Autoimmunity (Grayson)

Question 1

mechanisms that prevent self-reactivity

Answer 1

**central tolerance
*antigen segregation
*peripheral anergy
*regulatory T cells
*functional deviation
*activation-induced cell death

Question 2

central tolerance

Answer 2

deletion and editing of self-reactive lymphocytes in the thymus and bone marrow

Question 3

AIRE (autoimmune regulator gene)

Answer 3

controls the expression of a wide variety of non-lymphoid self-antigens in the thymus, allowing for SELECTION AGAINST MANY SELF-REACTIVE THYMOCYTES (deleting tissue-reactive T cells)

Question 4

autoimmune polyendocrinopathy syndrome-1

Answer 4

*caused by a mutation in the AIRE gene, leading to ineffective negative selection of T cells and impaired central tolerance
*presents as a broad range of autoimmune syndromes

Question 5

antigen segregation

Answer 5

physical barriers to self-antigen access to lymphoid system (via peripheral organs)
*some tissues are “immune privileged”

Question 6

immunologically privileged sites - definition

Answer 6

areas of the body that can tolerate the introduction of antigens WITHOUT INDUCING AN inflammatory immune response

Question 7

immunologically privileged sites - examples

Answer 7

*eye
*testis
*uterus

Question 8

peripheral anergy

Answer 8

cellular inactivation by weak signaling without co-stimulus (occurs in secondary lymphoid tissue)
*basically, if a T cell does not receive signal 2 during activation, the T cell will become anergic (non-responsive)

Question 9

benefits of peripheral anergy

Answer 9

prevents potentially autoreactive T cells from responding to self-antigen in the absence of a signal from a professional APC

Question 10

regulatory T cells - function

Answer 10

function to SUPPRESS the immune system by releasing TGF-beta, IL-10, and IL-35, which inhibit CD4 and CD8 effector function

*note: CD4+, CD25+, FOXP3+ T cells

Question 11

what genes contribute to predisposition to autoimmune disease

Answer 11

*complement genes
*signaling genes
*co-stimulatory molecule genes
*genes regulating apoptosis
*cytokine genes
*HLA genes

Question 12

mechanism of autoimmunity associated with AIRE gene

Answer 12

decreased expression of self-antigens in the thymus, resulting in defective negative selection of self-reactive T cells (autoimmune polyendocrinopathy syndrome-1)

Question 13

mechanism of autoimmunity associated with FOXP3 gene

Answer 13

decreased function of CD4 CD25 regulatory T cells (IPEX syndrome)

Question 14

Th17 T cells and autoimmunity

Answer 14

lacking Th17 T cells makes one LESS susceptible to autoimmune diseases
*Th17 cells have a beneficial role (protecting against bacteria) AND a pathogenic role (promoting autoimmunity)

Question 15

which gender has a higher incidence of autoimmune diseases

Answer 15

FEMALES

Question 16

graves’ disease - overview

Answer 16

*type II HSR
*antigen = TSH RECEPTOR
*consequence = hyperthyroidism

Question 17

graves’ disease - physiology

Answer 17

*antibody binds and stimulates TSH receptor, mimicking TSH (antibody becomes an AGONIST ligand)
*leads to overproduction of thyroid hormone
*TSH levels are low because T3 and T4 provide negative feedback to TSH production

Question 18

myasthenia gravis - overview

Answer 18

*type II HSR
*antigen = ACETYLCHOLINE RECEPTOR
*consequence = progressive weakness

Question 19

myasthenia gravis - physiology

Answer 19

*antibody to ACh receptor binds and BLOCKS ACh receptor (antibody is an ANTAGONIST)
*prevents neuromuscular transmission and muscle contraction

Question 20

rheumatoid arthritis - overview

Answer 20

*type III HSR
*autoantigen = rheumatoid factor IgG complex (rheumatoid factor is an antibody against the constant region of IgG)
*consequence = arthritis

Question 21

rheumatoid arthritis - physiology

Answer 21

*cytokines are produced in the synovium, promoting:
-thickening of the synovial membrane
-infiltration of neutrophils
-release of proteases that degrade connective tissue
-production of rheumatoid factors and complement activation
-osteoclast activation and associated bone resorption

Question 22

type I diabetes - overview

Answer 22

*type IV HSR
*autoantigen = pancreatic beta cell antigen
*consequence = beta cell destruction (by CD8+ T cells)

Question 23

type I diabetes - physiology

Answer 23

*CD8+ T cells recognize peptides from a pancreatic beta cell and then KILL the beta cell

Question 24

multiple sclerosis - overview

Answer 24

*type IV HSR
*autoantigens = myelin basic protein, proteolipid protein, myelin oligodendrocyte glycoprotein
*consequence = brain invasion by CD4 T cells, muscle weakness, and other neurological symptoms

Question 25

multiple sclerosis - physiology

Answer 25

*somehow, blood-brain barrier becomes locally permeable to leukocytes and blood proteins
*T cells specific for CNS antigen reencounter antigen on cells in brain
*inflammatory reaction in brain
*demyelination of neurons

Question 26

therapeutic approach to autoimmune disease

Answer 26

*corticosteroids
*anti-cytokine antibodies or soluble receptors
*antibodies against T-cell homing receptors
OVERALL = IMMUNOSUPPRESSION

Question 27

goal of treatment of autoimmune diseases

Answer 27

reintroduce tolerance to the auto-antigen triggering the immune response

Question 28

epitope spreading

Answer 28

as an autoimmune response becomes chronic, the number of autoantigens increases (start making responses to OTHER ANTIGENS)