Slide 1: FE A. BARTOLOME, MD, FPASMAP Department of Microbiology Our Lady of Fatima University
Slide 2: IMMUNOLOGICAL TOLERANCE
• State in which the individual is incapable of developing an immune response to a specific antigen • Self-tolerance lack of responsiveness to an individual’s antigens • Central tolerance & peripheral tolerance
Slide 3: CENTRAL TOLERANCE
• Clonal deletion of self-reactive T and B lymphocytes during their maturation in the central lymphoid organs
Slide 4: CENTRAL TOLERANCE
T cells • T lymphocytes that bear high-affinity receptors for self-antigens are negatively selected or deleted undergo apoptosis • occur during fetal development
Slide 5: CENTRAL TOLERANCE
B cells • Also undergo clonal deletion • Developing B cells encounter a membrane-bound antigen within the bone marrow B cells undergo apoptosis • Occur throughout life
Slide 6: PERIPHERAL TOLERANCE
• Self-reactive T cells that escape intrathymic negative selection are deleted or muzzled in the peripheral tissues
Slide 7: PERIPHERAL TOLERANCE
MECHANISMS: 1. Clonal deletion by activation-induced cell death 2. Clonal anergy 3. Peripheral suppression by T cells
Slide 8: PERIPHERAL TOLERANCE
Clonal deletion by activation-induced cell death • Apoptotic death of activated T cells by the Fas-FasL system • Self-antigens abundant in peripheral tissue (e.g. collagen, thyroglobulin) repeated & persistent stimulation of self-antigen-specific T cells activation of Fas-mediated apoptosis
Slide 9: Clonal deletion in thymus
Antigen
A Cell death
A
A
B
Two immature T cells (A and B) with different antigen receptors
B
Binding of self antigen to T-cell A in thymus but not to T-cell B
B
Death of self-reacting Tcell A; survival of T-cell B that reacts against foreign antigen
Slide 11: PERIPHERAL TOLERANCE
Clonal anergy
• Prolonged or irreversible functional inactivation of lymphocytes • Induced by encounter with antigens • T cells – due to absence of co-stimulatory molecules on APCs, such as B7-1 & B7-2 • B cells – due to lack of T cell help for antibody synthesis (T cell anergy or downregulation of surface IgM)
Slide 12: PERIPHERAL TOLERANCE
Antigen
Class II MHC TCR
Antigen
Class II MHC TCR
APC
B7 protein CD28 protein
Helper T cell
APC
CD28 protein CD4 protein
Helper T cell
CD4 protein
B7 protein on APC interacts with CD28 on helper T cells. Full activation of helper T cells occur.
B7 protein on APC is not produced. CD28 on helper T cell does not give a costimulatory signal. Anergy occurs.
Slide 14: PERIPHERAL TOLERANCE
Peripheral suppression by T cells • Suppressor T cells – with ability to down-regulate the function of other autoreactive T cells • Shift immune response from TH1 to TH2 • TH2 generally immunosuppressive down-modulate TH1 response
Slide 16: Factors Affecting ArtificiallyInduced Tolerance 1. Form, dose & route of administration
• Very simple molecules induce tolerance more readily than a complex one • Very high or very low doses of an antigen may result in tolerance instead of an immune response • Purified polysaccharides or amino acid copolymers injected in very large doses result in “immune paralysis”
Slide 17: Factors Affecting ArtificiallyInduced Tolerance 1. Immunologic “maturity” of the host
• E.g. neonates immunologically immature do not respond well to foreign antigens
2. Chimerism
• Tolerance induced by inoculation of allogeneic cells into hosts that lack immune competence
3. Antibodies to CD4 and CD8
• Tolerance of transplanted tissues by inoculating graft recipient with monoclonal antibodies against CD4 and CD8
Slide 18: Factors Affecting ArtificiallyInduced Tolerance
1. Clonal exhaustion
• Repeated antigenic challenge • Stimulate B and T cell to differentiate into short-lived end cells
Slide 19: Factors Affecting ArtificiallyInduced Tolerance
1. Clonal anergy induced by anti-idiotypic antibodies & antagonistic peptides
• Antibody combining site (idiotype) act as antigen induce formation of anti-idiotypic antibodies cross-link on B cells prevent interaction with Ag • Antagonistic peptides fit into Ag-binding site of MHC no activation of T cells
Slide 20: Other aspects of induction/maintenance of tolerance • • • • T cells become tolerant more readily and remain tolerant longer than B cells. Administration of a cross-reacting antigen tends to terminate tolerance. Administration of immunosuppressive drugs enhances tolerance. Tolerance is maintained best if the antigen to which the immune system is tolerant continues to be present.
