IMMUNOLOGICAL TOLERANCE

1. IMMUNOLOGICAL TOLERANCE Lecture 6 Jan Żeromski 2007/2008

2. BASIC FACTS ABOUT TOLERANCE • Tolerance – a state of unresponsiveness specific for a given antigen • It is specific (negative) immune response • It is induced by prior exposure to that antigen

3. BASIC FACTS ABOUT TOLERANCE-2 • Self tolerance – prevents the body to elicit an immune attack against its own tissues • Mechanisms of active tolerance prevent inflammatory reactions to many innocuous airborne and food antigens found at mucosal surfaces

4. Featuresof self-tolerance • Self-non-self discrimination is learned during development • Tolerance is NOT genetically programmed • The time of first encounter is critical in determining responsiveness

5. FACTORS IMPORTANT IN THE INDUCTION OF TOLERANCE • The stage of differentiation of lymphocytes at the time of antigen confrontation • The site of encounter • The nature of cells presenting antigenic epitopes • The number of lymphocytes able to respond • Microenvironment of encounter (expression of cell adhesion molecules, influence of cytokines etc.)

6. TOLERANCE – GENERAL PROPERTIES • Immature or developing lymphocyte is more susceptible to tolerance induction than mature one • Tolerance to foreign antigens is induced even in mature lymphocytes under special conditions • Tolerance of T lymphocytes is a particularly effective for maintaining long-lived unresponsiveness to self antigens

7. POSSIBLE WAYS OF PREVENTION OF SELF-REACTIVITY • Clonal deletion – physical elimination of cells from the repertoire during their lifespan • Clonal anergy – downregulating the intrinsic mechanism of the immune response such as lack of costimulatory molecules or insufficient second signal for cell activation • Suppression – inhibition of cellular activation by interaction with other cells: (Treg – CD4+, CD25+ T lymphocytes)

8. Central The site for T cells is the thymus The site for B cells is the bone marrow The mechanism – clonal deletion Peripheral The site – everywhere in the body Cells – both T and B Mechanisms – anergy, cell death, immune deviation DIVISION OF TOLERANCE

9. IMPORTANT OPPOSED TERMS • Central tolerance (self-tolerance) versus peripheral tolerance • Active tolerance vs. passive tolerance (ignorance) • T-cell tolerance vs. B-cell tolerance • Natural vs. artificial tolerance • Complete vs. incomplete tolerance

10. IMMUNOLOGICALLY PRIVILEGED SITES • Sites in the body where foreign antigens or tissue grafts do not elicit immune responses • These antigens do interact with T cells, but instead of destructive IR they induce tolerance or a response innocent to the tissue

11. IMMUNOLOGICALLY PRIVILEGED SITES - 2 • Immunosuppressive cytokines such as TGF-beta seem to be resposible for such unusual response • The sites include: brain, eye, testis, uterus (fetus)

12. IMPORTANT OPPOSED TERMS • Central tolerance (self-tolerance) versus peripheral tolerance • Active tolerance vs. passive tolerance (ignorance) • T-cell tolerance vs. B-cell tolerance • Natural vs. artificial tolerance

13. IGNORANCE OF SELF ANTIGENS • It is a passive form of immunological tolerance • It occurs when: • T cells can not contact with self – antigens, • if self antigen is present in too low an amount to be detected, • if it is present on cells with few or no MHC molecules • if there are not enough T cells to respond • if there is the absence of co-stimulation

14. FEATURES OF B-CELL TOLERANCE • Binding soluble self antigens is tolerogenic for B cells • Immature B cells that encounter self antigen undergo clonal abortion • The fate of self-reactive B cells depends on the affinity of the B cell antigen receptor and the nature of the antigen • Receptor editing - autoreactive B cells escape anergy or deletion by further rearranging their immunoglobulin genes

15. IMPORTANT OPPOSED TERMS • Central tolerance (self-tolerance) versus peripheral tolerance • Active tolerance vs. passive tolerance (ignorance) • T-cell tolerance vs. B-cell tolerance • Natural vs. artificial tolerance

16. ARTIFICIAL INDUCTION OF TOLERANCE • By chimerism in immunocompromized hosts • By antibodies to T cell receptors • By injection of soluble antigens

17. ARTIFICIAL INDUCTION OF TOLERANCE - 2 4. By oral administration of antigens 5. By clonal exhaustion via extensive clonal proliferation after repeated antigenic challenge 6. Anti-idiotypic antibody – partial result, affects B cells only

18. FUTURE APPLICATIONS OF TOLERANCE • To promote tolerance to foreign tissue grafts • To control the damaging immune responses in hypersensitivity states and autoimmune diseases

19. --{ THANK YOU }—and be tolerant to our imperfections!