Fringe resistance and Immunoregulation..

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Fringe resistance and Immunoregulation. Dr. C. Piccirillo Canada Research Seat Branch of Microbiology and Immunology McGill College MIMM-414A Address 1-Oct. 20, 2006 Why Immune system microorganism regulation?
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Fringe resistance and Immunoregulation. Dr. C. Piccirillo Canada Research Chair Department of Microbiology & Immunology McGill University MIMM-414A Lecture 1-Oct. 20, 2006

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Why T cell regulation? How does the resistant framework avoid self-reactivity while keeping up reactivity to trespassers/non-self? White blood cell regulation without administrative T cells? Concealment of autoreactive T cells Control invulnerability to enteric microorganisms Limit histopathology

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Self/non-self separation Turn of the twentieth century 1901: Ehrlich and Morgenroth Immunized goats with RBC from another goat to presume that host safe reactions react to outside antigens. They authored the Latin saying: awfulness autoxicus Why did the goats create autoAb to their own particular RBC? 1938-Traub incited resistance by infusing LCMV in utero into mice delivering a disease that was extensive in life. 1949-Macfarlane Burnet: proposed that the creature\'s age at the first\'s season experience with antigen was the basic determinant in the affectation of resilience. 1953: Medawar actuated invulnerable resistance to skin allografts in mice by neonatal infusion of allogeneic cells. Counteractive action or inability to mount reaction to self-segments?

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Immunological resilience A condition of useful lethargy for a specific antigen. May happen in the setting of a non-provocative safe reaction. Resistance is a dynamic procedure.

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Central resistance to a great extent controls self/non-self separation. Thymic deletional procedures are wasteful. Moderate-high liking TCR/pMHC cooperations - > clonal erasure Low-direct TCR/pMHC communications - > determination No connection disregard and passing BMDC included in clonal cancellation (cortico-medullary intersection) T cell maturational state is critical (nature,site and how) Role of AIRE (AutoImmune Regulator) Autoreactive T cells leave thymus and exist in outskirts. Nonattendance of malady recommends instrument of dynamic concealment.

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Multiple instruments guarantee fringe T cell resilience. Lack of awareness: life structures, lymphatics, Ag crypticity, benefit Deletion : cross-presentation of Ag by BMDC results in death (eg;CD8+) Anergy: Insufficient co-incitement on self-tissues Clonal weariness: CD8+ T cells in incessant viral contaminations Immune deviation: shift from provocative to mitigating cytokine generation (eg; Th1-Th2). Actuation prompted cell passing (AICD): Fas/FasL (IL-2) = Death Peripheral resilience is a versatile procedure.

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Tolerance to Self Antigen sequestration (lens of eye, spermatozoa) Low MHC expression (i.e. hepatocytes) Immune Response to Foreign Antigens Influence of Antigen Dose (low zone, high zone), timing/term of introduction, courses, nature of antigen , protein > CHO >> lipids , vicinity of adjuvants Influence of Antibody input restraint (IgG represses IgM), differential antigen tying proclivity Factors favoring resistance Age, neurological and endocrine elements, Nutritional status, MHC Haplotypes

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Acquired Tolerance In numerous cases, test lethargy may be interceded by silencer (T) cells , which effectively keep a safe reaction. Unique examinations of Gershon and Kondo (1970) demonstrated that T cells were needed for resilience actuation. In addition, T cells from tolerant mice stifled B cells from typical mice. Dynamic concealment by T cells additionally found in a few reactions under Ir quality control and in the regulation of IgE reactions (Tada). Concealment normally instigated by systemic organization of antigen-coupled to self cells; course of infusion is essential (i.v. favors; intradermal gives contact sharpening). Silencer T cells produce components. These elements may act specifically on T/B targets. Can be adaptively exchanged.

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Infamous Suppressor T cells Suppressor or Regulatory lymphocytes Patrol fringe, hushing self-responsive T cells and look after resistance. 1970’s-mid 80’s Gershon, Kondo, Tada….. Forbidden of T “suppressor” cells CD8+ Complex administrative systems mapping to I-J (inside of the MHC) Molecular cloning of TCR and MHC baffled in T cell hybridomas emitting “suppressor factors” No identifiable cell surface marker No clone or cell lines with silencer movement No antigen particular silencer variable quality recognized Transient phenotype

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The silencer\'s rebirth T cell More inquiries than answers. Questions ? n Number of productions * 1 1995 - Present Answers

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A system of CD4 + administrative T cells control safe reponses. Thymic CD4 + T cell pool Thymically-determined normally happening CD4 + CD25 + Treg cells (nTreg ) Peripherally-instigated CD4 + Treg cells ( iTreg ) Foxp3 + GITR + CTLA-4 + CD25 + TCR + Peripheral separation signals CD25 GITR CTLA-4 Foxp3 CD25 +/ - GITR +/ - CTLA-4 +/ - Foxp3 +/ - APC _ Activated Effector T cell Autoimmunity Transplantation Tumor Immunity Infectious illness Piccirillo et al. Patterns in Immunol. 2004. .:tsli

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