Immunological Tolerance and Autoimmune Diseases

Immunological Tolerance a state of specific immunological unresponsiveness to a particular antigen in a fully immunocompetent person - Immunogen - tolerogen

Immunological Tolerance Types of tolerance: Naturally acquired (Neonatal, self ,auto tolerance) Tolerance to self is initially induced during embryonic life, and is maintained by antigen , continues to occur at some level throughout life (as new lymphocytes are produced from bone marrow stem cells) Specifically Induced

Induced Tolerance Low Zone Tolerance High Zone Tolerance Therapeutic Inducing tolerance may be exploited to prevent graft rejection, treat autoimmune and allergic diseases -T cells becomes tolerance quicker & last longer than B cells -The simpler the Ag gets Better Tolerance because has less epitopes Can be achieved by Low Zone Tolerance High Zone Tolerance

Mechanisms of Immunological Tolerance - Overview Central Tolerance through Clonal Deletion Clones of cells that have receptors for self-antigens are deleted during development Peripheral tolerance

Peripheral Tolerance 1- Immunological ignorance to some self antigens (anatomical barrier) 2- T-cell anergy a- signal block: failure of APC to deliver a second signal during antigen presentation (example: B7-CD28 interaction) b- engagement of inhibitory receptors (CTLA-4)

Peripheral Tolerance 3- Suppression of responses by regulatory T- cells (CD4+ CD25+) : secretion of immunosuppressive cytokines (IL-10 & TGF-B) 4- Deletion (activation-induced cell death): T- cell apoptosis by engagement of death receptors (Fas-Fas L)

Central Tolerance

Foreign Ag + second signal Central Tolerance DEVELOPMENT MATURITY Clonal Deletion Anti-self Lymphocyte Self Ag Activation Differentiation Anti-non-self Lymphocyte Foreign Ag + second signal

Peripheral tolerance Normal T cell response Anergy Apoptosis APC CD28 Normal T cell response Activated T cells TCR APC Functional unresponsiveness Anergy Off signals TCR Activated T cell APC Apoptosis (activation-induced cell death) Deletion APC Suppression Block in activation Regulatory T cell

Pathways to Peripheral Tolerance

Pathways to Peripheral Tolerance Activated T cells Normal Response CD28 B7 Proliferation & differentiation Antigen Recognition without co-stimulation Anergy CTLA4 B7 Functionally Unresponsive CTL4-B7 interaction Fas Activation induced cell death Fas-FasL interaction Adapted From:   Van Parijs: Science, Volume 280(5361).April 10, 1998.243-248 Apoptosis FasL Inhibition of proliferation & effector action Cytokine-mediated suppression Cytokine regulation cytokines

Properties of regulatory T cells Th 3 (T reg) Phenotype: CD4, high IL-2 receptor (CD25), low IL-7 receptor, other markers Mechanisms of action: multiple secretion of immune-suppressive cytokines (TGF, IL-10, ), inactivation of dendritic cells or responding lymphocytes

Functionally Unresponsive T cell Regulatory T cells Production of IL-10 or TGF-b Functionally Unresponsive T cell Regulatory T cell

The Two Signal Hypothesis for T-cell Activation Mature Dendritic cell APC Activated TH cell TH cell MHC II TCR CD28 B7 Signal 2

Hypothetical mechanism of tolerance in mature T cells Signal 1 CD28 Resting B-cell APC TH0 cell Tolerant T cell Tolerance (anergy or apoptosis) from lack of signal 2

Functionally Unresponsive (Anergic) T cell Regulation by CTLA-4 CTLA4 CTLA4-B7 interaction Functionally Unresponsive (Anergic) T cell B7 Activated T cell

Summary: Lack of co-stimulation can lead to tolerance (anergy) Activated T cells CD28 B7 Proliferation & differentiation Normal Response Antigen Recognition without co-stimulation Anergy

Tolerance: Establishment and Failure Generation of immune repertoires Bone Marrow Thymus  Central Tolerance  Self-reactive lymphocytes Deleted by negative selection   Leakage of self-reactive lymphocytes controlled Peripheral Tolerance Wrong environment (viral infection?) Wrong genes or mutations Tolerance fails Autoimmune Diseases

Autoimmune Diseases Immune reaction against self-antigen which present in own tissues, they are characterized by tissue damage, disturbed physiological function, chronicity & usually non reversible Affect female > male Usually started at 20-40 years of age

Autoimmune Diseases Predisposing Factors: 1- Advancing age 2- Hormonal factors (more common in females) 3- Genetic predisposition 4- Environmental factors (infection, drugs, U.V light, psychological stress, dietary factors)

Mechanisms of Autoimmune Disease (Loss of self-tolerance) 1- Emergence of sequestered antigens (e.g., eye, brain ,thyroid , sperm ) 2- Molecular mimicry Microbes share epitopes with self-antigens Ex. Streptococci and rheumatic heart disease 3- Polyclonal lymphocyte activation (Endotoxin, EBV , AIDS , CMV)

4- Alteration of normal proteins Procainamide induces SLE 5- Inappropriate expression of class II MHC molecules Normally only on APC s After viral infection or trauma the released gamma IFN leads to expressing class II MHC molecules on some cells like Pancreatic beta cells ---IDDM or thyroid cells 6- Genetic predisposing (association with MHC gene) Ankylosing spondylitis (HLA- B27) SLE DR- 2,3 IDDM DR- 3,4

7-Cytokine dysregulation &Break down (FAILURE) of suppressor mechanisms 8-Thymus defect (Increasing with age) 9-Hormonal factor ( more in females)

Pathogenesis of autoimmunity Environmental trigger (e.g. infections, chemicals tissue injury) Susceptibility genes Failure of self-tolerance Activation of self-reactive lymphocytes Persistence of functional self-reactive lymphocytes Immune responses against self tissues

-Clinical types of auto immune diseases Organ specific Graves’ disease Myasthenia gravis Systemic SLE -Ab non specific but organ specific as primary biliary cirrhosis -Multiple autoimmune diseases can be occurred in the same patient

Tissue Damage in Autoimmune diseases can be classified like hypersensitivities Type II — Antibodies react with cell-surface antigens in specific organs Ex. auto-immune Hemolytic anemia Type III (Immune Complex) — IgM and/or IgG react with soluble cell material, complexes are deposited, initiate complement activation, inflammation Ex. SLE Type IV — Mediated by cytotoxic & CD4 + T cells Ex. MS 27

Type II autoimmune disease: Graves’ disease Stimulating auto-antibodies against growth receptors on thyroid gland Cross reactive autoantigens in the eyes Patients develop goiter, bulging staring eyes 28

Systemic Lupus Erythematosus Incidence 1:2500 Female: male 10:1 2nd/3rd decade of life Skin, kidney, serosal membranes, joints, heart Many autoantibodies Failure to maintain self-tolerance

Anti-Nuclear Antibodies (ANA) Abs to DNA Abs to histone Abs to non-histone proteins bound to RNA Abs to nucleolar antigens

Systemic Lupus Erythematosus Genetic factors 30% concordance in monozygotic twins Increased risk in family members HLA-DQ & DR locus and SLE association Non-Genetic factors Drugs: procainamide, hydralazine Sex hormones (estrogens>androgens)\ UV light

Type III autoimmune disease: systemic lupus erythematosus Auto-antibodies against nuclear components RBC, Platelets, clotting factors Immune complexes activate complement Excess complexes are deposited in small blood vessels Local inflammation in skin, joints and kidneys, multi-organ damage 32