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. Features of 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 1.The stage of differentiation of lymphocytes at the time of antigen confrontation 2.The site of encounter 3.The nature of cells presenting antigenic epitopes 4.The number of lymphocytes able to respond 5.Microenvironment of encounter (expression of cell adhesion molecules, influence of cytokines etc.)

6. TOLERANCE – GENERAL PROPERTIES 1.Immature or developing lymphocyte is more susceptible to tolerance induction than mature one 2.Tolerance to foreign antigens is induced even in mature lymphocytes under special conditions 3.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. DIVISION OF TOLERANCE 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

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: 1.T cells can not contact with self – antigens, 2.if self antigen is present in too low an amount to be detected, 3.if it is present on cells with few or no MHC molecules 4.if there are not enough T cells to respond 5.if there is the absence of co-stimulation

14. FEATURES OF B-CELL TOLERANCE 1.Binding soluble self antigens is tolerogenic for B cells 2.Immature B cells that encounter self antigen undergo clonal abortion 3.The fate of self-reactive B cells depends on the affinity of the B cell antigen receptor and the nature of the antigen 4.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 1.By chimerism in immunocompromized hosts 2.By antibodies to T cell receptors 3.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!