دكتر وجگاني گروه ايمونولو‍‍ژي دانشگاه علوم پزشكي تهران بسم الله الرحمن الرحيم Autoimmunity دكتر وجگاني گروه ايمونولو‍‍ژي دانشگاه علوم پزشكي تهران

Autoimmunity Origins Horror autotoxicus: the horror of self-toxicity. A term coined by the German immunologist Paul Ehrlich (1900) to describe the body's innate aversion to immunological self-destruction.

Immunity against self antigens (autoantigens) is called autoimmunity Autoimmunity results from a “loss of self tolerance” Approximately 3–4% of the population in industrialized countries suffers from autoimmune diseases

Autoimmunity Lack of immune unresponsiveness to an individual’s own tissue antigens

Examples of Autoimmune Diseases Multiple sclerosis Myasthenia gravis Crohn’s disease Grave’s disease Type 1 Diabetes mellitus Rheumatoid arthritis Psoriasis Scleroderma Systemic lupus erythematosus

Lupus “Butterfly Rash” Acute and chronic inflammation of various tissues of the body

Multiple sclerosis Myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination

Multiple Sclerosis

Rheumatoid Artheritis

Self -Tolerance

Peripheral T Cell Tolerance THYMUS Escape from Clonal Deletion Autoreactive T cell (Naïve) Suppression by Regulatory T Cells Repeated stimulation MHC/Ag No Costim. Antigen Sequestered Clonal Ignorance AICD Clonal Anergy Escape from peripheral tolerance Autoimmunity

What Causes Autoimmunity?

Mechanisms proposed for induction of Autoimmunity Release of “sequestered antigens”

sympathetic ophthalmia

is sequestered in the CNS Transgenic Mouse TCR specific to Myelin Basic protein (MBP) T cells carry the autoreactive TCR Brain autoantigen, MBP is sequestered in the CNS Inject MBP With adjuvant No Autoimmune Disease Activation of Autoreactive T Cells Immunological Ignorance Migrate to tissues Including CNS Encephalitis and Death Activated T cells cross BBB and cause CNS disease

Mechanisms proposed for induction of Autoimmunity Release of “sequestered antigens” Abnormal immunoregulation

Immuno-regulatory T cells

Autoimmunity: a question of balance Activating signals MHC-II peptide Cytokines (IFN-g) CD40/CD40L CD28/CD80,86 Downregulating signals Cytokines (IL-10,TGFβ) CD80,86/CTLA-4

Importance of T regulatory? Genetic mutations in Foxp3 in humans leads to development of a severe and rapidly fatal autoimmune disorder known as Immune dysregulation, Polyendocrinopathy, Enteropathy,X-linked (IPEX) syndrome. Foxp3 mutations lead to massive Lymphoproliferation, Diabetes, Dermatitis, Thyroiditis

Mechanisms proposed for induction of Autoimmunity Release of “sequestered antigens” Abnormal immunoregulation Bypass of helper T-cell tolerance

Bypass of helper T-Cell Tolerance 1) Modification of antigen (via drugs, microorganisms) Foreign Th epitope/self B-cell epitope Me-Dopa  altered synth. of Rh Ag  AIHA Procainamide SLE over 90% of patients undergoing treatment with procainamide for 1 to 2 years mount antinuclear antibodies and 20% of them develop lupus-like symptoms

2) Cross-reacting Antigens (Molecular Mimicry) Viruses and bacteria possess antigenic determinants that are very similar, or even identical, to normal host cell components This phenomenon, known as molecular mimicry, occurs in a wide variety of organisms Molecular mimicry may be the initiating step in a variety of autoimmune diseases

3- Shared Epitopes Rheumatic fever is a classic example of molecular mimicry

4- Bystander Activation

Recruit leukocytes into the tissues 4) Bystander activation Infections of particular tissues may induce local innate immune responses Recruit leukocytes into the tissues Result in the expression of co-stimulators on tissue APCs The breakdown of T cell tolerance to self antigens Infection results in the activation of T cells that are not specific for the infectious pathogen

Mechanisms proposed for induction of Autoimmunity Release of “sequestered antigens” Abnormal immunoregulation Bypass of helper T-cell tolerance Polyclonal lymphocyte activation

Polyclonal Lymphocyte Activation Endotoxins cause such activation independent of specific antigens Super antigens? TCR (V), MHC-II Mitogens? Con A - T cell mitogen PHA - T cell mitogen PWM - T and B cell mitogen LPS, EBV - B cells mitogen

Mechanisms proposed for induction of Autoimmunity Release of “sequestered antigens” Abnormal immunoregulation Bypass of helper T-cell tolerance Polyclonal lymphocyte activation Somatic hypermutation

Mechanisms proposed for induction of Autoimmunity Release of “sequestered antigens” Abnormal immunoregulation Bypass of helper T-cell tolerance Polyclonal lymphocyte activation Genetic Defects

MHC Association with Autoimmune Disease Many autoimmune diseases show association with specific MHC genes The number of autoimmune patients carrying a HLA allele compared with the prevalence of that allele in the general population

87 times more likely to develop AS than the non-B27 Figure 13-20 87 times more likely to develop AS than the non-B27

Relative Risk? or risk ratio TOTAL No AS AS 100 30 70 HLA-B27+ 90 10 HLA-B27- RR=70/100 ÷10/100

