Autoimmunity (Grayson) Flashcards
mechanisms that prevent self-reactivity
**central tolerance
*antigen segregation
*peripheral anergy
*regulatory T cells
*functional deviation
*activation-induced cell death
central tolerance
deletion and editing of self-reactive lymphocytes in the thymus and bone marrow
AIRE (autoimmune regulator gene)
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)
autoimmune polyendocrinopathy syndrome-1
*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
antigen segregation
physical barriers to self-antigen access to lymphoid system (via peripheral organs)
*some tissues are “immune privileged”
immunologically privileged sites - definition
areas of the body that can tolerate the introduction of antigens WITHOUT INDUCING AN inflammatory immune response
immunologically privileged sites - examples
*eye
*testis
*uterus
peripheral anergy
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)
benefits of peripheral anergy
prevents potentially autoreactive T cells from responding to self-antigen in the absence of a signal from a professional APC
regulatory T cells - function
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
what genes contribute to predisposition to autoimmune disease
*complement genes
*signaling genes
*co-stimulatory molecule genes
*genes regulating apoptosis
*cytokine genes
*HLA genes
mechanism of autoimmunity associated with AIRE gene
decreased expression of self-antigens in the thymus, resulting in defective negative selection of self-reactive T cells (autoimmune polyendocrinopathy syndrome-1)
mechanism of autoimmunity associated with FOXP3 gene
decreased function of CD4 CD25 regulatory T cells (IPEX syndrome)
Th17 T cells and autoimmunity
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)
which gender has a higher incidence of autoimmune diseases
FEMALES
graves’ disease - overview
*type II HSR
*antigen = TSH RECEPTOR
*consequence = hyperthyroidism
graves’ disease - physiology
*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
myasthenia gravis - overview
*type II HSR
*antigen = ACETYLCHOLINE RECEPTOR
*consequence = progressive weakness
myasthenia gravis - physiology
*antibody to ACh receptor binds and BLOCKS ACh receptor (antibody is an ANTAGONIST)
*prevents neuromuscular transmission and muscle contraction
rheumatoid arthritis - overview
*type III HSR
*autoantigen = rheumatoid factor IgG complex (rheumatoid factor is an antibody against the constant region of IgG)
*consequence = arthritis
rheumatoid arthritis - physiology
*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
type I diabetes - overview
*type IV HSR
*autoantigen = pancreatic beta cell antigen
*consequence = beta cell destruction (by CD8+ T cells)
type I diabetes - physiology
*CD8+ T cells recognize peptides from a pancreatic beta cell and then KILL the beta cell
multiple sclerosis - overview
*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
multiple sclerosis - physiology
*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
therapeutic approach to autoimmune disease
*corticosteroids
*anti-cytokine antibodies or soluble receptors
*antibodies against T-cell homing receptors
OVERALL = IMMUNOSUPPRESSION
goal of treatment of autoimmune diseases
reintroduce tolerance to the auto-antigen triggering the immune response
epitope spreading
as an autoimmune response becomes chronic, the number of autoantigens increases (start making responses to OTHER ANTIGENS)
