26. Autoimmunity II

Question 1

autoimmunity is a failure of what?

Answer 1

self-tolerance - esp peripheral tolerance (because it is more complex and less reliable than central tolerance0

Question 2

central tolerance

Answer 2

• devl antigens ubiquitously expressed throughout the body, incl thymus
• ** also to ectopically expressed antigens (insulin, thyroglobulin, myelin basic protein) under control of AIRE (autoimmune regulator)
• relaiable mech - defects in AIRE causes autoimmune polyendocrinopathy
• normally “leaky” - some self-reactive antigens escape to periphery where they are normally controlled by peripheral tolerance

Question 3

checkpoint 1 in peripheral tolerance?

Answer 3

deletion: activation-induced death

to prevent unwanted stimulation when there is NO COSTIM

lack of co-stimulation leads to death of activated cells by apoptosis, Fas and FasL not necessarily expressed on the same cell

activation induced cell death via death receptors or pro-apoptotic proteins

Question 4

checkpoint 2 in peripheral tolerance?

Answer 4

anergy: T cell activation through T cell receptor and CD28 leads to the increased expression of CTLA-4, an inhibitory receptor for B7 molecules

to prevent too much stimulation through negative feedback mechanism

disturbance in CD28 and CTLA-4 regulation, mutations in CTLA-4 genes lead to autoimmunity

Question 5

checkpoint 3 in peripheral tolerance?

Answer 5

T cell mediated suppression - regulatory T cells

- release IL-10, TGF-B to suppress super active T cells

Question 6

please describe immune deviation

Answer 6

Th1 Th2 switch can be used to treat autoimmunity by artificially changing the profile in order to deviate immune repsonse (Th1 and Th2 are mutually exclusive)

a switch b/w Th1, Th2, Th17 may be protective

eg Graves involves Th2 cells activating B cell and hashimotos involves Th1 cell mediated problems…so if deviate could possibly treat

Question 7

generally, what things cause a loss of tolerance?

Answer 7

genes: being a female (sex hormones) and having pathogenic gene variations, including MHC
environment: loss of immune privelage, infections/molecular mimicry, drugs, epigenetic regulation

Question 8

HLA allele commonly associated with RA?

Answer 8

DR4

Question 9

HLA allele commonly associated with IDDM?

Answer 9

DR3, DR4, DR3/DR4

Question 10

HLA allele commonly associated with MS?

Answer 10

DR2

Question 11

HLA allele commonly associated with SLE?

Answer 11

DR2/DR3

Question 12

HLA allele commonly associated with AK?

Answer 12

B27

Question 13

immunologically privelaged site?

Answer 13

a site privileged enough to not need immune response (ie high levels of Fas to kill ANY foreign cell or immune cell, high factor H to inhibit C’)

eg eye, brain, etc

when there is trauma or disruption of this it is BAD

eg if trauma to one eye mediates immune reaction, it is best practice to just take the eye out before it even has a chance to spread to the other eye

Question 14

alopecia areata

Answer 14

hair follicle is immunologically privelaged - loss of privelage results in alopecia areata

Question 15

rheumatic fever

Answer 15

streptococccal infection - molecular mimicry - rheumatic fever: antistrep antibodies react w/ myocardial and joint self-antigens. Rheumatic fever begins w/throat infection, but progressively causes other sxs, including fever, rashes, and inflammation in various organs (incl heart valves). Mitral stenosis or regurgitation.

Question 16

HSV uses molecular mimicry to cause what disease?

Answer 16

Myasthenia Gravis

Question 17

drug induced autoimmunity

Answer 17

• small # of people taking spec Rx develop autoimmune-like syndromes without true autoimmunity. In other cases, drugs may exacerbate true underlying autoimmunity, causing disease flares
• mimics autoimmune disease clinically
• different from true autoimmune disease: blood tests are different, involvement of internal organs is rare.
• sxs stop when the drug is discontinued

Question 18

drug induced MG

Answer 18

small # of people taking penicillamine (associated w/ HLA-DR1), diphenylhydantoin, chloroquine, quinidine, trimethadone, procainamide

• mimics myasthenia gravis
• anti-AChR antibodies may be present
• rapid disappearance after drug withdrawal

Question 19

histo of thyroid gland in graves’ disease pt?

Answer 19

hypercellularity, papillae, and scalloped margins of the colloid

Question 20

histo of thyroid gland in hashimoto thyroiditis?

Answer 20

glandular destruction: diffuse infiltration of the thyroid by mononuclear inflamm cells (lymphocytes) w/ well defined germinal centers

HURTHLE cell changes (red is dead)

Question 21

RA histology

Answer 21

pannus (joint): synovium edematous, thickened, and hyperplastic - inflamm cells, granulation tissue, fibroblasts - inflamed synovium appears hypertrophic w/formation of villi

nodule (soft tissue): central zone of fibrinoid necrosis surrounded by inflammatory cells

Question 22

SLE histology

Answer 22

immune complex: full house IF

glomerular wire loops, subendothelial dense deposits, granular immunoflourescence, and proliferative glomerulonephritis - all due to deposition of immune complexes

Question 23

goodpasture disease histo

Answer 23

glomerulonephritis: crescents are a sign of severity, severe necrotizing glomerulonephritis

linear indirect immunoflourescense pattern

pulmonary hemorrhage: cross-reacting antigen in lung tissue