fig. 12.2). The anti-drug antibodies are made in only a minority of individuals and it is not clear why these individuals make them. The cell-bound antibody triggers clearance of the cell from the circulation, predominantly by tissue macrophages in the spleen, which bear Fcγ receptors

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Type II HS

Antibodies involved are IgG and/or IgM
Specific antibodies attack antigens on cell surfaces, tissues, or organs. Antibodies initiate: damage by cell lysis via activation of complement, attack by neutrophils via Fc receptor, release of cytokines, radicals, inflamm, opsonization and phagocytosis of cells ie RBC, Killing of Ab coated cells by ADCC.

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Blood transfusion Reaction

Type II Hypersensitivity. Individuals with Type O have natural IgM Ab against A and B type antigens. If O receives blood from A or B, IgM will bind and lyse transfused RBC.

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Pentamidine

Anti-Protozoal. Blocks DHF reductase thus inhibiting protein synthesis.

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Metronidazole

Anti-protozoal. Chemically an azole, but not a fungal Azole. Blocks DNA Replication, requires an anaerobic pathway. Ex. Giardiasis, Trypomaniasis, T vaginalis

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Artemisinin Combination Therapy (ART)

Artemisinin delivers free radicals into parasite vacuoles, damaging membranes, inhibiting glycolysis. Usually administered combined with aminoquinolone for malaria to delay development of resistance.

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Praziquantel

Anti-helminthic drug. Affects Ca2+ channel. Increased calcium entry across tegument --> paralysis

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Ivermectin

Anti-helminthic Drug. Targets Cl- channels, inhibits neural and neuromuscular transmission

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Nitazoxanide

Antihelminthic. Targets Pyruvate ferrodoxin oxidoreductase. Inhibits anaerobic metabolism, also works aganst protozoa.

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Thiabendazole

Anti-helminthic. Blocks B Tubulin - immobilization.f

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Plasmacytoid Dendritic Cells

Mostly in the blood and tissue - major source of Type I IFNs for antiviral defence. . Ie IFN alpha and IFN B. Which inhibit viral replication and propagation ,increase MHC I expression and activate NK cells

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Conventional Dendritic Cells

CD11c and b surface markers. Located in the tissues. Express TLRs 4,58. Produce TNF, IL-6 and IL-12. Induction of T cell responses against most antigens.

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IL-17

Secretd by Th17 in response to bacterial or fungal infection. Targets fibroblasts, endothelial cells, macrophages.
Attracts PMNs (neutrophils and monocytes), induces IL-6, IL-1, TGF-B, TNFa, IL-8, CSFs. Role in autoimmune disease and allergy.

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IL-22

Secreted by Th17 cells in response to bacterial and fungal infections. Targets epithelial cells, to produce defensins and increased barrier function.
Also acts on hepatocyte survival.

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IL-12

Produced by macrophages and dendritic cells. Stimulates proliferation of NK and Th1 cells ONLY.
Acts synergistically with Il-2 to induce differentiation of pCTLs to CTLs.

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TGFB

Secreted by Tregulatory cells and macrophages. Is anti-inflammatory, differentiates Tregs further, but in presence of IL-6 is pro-inflammatory toward production of Th17.
Inhibits macrophage activation, stimulates angiogenesis and collagen synthesis.

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IL-6

Secreted by macrophages, Th2, Th17. Terminal differentiation of B cells to plasma cells, stimulates antibody secretion Production of Th17 with TGFB. induces synthesis of APRs - pro-inflammatory. But acts as an anti-inflammatory myokine (in muscle cells)

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Follicular Th Cells

responsible for generating highly proliferative, long lived B cells that establish the germinal centers. Are activated T h cells following migration into the lymph follicles. Have High CXCR5 instead of CCR7 expressoin. Their development linked to CD28 costimulatory molecules. Originate from Th1 2 or 17, and produce IFN y, IL-4, IL -17, and IL-21. Extensive isotype class switch and somatic mutation.

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Splenectomy

Causes disseminated infection by encapsulated bacteria. Antibodies produced to blood born pathogens by B cells in spleen. No spleen, no clearance of encapsulated bacteria because antibody mediated phagocytosis is the major defence mechanism against encapsulated bacteria.