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Flashcards in immuno: tolerance and autoimmune disease Deck (57):
1

tolerance

process by which body ensures immune responses are directed against foreign Ags or altered self (tumors) NOT against normal self tissues/cells
-specific unresponsiveness of individual to an Ag
*need Ag-sp rec. to be tolerant

2

T and B lympho: Ag binding rec

TCR (T)
Ig (B)
generated at random, potential for self rxn

3

tolerance that occurs early in lymphocyte development

central tolerance
peripheral tolerance catches "escapees" (from both is rare)

4

central B cell tolerance: once B cells express IgM on surface in BM-->tolerance induced via

clonal anergy: (soluble Ags) become "tolerant" OR
clonal deletion: (particulate, cell-assoc. Ags) dev. arrested-->apoptosis

5

peripheral B cell tolerance

constant low level stim. of BCR but no secondary sigs (T cell, inflamm) maintains B cell in anergic/unresp. state

6

central T cell tolerance

in thymus
cell clones that strongly recog. self-peptides pres. in MHC molecules-->apoptosis
(almost always self peps in thymus)

7

peripheral T cell tolerance

primary stim of T cells (MHC/peptide-TCR) w.out secondary stim (B7-CD28)-->no IL-2 prod-->clonal anergy
B7-CD28 interaction needed to stabilize IL-2 mRNA
cannot become activated
if repeatedly stim-->apoptosis
more rapid and prolonged than B cell tolerance
reg. T cells can inhibit activation of T cells by self peptide/MHC

8

regulatory T cells (Tregs/T suppressor cells)
+??
cytokines??
lysis of ??

typ. CD4+, FoxP3+
produce inhib. cytokines:
IL-10 (Th2) inhibits Th1 response
TGF-B suppresses T lymphocyte prolif (w.out: uncontrolled inflamm. response)
lysis/apotosis of B/T cells expr. peptides w. HLA (via CD8+)
specific suppression

9

regulatory B cells (Bregs)

produce IL-10: inhib Th1 CD4+ and CD8+ cells, can dampen auto reactive responses
(dec. in MS, SLE)

10

individuals that may be anergic to TB skin test

MMR vaccine, have measles

11

immune response depends on inherited HLA types, i.e.

HLA-B27 in ank spond and reactive arthritis

12

immunogen factors

dosage over time may induce tolerance
self-Ags may be hidden-->exposed by trauma-->IR (lens prot. of eye, synovial chondrocytes, sperm. Ags)-sympathetic opthlamia
weak immunogens induce tolerance

13

etiology of AIs

genetics (HLA)
molecular mimicry of IDs-->cross-reacting IR
environ. triggers (celiac)
impaired immunoreg mechs (T cell defects, imm. deficiency)
hormonal/gender (F>M, estrogen)

14

exs of molecular mimicry

S. pharyngitis: RF and heart valve destruction
H. pylori: gastric ca
Campylobacter jejuni: Guillain-Barre (IR agains LPS, cross reacts with motor nerves-->sev. paralysis, polyneuritis)
Klebsiella: ank spond (chr. inflamm, fibrosis, ossification of spine articulations, 90% HLA-B27+, HLA classI)
pathogens that can polyclonally activate lymphos

15

celiac disease (CD)

malnutrition, diarrhea, abd pain from intestinal inflamm. from gluten
-bowel mucosa changes: villus atrophy, T cell infiltration (CMI)
>95% have autoAgs agains tissue transglutaminase (anti-TG)
>90% have HLA-DQ2, the rest 10% HLA-DQ8
-assoc. with IgA deficiency

16

Myasthenia gravis

organ-specific: anti-ACh receptor Abs at NM junctions, organ specific
blocks nerve impulses-->sev. musc wkness
eyelid drooping, diff chew/swall/breathe-->resp fail
*assoc. w/ HLA-DR3*

17

autoimmune hemolytic anemia (AIHA)

org-sp: Abs agains Rh antigen or "I" Ags, target RBCs for destruction via compl. med lysis or phago by macros (spleen)
primary or sec. to another illness

18

AIHA dx

anemia, hemolysis, reticulocytosis, low haptoglobin, inc. LD, elev. ind. bilirubin, + direct antiglobulin test (Coombs test)

19

AIHA caused by...

hemagluttinins:
warm (IgG, find RBC at 37d, sp. for Rh Ag) or
cold (IgM, attach RBC when seen up to 30% of pts w. Mycoplasma pneumonia)

20

SLE

systemic, multi organ: Abs against ds-DNA (ANAs)-->form soluble ICs-->trapped in BM of kidneys, arteriolar walls, synovium-->activate complement, attract PMNs and other granulos-->local, acute inflammation-->fever, jt pain, malar face rash (butterfly) CNS, heart, *kidney* damage

21

80% of individuals with ??? will have SLE

complement deficiency: C1, C4, C2
due to lack of C3b production (opsonizer for phagos)

22

SLE: spontaneous ??
loss of control of ???
M or W??
presenting age??

remissions and exacerbations
B cell system (lack of C3b)
10x more freq. in women
15-45 yrs

23

SLE genetically linked to HLA...

