Tolerance and Immune Regulation Control of the Immune

Tolerance and Immune Regulation

Control of the Immune Response (Immunomodulation) • Specificity • Self - recognized but not responded to • Nonself - discerned as foreign » Pathogenicity: recognize intracellular/extracellular organisms • Intensity • Sufficient for protection against invading organisms • Prompt down regulation to minimize deleterious effects • Duration • Long enough to generate protection • Generates appropriate intensity for protection • Sufficient to protect host, but does not persist after challenge resolved • Memory retained for future assaults

Mechanisms of Immune Regulation • • Isolation of self antigens (privileged sites) Deletion of self-reactive clones Active immunoregulation to prevent sensitization Down regulation of mature self-reactive clones

Immunological Tolerance General Considerations • Definition • State of unresponsiveness to a particular antigenic epitope while the remaining immune response remains intact. • Only antigen receptor-bearing cells (i. e. lymphocytes) can be tolerized • Types • Central: occurs during lymphocyte development • Peripheral: induced in mature cells • Consequences • • • Apoptosis: clone is deleted (programmed cell death) Anergy: clone is inactivated (but not deleted) (Clonal Ignorance)

Immunological Tolerance Central vs. Peripheral Mechanisms Self reactive clones arise during process of generating B and T receptor diversity. • Central: Negative selection. Ensures that B and T cells that emerge into peripheral tissue react only with foreign antigens. • Peripheral: Other mechanisms must be available for maintaining self tolerance once cells enter B and T cell compartments.

Immunological Tolerance Immature T and B Lymphocytes • Major mechanisms is central tolerance (apoptosis) of self reactive clones. • T Lymphocytes – Negative selection in thymus • B Lymphocytes – Negative selection in bone marrow

Induction of Tolerance Mature T and B Lymphocytes • • Anergy Receptor Editing Deletion Clonal Ignorance

Induction of Tolerance Mature T and B Lymphocytes • Anergy – Functional inactivation of a cell, resulting in nonresponsiveness upon contact with self antigen. • Receptor Editing • Deletion • Clonal Ignorance

Inhibition of Lymphocyte Activation • T cells – Inhibit costimulatory molecules (eg. CD 80, 86) – Anergizes CD 4+ T cells • No more IL-2 • Unresponsive to subsequent antigen challenge – Anergy is a major mechanism of peripheral tolerance

Induction of Tolerance Mature T and B Lymphocytes • Anergy • Receptor Editing – Process where a rearranged immunoglobulin H or L chain gene undergoes secondary rearrangement (under control or RAG-1/RAG-2). Leads to a BCR or TCR with new specificity. • Deletion • Clonal Ignorance

Induction of Tolerance Mature T and B Lymphocytes • Anergy • Receptor Editing • Deletion – Autoreactive T or B cells are eliminated from the repertoire of reactive population. Can occur with cells that bind with extremely high affinity. • Clonal Ignorance

Induction of Tolerance Mature T and B Lymphocytes • • Anergy Receptor Editing Deletion Clonal Ignorance – Refers to a state where autoreactive cells are neither anergized, receptor edited, or deleted. They co-exist with antigen in an unactivated state with low affinity for antigen.

Induction of Tolerance Mature T and B Lymphocytes • • Fas-Fas Ligand interactions Inhibition of T and B cell activation Suppressor/Regulatory T cells Idiotype Network

Peripheral Tolerance Mature T and B Lymphocytes Occasionally autoreactive B and T lymphocytes escape negative selection and enter the periphery. • Elimination of these cells usually occurs by Fas-Fas Ligand interactions. • Alternative mechanism is regulation through suppressor cells.

Mechanisms of Acquired Tolerance • Suppressor Cells • Very low or very high doses of antigen may induce suppressor T cells which can suppress immune responses of both B and T cells, either directly or by production of cytokines, most importantly, TGF-beta and IL-10. [CD 8+ “classic” suppressor cell] • Regulatory T cells • capable of suppressing normal T cell activity • Treg [CD 4+CD 25+], TR 1[TGF , IL 10], TH 3[TGF ] • Idiotype-Antiidiotype Networks • An autoantibody, the specificity of which is directed against one of one's own idiotypes • V region genes code for idiotype

Coico, Sunshine, Benjamini; 2003 • Regulatory CD 4+CD 25+ T cells can induce contact mediated suppression of effector responding cells.

Control of Immune Response to Self Antigen • Immunologically Privileged Sites – Sequestration from Immune surveillance • lens of eye, spermatozoa/testes, brain, ovary, placenta – Tissue expression of Fas. L which would induce apoptosis of activated T cells that migrated into tissue • Fetal Immune Development • • • Antigen sequestration – • Immunologically privileged site Fetal cells lack MHC I until late in development injury/inflammation can initiate response Low MHC expression (i. e. neural tissue) – normally, lack of immune response

Inhibition of Lymphocyte Activation • B cells – More difficult to tollerize – occur at level of 2 nd signal (IL-4, 5) – Requires large antigen dose • • • Bypasses Th cells directly binds surface Ig on B cell bypass TH (and thus IL-4, 5) No costimulation (CD 40 L, MHC II) Result is anergy

Control of Immune Response to Foreign Antigens • Factors favoring tolerance • • Age – young and old Neurological and endocrine factors Nutritional status MHC Allotypes

Impact of Age on Individual Immune Responses • Young – Fetus makes Ig. M but not Ig. G until late – Term babies immunocompetent but immature – Takes months and exposures to develop immunocompetence • Elderly – Immune senescence – deficiency vs. dysregulation – Good memory response, poor primary – Infectious deaths with new strains

Neurological and Endocrine Factors and Immunity • Psychoneuroimmunology – stress-distress-immunity-health • hypophyseal-pituitary-adrenal axis : corticosteroids • sympathetic nervous system : catecholamines • Hypophyseal-pituitary-gonadal axis – estrogen/progesterone – Immune diseases of women • Nutritional influences – Trace metals – Malnutrition