Genes and Autoimmunity The concept that a single gene mutation leads to a single autoimmune disease is the EXCEPTION not the rule. Because of this autoimmune diseases are generally classified as complex diseases as there is not a single “pinpoint-able” gene

Exceptions to the Rule – Simple Genetic Autoimmune Illnesses Disease Gene Mechanism APS-1 (Autoimmune polyglandular syndrome type 1) AIRE Decreased expression of self-antigens in the thymus, resulting is a defect in negative selection IPEX (Immunodysregulation, polyendocrinopathy, enteropathy, X-linked) FOXP3 Decreased generation of Tregs ALPS (autoimmune lymphoproliferative syndrome ) FAS, FASL Failure of apoptotic death of self reactive T or B cells

Other Genetic Factors Genetic defects in: Signaling (TCRζ) Co-stimulatory molecules (CTLA-4) Apoptosis (Fas & FasL) Cytokines (IL-2)

Mechanisms proposed for induction of Autoimmunity Release of “sequestered antigens” Abnormal immunoregulation Bypass of helper T-cell tolerance Polyclonal lymphocyte activation Somatic hypermutation Genetic Defects Danger theory

Danger theory Proposes anti-self B & T-cells are always present AIR is due to release of “danger signals” Response to tissue damage, necrosis or cell distress, ( infection or injury) Inflammation response to danger signals are mediated by effector molecules ( cytokines)

Mechanisms proposed for induction of Autoimmunity Release of “sequestered antigens” Abnormal immunoregulation Bypass of helper T-cell tolerance Polyclonal lymphocyte activation Somatic hypermutation Genetic Factors Danger theory Hormonal status

Hypothesis: estrogen response elements (EREs) in several genes Hormones Females are much more likely to develop autoimmune illness Rise in hormones associated with pregnancy may even cause abortion of the fetus (RSA) Hypothesis: estrogen response elements (EREs) in several genes

Hormones Females are much more likely to develop autoimmune illness

Environment Pathogens, drugs, hormones, and toxins are just a few ways that the environment can trigger autoimmunity

Sex-based Differences in Autoimmunity Differences can be traced to sex hormones - hormones circulate throughout the body and alter immune response by influencing gene expression - (in general) estrogen can trigger autoimmunity - androgens (such as testosterone) and progesterone can protect against it Difference in immune response: - ♀ mount more vigorous immune responses than ♂ - ♀ have higher serum antibody concentrations, numbers of CD4+ T cells and CD4/CD8 ratios in blood

Autoimmunity Classification Can be classified into clusters that are either organ-specific or systemic

Examples of Organ Specific Lungs of a patient with Goodpasture’s Hashimoto’s disease (thyroiditis) Vitiligo

Mechanisms of Autoimmune Damage

Mechanisms of Autoimmune Damage Autoimmunity is initiated in the same way as adaptive immune responses The mechanism of tissue damage is classified by the scheme adopted for hypersensitivity reactions More than one type of hypersensitivity may be involved Tissue injury is caused by a response to self Ag (Chronic diseases) The Ag cannot be removed so the response persists Epitope spreading Progressive diseases

Figure 13-7 Epitope spreading

Autoimmune responses resemble hypersensitivity reactions Type II: Antibodies (Abs) against cell surfaces/extracellular matrix Type III: Soluble immune complexes deposited in tissues Type IV: Effector T cells

Type II Hypersensitivity Autoimmunity

Graves’ Disease

Abs against the TSH receptor mimic the natural ligand leads to chronic overproduction of T3/T4 insensitive to regulation •Results in hyperthyroidism •Individuals suffer from heat intolerance,nervousness, weight loss, outwardly bulging eyes

Myasthenia Gravis

Abs bind to the Ach receptor on muscle cells, resulting in their endocytosis and degradation Results in loss of muscle sensitivity to neuronal stimulation, progressive muscle weakness • Often characterized by droopy eyelids, double vision

Pernicious Anemia

Type III Hypersensitivity Autoimmunity

Type IV Hypersensitivity

Multiple Sclerosis MS patients can have autoantibodies and/or self reactive T cells which are responsible for the demyelination

Rheumatoid arthritis Non-suppurative proliferative synovitis which leads to descruction of articular cartilage and progressive disabling arthritis 3-5X more common in women than in men Initiated by activation of T-helper cells which produce cytokines and activate B cells to produce antibodies 80% of patients with rhematoid factors (antibodies against Fc portion of IgG) precise trigger which initates destructive immune response is not known

Systemic Lupus Erythematosus (SLE) Multisystem autoimmune disease Abs against DNA, histones, ribosomes form immune complexes with Ags released from damaged cells B-cell hyper-reactivity is a feature of SLE, caused by excess T-helper activity Affects skin, kidneys, serosal surfaces, joints, CNS and heart (deposition of Immune complex)

Insulin-dependent diabetes mellitus (IDDM) Selective destruction of insulin-producing β cells located within the islets of Langerhans by T cells Several autoantigens are recognized by both Abs and T cells, including insulin and glutamic acid decarboxylase (GAD)

Diabetes Disease in which the body does not produce or properly use insulin “ T cell” Disease T cells attack and destroy pancreatic beta cells

Susceptibility loci for autoimmune diseases