HLA-DR3 and -DR2 (MHC Class II)

24

SLE dx

presence of ANA by ind. fluorescent Ab staining on Hep-2
type/pattern helps w. dx, px, classification

25

scleroderma

systemic: fibrosis, arthritis, hair loss, arteritis, GIT, kidneys, lungs, Raynaud's
more EC matrix molecules (collagen) produced
ANAs against topoisomerase-1 and RNA polymerase I (sometimes centromere Ags) (synthesis enzs. vs DNA, RNA)
diff. staining patter than SLE
W>M, pres. 30-50 yrs

26

Sjogren's syndrome

systemic: inflamm./destruction of exocrine glands (sal, lacrimal)-->dry mouth, dry eyes
50% have coex. AI
Abs against SS-A (Ro) and SS-B (La) (cytoplasmic prot-RNA complex Ags)
Abs agains muscarinic ACh rec (M3R) responsible???

27

Sjogen's dx

ELISA, western blot
NOT IFA

28

Graves' disease

hyperthyroidism
TSI (TS Ig) mimics TSH and binds/activates TSH receptor
W>M 4:1
*HLA-DR3*
passive, natural acq. Ab in neonate-->transient hyperthy.

29

TBIIs

thyroid binding inhibitory IgGs: block TSH rec-->hypothyroidism (diff. epitope)
NOT Grave's

30

Goodpasture's syndrome
type ?? hypersn

type II hypersn-med
Abs agains a3chain of BM collagen (type IV), bind BM in renal glomeruli-->dec. Ur output, inc. BUN, Cr
sometimes pulm alveoli-->hemoptysis, diff breathing
Fc portion of Ab ligates Gcy rec on monos, neutros, tissue basos, mast cells-->activation, complement activation, tissue injury

31

MS

T cell mediated, demyelination of CNS tissue, loss in nerve transmission
gen. susc, environ. exposure
CD4+, CD8+ involved, MHC class II present-->DTH response

32

relapsing-remitting MS

myelin destroyed, inc. in density of Na+ channels to overcome loss of AP-->neurological function restored

33

chronic progressive MS

myelin AND AXONS destroyed-->preventing function return

34

MS links

EBV
Adenovirus 2
Hep B
*HLA-DR2*

35

DM type 1

T cell-mediated, CD8+ CTLs destroy insulin-prod. Beta cells of pancr. islets of Langerhans (Abs play minor role)
CD8+ T cells sp. for insulin pres. in HLA-A2-->Beta cell destruction
"reverse vaccine" in making, dec. CD8+ response against pro-insulin

36

RA

BOTH Ab and T cell mediated
initiated by IC deposits-->sustained by chronic inflamm. infilt of synovial mem: macros, T cells, plasma cells-->aff. cells rel. cytokines, enz, granular components-->create "pannus" (fibrovasc tissue)-->destroys cartilage, exposes chondrocytes to imm. damage

37

RA markers

ACPAs : anti-citrullinated peptide Abs (2/3 RA pts), 90-95% likelihood, early marker
RF (IgM agains IgG Fc) titer do not always correlate with occurrence/severity

both form ICs deposited in synovium-->complement-->rel. chemotactic factors
-20-30% RA pts have no RF, other conditions have RF (SLE)
-RA may be ANA+

38

RA may happen in ?? pts, showing Ab response is not essential to pathogen of disease

agammaglobulinemic

39

Hashimoto's thyroiditis

T cell mediated (mono infiltrate, DTH, *Type 4 hypersn. rxn*)
Abs against thyroid peroxidase and thyroglobulin
dry skins, puffy face, brittle hair/nails, cold feeling
*HLA-DR5, -DR8, -B8*

40

myasthenia gravis tx

cholinesterase inhibitors

41

SLE lupus nephritis tx

organ transplant/renal dialysis (IC formation)

42

IC mediated AI disease can be tx w.

plasmaphoresis

43

immunosuppressive tx

anti-mitotics and cyclosporine (bad SEs! like infection)
anti-inflammatory (steroids, NSAIDs-PUD)
*these do not reverse cause, tx end-stage*

44

new, radical tx for life-threatening SLE, scleroderma

BM ablation

45

cytokine tx for MS

INF-B 1a

46

Ab tx: RA, ank spond, psoriasis

TNF-a or TNF-a rec blockade
Infliximab, Etanercept, Adalimumab, Golimumab, Certolizumab pegol

47

Ab tx w. costim modulation of T cell activation for RA

abatacept (CTLA-4-IgG fusion protein)

48

targeting B- cell using anti-CD20 Ab tx

Rituximab

49

IL-6 rec blocking for RA

Rocilizumab

50

???: humanized Abs against ??? for MS

Natalizumab
a4 integrins

51

???: human MoAb against BAFF cytokine (dec. B cells) used for ???

Belimumab, Benlysta
SLE

52

give low dose Ag....

"oral tolerance"

53

another tx: activation of Ag-sp. Th3 following low oral doses of Ag, how it works

CD4+ T cells (in Peyer's patches, LP of intestine) cause isotype switching of B cells to produce IgA
if low dose Ag, T cells
-->Th2-->IL-4 and IL-10 (suppr. Th1) OR new phenotype:
-->Th3-->only TGF-B (suppr. Th1 and Th2 activation, inhib. inflamm. cytokine production)

54

if large dose Ag admin..

CD4+ T cells clonally exhausted, anergic (unknown)

55

clin. trials for MS

oral bovine myelin-->appearance of myeline basic protein-sp. Th3 in blood

56

clin. trials for RA

oral type II collagen, improvements

57

clin. trials for preventing allograft rejections

oral feeding of HLA molecules

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