Tolerance and Autoimmunity

Question 1

Tolerance

Answer 1

Needed because random generation of diversity is dangerous

Unresponsiveness to an antigen induced by previous experience to that antigen

Question 2

Self-tolerance

Answer 2

Can distinguish self from non-self

Question 3

Mechs that contribute to self tolerance

Answer 3

Neg B cell selection in BM
Neg T cell selection in Thymus 
Exlusion of lymphos from tissues 
Induction of anergy in some cells that reach periphery 
Tregs

Question 4

Central tolerance in the bone marrow

Answer 4

No self reaction - Mature B cell
Multivalent self molecule on a cell - Receptor editing/apoptosis
Soluble self molecule - Anergic B cell
Low-affinity, non-cross linking self - mature but clonally ignorant B cell

Question 5

Peripheral tolerance in the spleen

Answer 5

Multivalent self molecule - apoptosis
Soluble self molecule - anergic B cell that undergoes apoptosis
Low-afinity, non-cross linking self molecule - Mature, clonlally ignorant B cell
No reaction - mature B cell

Question 6

Affinity model of T cell selection

Answer 6

Positive selection to make sure that they can recognize self MHC molecules
Negative selection - if they recognize self antigens, they die

Question 7

If TCR is low then

Answer 7

Cells undergo apoptosis because can’t bind to the MHC molecule to undergo positive sleection

Question 8

Central T cell tolerance

Answer 8

3 way - recognition of self antigen on cortical OR medullary epithelial cell
Recgonition of self antigen on thymic bone marrow derived cell (dendritic cells, macrophages)…these cells die

Question 9

How are self antigens presented in the thymus?

Answer 9

AIRE controls expression of a lot of these proteins

Question 10

APECED

Answer 10

Defective AIRE gene…destruction of endocrine tissues including pancreatic islets and susceptibility to fungal infections like Candida

Question 11

Immunologically privileged sites

Answer 11

Brain, eye, testis, uterus

Question 12

Regulatory tolerance

Answer 12

T cell specific for self antigen in the thymus becomes a Treg
T cell specific for self or commenssal microbiota antigen in periphery in presence of TGFbeta becomes Treg

IL-10 and TGFbeta from Tres inhibit other self-reactive T cells

Question 13

Lymphoproliferative dz can be from

Answer 13

Absence of Tregs

Question 14

Autoimmunity is combination of

Answer 14

Infection/environmental exposre and genetic factors

Question 15

Graves dz mech and consequence

Answer 15

Antibody against cell surface or matrix antigen (type 2)

Autoantibodies against TSHR

Hyperthyroidism

Question 16

SLE mech and consequence

Answer 16

Immune complex dz

Autoantibodies and autoreactive T cells to nuclear contents

Glomerulonphritis, vasculitis, rash

Question 17

HLA associated risk factor for Graves

Answer 17

DR3 - not everyone will have it but 4X as likely to have graves

Question 18

Men or women more likely for autoimmune?

Answer 18

Women

Question 19

Graves symptoms

Answer 19

Heat intolerance
Nervousness
Irratability 
Warm and moist skin 
Weight loss with increased appetite 
Enlarged thyroid 
Optho problems

Question 20

Genetics of Graves

Answer 20

Polymorphim in TSHR gene can result in decreased thymic expression (lose central tolerance)
Mutation in Foxp3 and CD25 associated with Tregs
CTLA4 mutation
CD40 mutation changes translation efficiency
HLA-DR3 increased ability to present thyroglobulin antigens
BAFF and APRIL

Question 21

SLE symptoms

Answer 21

Joint/muscle pain
Fever
Red rash
Chest pain 
Hair loss
Puprle or pale fingers/toes 
Sensitivity to sun 
Edema in legs/eyes 
Oral ulcers
Swollen glands
Fatigue

Question 22

Genetic and environmental for SLE

Answer 22

Anti-DNA antibodies
C1q, C4, C2 changes mean can’t clear immune complex
Sunlight, smoking, alcohol, female
HLA DR3, DR2, and DR5
Abberant DNA methylation (like Foxp3)
BCR signaling genes
IRF5 expressed increases cytokines that impair B cell selection and modulate differentiation

Question 23

Giant cell arteritis

Answer 23

Vasculitis of arteries combined with polymylagia rheumatica

Granuloma formation in the mural layers of inflamed arteries (macrophages form and fuse urrounded by CD4 cells)

Question 24

Clinical features of giant cell arteritis

Answer 24

Fever of unknown origin 
HEadache
Scalp and temporal artery tenderness
Jaw muscle ischemia 
Vision impairment can include blindness
Aortic anyeurysm

Question 25

Genetics and environmental of GCA

Answer 25

HLA-DRB1*04 
History of smoking in women 
Varicella zoster virus infection 
Older than 50 
Women more likely 
More likely in whites

Question 26

GCA granuloma CD4 types

Answer 26

Th1 and Th17 but NOT Th2