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!
hyperacute rejection
mismatched blood group antigens (lab/transplant team error)
= type 2 hypersensitivity reaction
blood group antigens are expressed on vascular endothelial cells –> Preexisting anti-blood group antibodies will bind to these endothelial cells, causing rapid inflammation and destruction of the transplanted organ. NO WAY TO RESCUE SUCH GRAFTS!!!
acute rejection
caused by T cell responses to non-self HLA alleles expressed on an allograft
= a type 4 hypersensitivity reaction
Donor dendritic cells migrate from graft to recipient lymph node, activating naïve T cells (reactive to allo-MHC). The resulting activated effector cells migrate to the graft, attacking and destroying it.
Mixed Lymphocyte Reaction Test
test to predict the degree of recipient T cell activation by the donor graft
Degree of cytotoxicity and proliferation in the MLR test is a good predictor of acute rejection
• Rarely used now – replaced by MHC typing
Graft survival is inversely related to …
the number of HLA mismatches = less mismatches is better prognosis!
chronic rejection
caused by formation of antibody/HLA immune complexes
=a type 3 hypersensitivity reaction
Uptake of fragments of dead donor cells by recipient dendritic cells leads to presentation of allo-HLA peptides to recipient CD4 T cells, some of which differentiate into Tfh cells.
Tfh cells help recipient B cells that are specific for the allo-HLA of the donor
allo-specific B cells differentiate into plasma cells, secreting anti-allo antibodies that bind donor HLA (fragments of dead donor cells) causing a Type III hypersensitivity reaction
Immune complexes are deposited in the blood vessel walls of the transplanted organ and recruit inflammatory cells –> increasing damage enables the immune effectors to enter the tissue of the vessel and inflict more damage
immune suppressive drugs used with transplants either….or….
deplete T cells (reduces T cell count that can respond to the graft)
or
interfere with T cell activation (long term maintenance)
balatacept
a soluble chimera of Ig Fc region and CTLA4
long term suppression of activation of allo-reactive T cells
alloreative T cell receptor binds foreign MHC and generates signal 1 –> belatacept binds B7 and prevents engagement of B7 and CD28 = prevents a signal 2
tacrolimus (FK-506) and cyclosporine A
inhibit IL-2 production
CsA or FK-506 both block signaling from ZAP-70 to nuclear transcription factors –>L2 gene transcription is NOT activated!
in transplant rejection, what attacks the transplant?
recipient T cells
graft vs host disease
GVHD
If the recipient expresses HLA molecules not expressed by the donor, mature T cells from the donor attack tissues of the recipient = graft versus host disease (GVHD)
how to minimize occurence of GVHD
Depletion of T cells from the donor graft
when is GVHD good?
Some malignant diseases are treatable by hematopoietic cell transplantation –> The “graft versus leukemia” effect can be helpful for eliminating irradiation-resistant cancer stem cells
Like, aplastic anemia, leukemia, multiple myeloma, Hodgkins disease and Nonhodgkins lymphoma
