tolerance, autoimmunity, and transplantation Flashcards
T cells are activated when ____ interacts with ___
MHC and antigen
for a naive T cell to be activated, you need 2 signals:
2 signal model
1) TCR + CD3
2) costimulation of CD28 (on the Tcell) + B7 costimulatory molecule (on the antigen presenting cell)
**must be a professional antigen presenting cell!
4 mechanisms that contribute to immunological self tolerance
1) negative selection of self reactive B cells in the bone marrow
2) central thymic tolerance = positive + negative selection
3) exclusion of lymphocytes from certain tissues (eyes, brain, testis)
4) peripheral tolerance of self antigens (for the self reactive T cells that escape the thymus)
central tolerance
thymus expresses tissue specific proteins that
1) select for TCR with affinity to MHC (others die)
2) negative selection of cells with high reactivity against self
end up with Tcells with MHC affinity without high self-reactivity
lymphocytes are excluded from what tissues
eyes brain and testis (immunologically priivileged = no T cells allowed)
peripheral tolerance to self-antigens
since some T cells with reactivity against self do get out of the thymus, there are two peripheral ways to prevent autoreactions
1) anergy = permanently inactivates auto-reactive T cells by preventing 2nd costimulatory signals (only signal 1 occurs)
2) suppression of autoimmune responses by Tregs (regulatory T cells)
Tregs suppress the activation of all the other self reactive CD4 T cells using
–TGFbeta
–IL-10
and
–direct cell-cell contact by reacting with the same APC (antigen presenting cell)
development of autoimmune disease
3 mechanisms
• Failure or reversal in T cell tolerance = auto reactive T cells must be present in the development of autoimmune disease
- release of antigens that are normally sequestered
- failure of central tolerance
- failure of peripheral tolerance (failed anergy or Tregs)
autoimmunity due to eye trauma
eye specific proteins are released into periphery, resulting in T cell activation and immune response against both eyes
(t cells normally cant get into the eye -havent been exposed to eye specific antigen before)
causes immune mediated blindness in BOTH eyes
AIRE mutation
= APECED (autoimmune polyendocrinopathy)
defective negative selection of self-reactive T cells
group A strep infection is associated with what autoimmune condition?
rheumatic fever (carditis and polyarthritis)
d/t molecular mimicry
o Regardless of the trigger, a major mechanism underlying most autoimmune diseases is …
activation of T cells by self-antigen presented by specific MHC alleles
they are basically type 2,3, or 4 hypersensitivity reactions directed against self-antigens
hypersensitivity type 1
name?
associated diseases?
mediator?
immediate
atopy, anaphylaxis, and asthma
IgE
hypersensitivity type 2
name?
associated diseases?
mediator?
antibody mediated
hemolytic anemia, goodpastures, and erythroblastosis fetalis
IgG or IgM and complement
hypersensitivity type 3
name?
associated diseases?
mediator?
immune complex-mediated
serum sickness, arthus reaction, lupus nephritis
IgG and complement
hypersensitivity type 4
name?
associated diseases?
mediator?
delayed
transplant rejection, contact dermatitis, and TB
tcells, macrophages, and histiocytes
autoimmune hemolytic anemia
type 2 hypersensitivity like autoimmunity
the autoantigen is an RH blood group antigen and the consequence is the destruction of RBCs by complement and phagocytes –> anemia
RBCs bind anti-erythrocyte antibodies –> lysis
graves disease
type 2 like hypersensitivity autoimmunity
autoantigen is the TSH receptor –> hyperthyroidism
Pathologic activation of thyroid follicle secretion by anti-receptor antibody
SLE
type 3 like hypersensitivity autoimmunity
autoantigens are the DNA, histones, ribosomes, snRNP, and scRNP; leads to glomerulonephritis, vasculitis, and arthritis
Anti-self-antibodies trigger immune complexes which disrupt function of circulatory and or renal systems
T1 Diabetes, Rheumatoid arthritis, and MS are all autoimmune disorders like what type of hypersensitivity?
type 4 (T cell mediated)
allograft
a graft from an individual other than an identical twin
does blood transfusion require MHC compatibility?
NO
what are blood group antigens?
o Blood group antigens are carbohydrates the O antigen carbohydrate structure is common to all 3 blood groups
they are expressed on vascular endothelial cells
transplants with HLA expressing tissues
what do they require?
in HLA expressing tissues, many peripheral T cells are allo-reactive to any given non-self MHC molecule (very strong allo-reactions)
any allograft other than blood involves tissues that express HLA proteins –> any transplant from other than an identical twin requires chronic immunosuppression!
