Regulation of the Immune System Flashcards
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)
- immunosuppression
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
