Tolerance and Autoimmunity 9/10 Flashcards
Tolerance
- Unresponsiveness to self Ags
- Central tolerance: (occurs in bone marrow and thymus)
- negative selection occurs if immature B or T cells recognize self. they will either be apoptosed or the B cell will undergo receptor editing
- Peripheral Tolerance: (occurs in peripheral tissue)
- occurs when mature B or T cell recognizes self. They will undergo anergy, apoptosis/death or will be suppressed by a T regulatory cell
Development of T cell in Thymus (Central T cell tolerance)
- T cell precurosor becomes an immature thymocyte expressing a TCR, CD8, CD3 and CD8 (DP)
- Positive selection occurs where cells are selected by eptihelial cells that bind MHC molecules either Class I or CLass II (Cells that do not interact with MHC are put to death)
- when DP cell has weak recognition of class II MHC –> mature CD4+ (SP) (positive selection)
- when DP has weak recognition of class I MHC –> mature CD8+ (SP) (positive selection)
- when DP has no recognition of MHC and peptide –> apoptosis (failure of positive selection due to “death by neglect”)
- DP cells go to interact with macrophages and dendritic cells - undergoes negative selection and death of cells occurs with those that have high-affinity receptor for self MHC and self Ag.
- Strong recognition of either class I or class II and peptide –> apoptosis (negative selection)
Formation of T regulatory cells
thymocyte in thymus when expresses intermediate affinity for self Ag, results in up-regulation of txn factor Foxp3, becomes a T regulatory cell in the peripheral tissue
- if T cells regognize self Ag in thymus or in peripheral tissue they express IL-2. IL-2 binds to CD25 on T cells and results in turning on of Foxp3 and survival of T regulatory cells. T regulator cells go on to inhibit T cell effector functions and inhibit T cell activation.
Functions of T regulatory cells:
- prevent autoimmune diseases
- downmodulate immune response to allergens, pathogens and cancer cells
- mediate transplantation tolerance
–> loss of Foxp3 would result in widespread autoimmunity, because would lose production of Treg cells
- T reg cells are dependent upon IL2 secretion for cell survival
T cell anergy (unresponsive cells)
T cell anergy occurs when the naive T cell binds the APC presenting self Ag. The naive T cell recognizes self-Ag on MHC but doesn’t receive co-stimulatory siignal. this results in
- signal block –> unresponsive (anergic) T cell
- engagement of inhibitory recptor CTLA-4 –> undresponsive anergic T cell
- Why is peripheral tolerance necessary? it is necessary because central tolerance is not always absolute - sometimes get T cells that bind too strongly
- what induces co-stimulatory signals? LPS or “danger signals” provide signals that upregulate or activate the B7/CD28 - this is necessary to provide the second signal to naive T cells. If the signal is not there, then the T cell will become anergic
- What could break anergy? A widespread/strong signal infection
Peripheral T cell Tolerance
- T regs, anergic cells and cell death….
- If naive T cell binds APC presenting a self Ag, it induces pro-apoptotic protein (Bim) and undergoes apoptosis
- mitochondrial-mediated
- caspase actiation
- anti-apoptotic factors are not induced after microbial infection
- If naive T cell binds APC presenting a self Ag, and does not have a costimulatory signal, it can engage death receptors FasL/Fas and undergoes apoptosis
- children with mutations in FAS develop autoimmune disease
Tolerogenic vs. Immunogenic Ags
Tolerogenic Self Ags:
- Located in generative organs, and induce negative selection and other mechanisms of central tolerance
- Deficiency of costimulators may lead to T cell anergy or apoptosis, development of Treg, or sensitivity to suppression by Treg
Immunogenic Foreign Ags:
- Location in blood and peripheral tissues, permits concentration in secondary lymphoid organs
- expression of costimulators are typically seen with microbes, they promote lymphocyte survival and activation
Central B cell Tolerance
If immature B cell has strong recognition of self Ag in bone marrow it will either:
- undergo negative selection (apoptosis/deletion)
- undergo receptor editing (to change expression of light chain rearrangement). If this produces a mature B lymphocyte that does not recognize self Ag, then it is released into the periphery
Peripheral B cell tolerance
- if mature B lymphocyte binds self Ag in the periphery without T cell help then anergy will ensue due to block in Ag receptor-induced signals
- if mature B lymphocyte binds self Ag with partial recognition, it will be excluded from lymphoid follicles = death for a B lymphocyte
Autoimmunity
- immune response against self (autologous) Ags
- this can occur through immune complexes, circulating autoantibodies, and autoreactive T lymphocytes
- Principles factors in the development of autoimmunity are inheritance of susceptibility genes and environmental triggers and infections
- Both mutations in HLA and Non-HLA genes result in development of auto-immunity
- sex distribution of autoimune conditions is femal predominant
Factors that hinder our understanding of autoimmune diseases
- Heterogeneous and multifactorial and environmental
- Self antigens are often not identified
- Clinical manifestation is prolonged and variable after initiation
HLA alleles in autoimmunity
- having certain varities of an allele can increase your risk of developing certain autoimmune diseases:
- Ankylosing spondylitis
- Rheumatoid arthritis (HLA-DR4)
- Type 1 Diabetes Mellitus (HLA-DR3-DR4, DQ8)
- Pemphigus Vulgaris
Non-HLA genes that may contribute to genetically complex autoimmune diseases (Nod2, CD25) — not as important
- PTPN22: results in RA (abonormal T cell regulation/selection)
- NOD2: results in Crohn’s Disease (defective resistance to intestinal microbes)
- CD25(IL-2R): results in MS, type I Diabetis (abnormal regulatory T cells)
- C2/C4 complement proteins: results in SLE (defects in clearaance of immune complexes)
Non-HLA Single Gene defects that cause autoimmunity (mendelia diseases) - AIRE, FOXP3, FAS
AIRE: results in Autoimmune polyendocrine syndrome (APS-1)
- reduced expression of peripheral tissue Ags in thymus, leading to defective elimination of self-reactive T cells
- can lead to a number of AI diseases
FOXP3: results in X-linked polyendocrinopathy and enteropathy (IPEX)
- Deficiency in Regulatory T cells
FAS: resutls in autoimmne lymphoproliferative syndrome (ALPS)
- defective apoptosis of self-reactive T and B cells in periphery
–> if these genes are lost, you will get numerous autoimmnune diseases early on in life
IPEX: Treg cells and IgE production
- T reg cells produce:
- IL-10: suppresses IgE production
- TGFbeta: inhibits IgE production
–>T regulatory cells suppress Th1 and Th2 cytokines and suppress IgE by inducing IL-10 and TGF-B
loss of Foxp3 = IPEX = loss of T reg cells
loss of CD25 would also result in similar problems such as IPEX
2 hypothetical mechanisms of infection–> triggering autoimmune response
- induction of costimulators on APCs: microbe binds APC presenting self Ag , activating it and resulting in induction of costimulators on APCs. the T cell binds via B7/CD28 and results in activation of self-reactive T cell which will bind to self tissue
- molecular mimicry: the microbe binds APC - Self reactive T cell recognizes the microbia peptide, but it looks similar to self peptide, so T cells are activated against self tissue.
- We know infections trigger rheumatic fever – infection with streptococous can lead to rheumatic fever, where T cells that are activated against strep home back and start attacking cardiac cells through molecular mimicry mechanism at play
Autoimmune disease can involve both T cell responses and B cell responses:
Lupus: pathogenic T cells and Abs
Diabetis: pathogenic T cells
MS: pathogenic T cells (especially Th1)
Myasthenia gravis: pathogenic Abs
