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Flashcards in Regulation of the Immune System Deck (22)

What is immunological tolerance?

lack of response to a specific antigen
-it is important because we can not allow reactivity to self antigen or we will have autoimmune disease


How is immune tolerance achieved?

-the elimination of cell populations reactive to that antigen
-the neutralization of reactive cell populations
-the generation of unique cell populations that can produce antigen specific tolerance


Tolerance overview

-tolerance can be induced in B cells and T cells
-tolerance to self is learned/acquired
-tolerance is more easily induced in young animals/humans (but occurs throughout the life of an organism


Major mechanisms of tolerance

1) Deletion of reactive cells
2) inactivation of reactive cells: Anergy


Clonal Deletion

-immature or developing T cells are deletion
-the mechanism appears to be a form of programmed cell death or apoptosis
-it is caused by tight association of the autoreactive TCR to MHC presented antigen on specialized thymic dendritic cels


Clonal Anergy

-immature cells exposed to antigen in association with appropriate MHC can be functionally eliminated especially if those cells do not receive an appropriate co-stimulatory signal
-these cells still express receptor but they do not respond in immunologic assays


Functional deletion

-loss of T cell help by CTL (cytotoxic T cells) or B cells
-bias towards an inappropriate Th1 or Th2 response


Generation of suppressor or regulatory T cells

-suppression of autoreactive T cells by regulatory T cells requires them to interact with the same antigen-presenting cell


Blocking of presentation or activation

--cross-linking of CD28 delivers the co-stimulatory signal during activation of naive T cells and induces the expression of CTLA-4
-CTLA-4 binds B7 more avidly than does CD28 and delivers inhibitory signals to activated T cells


Clonal deletion of B cells

-in some of the cases observed, especially in immature cells, while developing in the marrow
-However, B cell developmental environment (bone marrow and, in avian species the bursa) do not appear to function as educators like the thymus does
-mechanism of tolerance


Clonal abortion/clonal anergy of B cells

-elimination of reactive clones when they are immature
-requires low doses with a multivalent antigen
-the immature cell expressed IgM on its surface, but when exposed to polyclonal anti-IgM or a tolerizing antigen exposure, it is capped, and the IgM internalizes
-in mature B cells re-expression occurs in 24-48 hrs
-immature cells sometimes do not re-express surface Ig
-another consequences is that the cell will express the surface antigen but it will not respond by proliferation or maturation


Functional deletion of B cells

-either unavailibility of T cell help for T dependent antigens; or in the case of a T-independent response, presentation of the antigen (usually a high molecular weight multiply repeating polymer) to the B cell in a non-crosslinking form


Inducing and maintaining tolerance

-maturity of the immunized host
-inherent immunogenicity of a substnace
-antigen dose
-form of antigen (aggregated vs soluble)


Inducing and maintaining tolerance determinants, favor immune response, favor tolerance

-determinant; favor immune; favor tolerance

-physical form of antigen; large, aggregated, complex molecules; soluble, aggregate-free relatively smaller, less complex molecules not presented by APC

-route of antigen administration; subcutaneous or intramuscular; oral or intravenous

-Dose of antigen; optimal dose; very large or very small

-Age of responding animal; older and immunlogically mature; newborn (mice), immunologically immature

-Differentiation state of cells; fully differentiated cells, memory T and memory B cells; relatively undifferentiated, B cells with only IgM thymocytes


Generation of self tolerance

-depends on clonal elimination or inactivation in the thymus
-the tolerance at this level depends on education in the thymus against self
-the thymus selects the useful, destroys the harmful and ignores the useless
-weak or no signal= cell fails to be positively selected and the cell dies by apoptosis
-partial signal= cell rescued from apoptosis, survives and matures
-peptide recognized well= cell induced to undergo apoptosis


Necessity for regulation

-prevent uncontrolled proliferation of individual B or T cell clones
-prevent an indefinite response to one challenge
-conserve resources by fine tuning the response


Regulatory T cells (T regs)

-FoxP3+, CD25+, CD4+
-thymectomizzed mice develop autoimmune disease- Transfer of CD25+ T cells from adult mice prevented autoimmunity
-selected in thymus on MHC II


T-regs have role in

-EAE (mouse MS)
-graft vs host disease
-graft rejection


Mechanism of Tregs

-direct contact with target cells
-cytokine mediated suppression of T cells (IL-10, TGF-B)
-cytokine-mediated suppression of pAPC function
-regulation tolerance by Tregs is an active process so it could be used for autoimmune therapy


Antigen itself can regulate the immune response

-chemical nature of the antigen (protein antigen for CMI and humoral immunity, polysaccharides and lipids for humoral immunity)

-amount of antigen (very large or small can inhibit)

-portal of entry of antigen (subcutaneous- immunogenic, large doses iv or orally- tolerizes)

-packaging of antigen (adjuvants)

-presentation of antigen is affected by genetic background (MHC restriction)


Other factors influence immunogenicity of pathogens

-size: large is more immunogenicity
-similarity to self protein: different more immunogenic
-adjucants- slow release and bacteria more immunogenic


Antibody can regulate the immune response

-antigen blocking or sequestration of antigen
-crosslinking of Ig and Fc receptors on the same cell
-example Rh disease, negative mother is given a large dose of anti Rh antibody- Coombs test