Slide 21: AUTOIMMUNITY
• Immune reaction against self-antigens • Requirements: 1. Presence of an autoimmune reaction 2. Clinical or experimental evidence that reaction is not secondary to tissue damage but is of primary pathogenetic significance 3. Absence of another well-defined cause of the disease
Slide 22: AUTOIMMUNITY
• Most important step in production of autoimmune disease: activation of self-reactive CD4 T cells • Most are antibody-mediated
Slide 23: AUTOIMMUNITY
GENETIC FACTORS • (+) genetic predisposition • Strong association with HLA specificities, especially class II genes • Class I MHC-related: ankylosing spondylitis & Reiter’s syndrome; more common in men • Class II MHC-related: RA, Grave’s disease, SLE; more common in women
Slide 24: AUTOIMMUNITY
HORMONAL FACTORS • Approximately 90% occur in women • Estrogen can alter the B-cell repertoire and enhance formation of antibody to DNA
Slide 25: AUTOIMMUNITY
ENVIRONMENTAL FACTORS • Exposure to an environmental agent can trigger a cross-reacting immune response against some component of normal tissue • Example: S. pyogenes & rheumatic fever
Slide 26: AUTOIMMUNITY: Mechanisms
Defects in clonal deletion mechanisms • Thymic defects that lead to proliferation of self-reactive T cells • Failure of central tolerance
Slide 27: AUTOIMMUNITY: Mechanisms
Polyclonal lymphocyte activation • Microorganism-derived mitogens stimulate lymphocytes • Microbial products (e.g. LPS) act as superantigens activate a large pool of T and B cells
Slide 28: AUTOIMMUNITY: Mechanisms
Molecular mimicry • Microbial antigens with similar structure to self-antigens activate autoreactive T cells • Cross-reactivity-induced immune response • Example: M protein of S. pyogenes and myosin of cardiac muscle
Slide 29: AUTOIMMUNITY: Mechanisms
Release of sequestered antigens • Immunologically privileged sites (brain, ant. eye chamber, ovary, placenta, testis, pregnant uterus) not exposed to immune system • Damage release of antigens elicit immune response
Slide 30: AUTOIMMUNITY: Mechanisms
Defects in the regulation of TH1 and TH2 cells • Impaired T suppressor cell immunoregulation
Slide 31: Microbial infections associated with autoimmune diseases
Microbe
BACTERIA Streptococcus pyogenes Campylobacter jejuni Escherichia coli Chlamydia trachomatis Shigella sp. Yersinia enterocolitica Borrelia burgdorferi VIRUSES Hepatitis B virus Hepatitis C virus Measles virus Cytomegalovirus
Autoimmune disease
Rheumatic fever Guillain-Barre syndrome Primary biliary cirrhosis Reiter’s syndrome Reiter’s syndrome Grave’s disease Lyme arthritis Multiple sclerosis Mixed cryoglobulinemia Allergic encephalitis Scleroderma
Slide 32: ORGAN-SPECIFIC AUTOIMMUNE DISEASES
Type of Immune Response Antibody to receptors Antibody to cell components other than receptors Autoimmune Disease Myasthenia gravis Grave’s disease Pernicious anemia Goodpasture’s synd. IDDM Addison’s disease Male infertility Pemphigus Hashimoto’s Primary myxedema Target of Immune Response Acetylcholine receptor TSH receptor Intrinsic factor and parietal cells BM of kidney & lung Islet cell Adrenal cortex Sperm Desmoglein in tight junctions of skin Thyroglobulin Thyroid peroxidase
Slide 33: NON-ORGAN SPECIFIC AUTOIMMUNE DISEASES
Type of Immune Response Antibody to cell components other than receptors
Autoimmune Disease Rheumatoid arthritis SLE Sjogren’s syndrome (Sicca syndrome) Guillain-Barre synd.
Target of Immune Response IgG in joints dsDNA, histones RNP antigens (SSA/Ro and SS-B/La) Myelin protein
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