Autoimmunity Flashcards
Central tolerance
Induced in immature self-reactive lymphocytes in primary lymphoid organs.
Peripheral tolerance
Induced in mature self-reactive lymphocytes in peripheral sites.
Fate of cells w/ central tolerance
Apoptosis
Develop into Treg cells
B cells can attempt a change in BCR specificity
Fate of cells w/ peripheral tolerance
Anergy
Apoptosis
Suppressed by Treg cells
AIRE
Found in the thymus and exposes T cells to antigens from all kinds of cell types.
Helps to protect against autoimmunity.
Central tolerance curve explanation
Cells with weak avidity undergo apoptosis (nonfunctional)
Cells with high self- reactivity are deleted.
Thymocytes activated below a threshold are postively selected to become mature T cells.
A small percentage express FOXp3 and develop into Treg cells.
Mechanism of anergy
T cells engage inhibitory receptors CTLA-4 or PD-1 that block activation.
Checkpoint blockade
Treatment of cancer patients with anti-CTLA-4 and anti-PD-1. This can also cause autoimmune reactions.
Cytokines affecting Treg
Generation of Treg requires TGF-beta Express FOXp3 and are CD4+CD25+. Express high levels of CTLA-4. Cells are long-lived. IL-2 IS CRITICAL FOR THEIR SURVIVAL.
Inducible Treg cells (iTreg)
FOXp3 can be induced in mature T cells by presence of TGF-beta IF IL-6 is not present (hence a strong relationship between Th17 and iTreg).
Retinoic acid receptor (RAR)
Inhibits formation of Th17 but promotes FOXp3 expression.
Basic mechanisms for Treg cells (4)
Secrete inhibitory cytokines (TGF-beta and IL-10)
Cell-to-cell contact to block DC function
Metabolic disruption (death of target by deprivation of cytokines, specifically IL-22)
Cytolysis via granzyme and perforin
Targeting of DCs by Treg mechanism
Binding of CTLA-4 and B7 inhibits DC maturation AND induction of IDO, which degrades Trp (an essential AA).
B cell Central Tolerance
Immature B cells that recognize self-ags undergo receptor editing (further rearrangement and replacement of IgL-chain genes). If this fails, cells undergo apoptosis.
Weak recognition leads to anergy.
Retinoic acid in Treg development
DCs secrete RA which stimulates developmento of Treg cells from naive CD4+CD25- T cells.
CD22 receptor
An inhibitory receptor that is phosphorylated by Lyn and recruits SHP-1 to inhibit BCR signaling.
Defects in Lyn, SHP-1, and CD22 inhibitory receptor can lead to autoimmunity.
AIRE gene causes a failure of what?
Central tolerance. All others cause failure of peripheral tolerance.
AIRE Deficiency causes:
Autoimmune polyendocrine syndrome
FOXp3 causes
IPEX Syndrome
Mutations in AIRE are associated with:
Decreased expression of self-Ags in the thymus.
Diseases associated with polymorphisms in CTLA-4 (know 2)
Type I Diabetes
Grave’s Disease
2 improtant properties of CTLA-4
CTLA-4 expression is low on resting T cellls until activated by Ag.
CTLA-4 terminates continuing activation of responding T cells (the brakes of the system).
CTLA-4 has both intrinsic and extrinsic actions. Explain.
Engagement of CTLA-4 can deliver inhibitory signals that terminate activation (intrinsic).
CTLA-4 on Treg (or any responding T cell) can bind to B7 molecules and make them unavailable to CD28.
Polymorphisms of what genes has the strongest association with autoimmunity?
MHC/HLA genes
Non-HLA genes can also play a role.
3 ways microbial Ags can elicit autoimmunity:
- Molecular mimicry (Rheumatic fever, MS)
- Polyclonal (bystander) activation to actiavte autoreactive lymphocytes (create cytokine field).
- Release of previously sequestered Ags.
MS molecular mimicry by microbial Ag
T cells react w/ myelin basic protein and peptides from EBV, influenza A and HPV
Rheumatic fever
Triggered by Streptococcal infection and mediated by cross-reactivity between strep Ags and cardiac myosin.
Estrogens exacerbate:
Systemic lupus erythematosus by altering B-cell repitoire in absence of inflammation.
Penicillins can bind RBCs and:
Generate a neoantigen and cause hemolytic anemia.
Immune privileged sites (7)
Eye Brain Pregnant uterus Ovary Testes Adrenal cortex Hair follicle
Immune privilege
These tissues are able to tolerate the introduction of antigens without eliciting an inflammatory immune response.
Strongest associations with MHC genes 1-4
ATRP
Ankylosing spondylitis (MHC I)
Type I DM (MHC II)
RA (MHC II)
Pemphigus vulgaris (MHC II)
