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Compare and contrast peripheral and central tolderance for B and T lymphocytes Central tolerance refers to the negative selection that cocurs in the BM and the thymus for B and t cells. In those lymphoid organs, precurosrs are exposed to self antigen: Thymus: o Postiviie selection ensures that T cells responds to foregin peptides being presented on MHCs and that TCRs, co-receptors (CD4/CD8) and MHC Class 1/II are matched. o Negative slection ensures that cells whobind stoo tsronglyh to self peopeides are elmintaed o Aire locus - responsible to expressing peripheral self antigens in emduallary epithelical cells and providing the appartatus for effective antigen presentation, thereby ensuring effacing pruing of self reactive T cels Small minority of cells untiately become nave T cells or T regs (which express CD4+CD25+; T regs recognize self-antignes). It is unclear as to what incudes negative selction verus Treg expression o The aiire locus is the key influencer of negative selction of T cells o Mutation s in the aire locus result in multi organ autoimmune disease now as APECED o Extrathymic aire-expressing cells eist outside fo the thymus and may act to help elmiante autoimmune cells BONE MARROW: immature B cells that interact strongly with self antignes in the BM are eliminated (clonally deleted ) from the repertoire. This process of negative selction is simulator to that of immature T cells, except there are no MHC molecule involved o B cells can also undergo recetpor editing, where B cells can alter their recetpor sepcifcicity be expressing a new ligh chaing , producing a new recetport that doesn't interact with self antigen . The primary distinction between BM and thymus - BM continually turns over the B cell repertorie whiel the thymus principally workds during youth. People must accumulate a repertorie of T cells when they are young and T cells are used throughout life. Why does T cell involution happen in old people? 5 theories: 1. anive and memory T cells are long lived 2. continuous thombobobpopeieis is inefficient and potentially dangerious (autoimmunity) 3. thymus evoled before modern medicine 4. thymus evolved before air travel 5. consequences occur in post reproductive dadults - may not be useful to vaccinate older people who have no thymus Peripehral tolderance: induced when mature nave B and T cells regonize slef antigens in peripheral tissues. They are inactivated (angery) killed or suppressed by T regs. 2. Describe anergy in peripheral B and T lymphocytes Anergy in T cells- occurs in 2 wyas When a TCR on a T cell binds to a MCH that does not express costimulatory molecule B7, the T cells become anergic. IN other wrods, T cell meets an APC that is constimulator deficient When a T cell engages in a CTLA-4:B7 interacton, it becomes angeric. CTLA downregulates the wimmune response

Anergic cells cannot express IL-2 and are unable to stimulate their own proliferation and ifferentaion, Angery in B cells: when GB cells encounter self antign in peripheral lymphoid tissues, they come anergic Anergic B cells express high IgD and low igM. They also develop a paratial block in signal transduction, migrate to the periphery and rapidly lost in competition with other B cells 3. what is activation induced cells death Repeated stimulation of a T cell without costimuation will actually kill off the cell (instaed of just anergy). This is known as actiavation induced cell death., whcere leack of costimuation results in the xpression of Fas and FasL, which induces 2 T cells to intitatie the apoptosis of each other 4. why are T regs important Fuction: T regs mediate tolderance by inhibiting surrounding autoreactive cells What they do: T regs arise fro mteh thymus as well as peripheral lymphoid organs in roespnse to strong recognition of self antigens. These cells can hinbigibt the activation and andifferenatiaon of aniive T Cells by contact dependent mechanisms or by secreting cytokines that inhibit T cell profilerations Antigens: T regs express CD4 and CD25 on their surfaces, and FOX P3 transcription factor within Mutatiions in FOXP3 result in IPEX, a severe autoimmune diease resulting in diarrhea in infancy, dermatitis, autoimmune endocrinopathies, and death in frist 2 years of life. Imprornat because they have applications to cancer, transplant rejection, infection and allergy

Immune privilege: immune repsones in immunologicaly privileged sigtes are tightly regulated and have anti inflammatory profiles. They include the brain (BBB), eyes(blood-retianl bbarreir), testis, and fetus( the placenta sequesters the fetus from the mtohers T cells, which would otherwise go asints the fathers froeign MHC molecules) - disavanatage of hainvg immune privielege is the the issues have lmited capacitiy for regeneration (like brain damage( and imue mediated inflammation can hae devasting conseuqensces