Autoimmunity AUTOIMMUNITY • Condition in which the body’s own immunologically competent cells or antibodies act against its self-antigens resulting in structural or functional damage. • Paul Ehrlich had first introduced the concept of autoimmunity; he termed this condition as “horror autotoxicus”. AUTOIMMUNITY • Normally immune system does not react to its own antigens due to a protective mechanism called tolerance. • Any breach in tolerance mechanisms predispose to several autoimmune diseases. IMMUNOLOGICAL TOLERANCE • State in which an individual is incapable of developing an immune response against his own tissue antigens. • Mediated by two broad mechanisms: o Central tolerance o Peripheral tolerance. Central tolerance • Refers to the deletion of self-reactive T and B lymphocytes during their maturation in central lymphoid organs (i.e., in the thymus for T cells and in the bone marrow for B cells). • In thymus: o During the T cell development in thymus  any self-antigens are encountered  processed and presented by thymic antigen presenting cells (APCs) in association with self-MHC. o Any developing T cell that expresses a receptor for such selfantigen is negatively selected (i.e. deleted by apoptosis). Central tolerance • In bone marrow: Self antigens are eliminated by o Receptor editing - process by which many of the B cells reactivate the machinery of antigen receptor gene rearrangement (mainly genes coding for light chains), so that a different (edited) B cell receptor will be produced which no longer recognizes the self-antigen. o Negative selection- If receptor editing fails, they undergo apoptosis. Peripheral tolerance • Back-up mechanisms that occur in the peripheral tissues to counteract the self-reactive T cells that escape central tolerance. Peripheral tolerance - Mechanisms • Ignorance- Self-reactive T cells might never encounter the self-antigen which they recognize. • Anergy: o Defined as unresponsiveness to antigenic stimulus. o The self-reactive T cells interact with the APCs presenting the self antigen, but the costimulatory signal is blocked. o The B7 molecules on APC bind to CTLA-4 molecules on T cells instead of CD28 molecules. Peripheral tolerance • Phenotypic skewing: o Self-reactive T cells interacting with APCs presented with self-antigens, undergo full activation. o Secrete non-pathogenic cytokines and chemokine receptors profile. Peripheral tolerance • Apoptosis by AICD: o Activation-induced cell death o Activation of T cells induces upregulation of Fas ligand which subsequently interacts with the death receptor Fas leading to apoptosis. Peripheral tolerance • Regulatory T cells (Treg cells): o Treg cells can down regulate the self-reactive T cells through secreting certain cytokines (e.g., IL-10 and transforming growth factor β [TGF-β]) or killing by direct cell to cell contact. • Dendritic cells (DCs): o Immature DCs and tolerogenic DCs capture the self-antigen for processing. o Down regulate the expression of molecules of co-stimulatory ligands such as CD40 and B7 molecules or act indirectly by induction of regulatory T cells. • Sequestration of self-antigen: Certain self-antigens can evade immune recognition by sequestration in immunologically privileged sites, e.g. corneal proteins, testicular antigens and antigens from brain. MECHANISMS OF AUTOIMMUNITY • Breakdown of T-Cell Anergy: In the presence of tissue necrosis and local inflammation express co-stimulatory molecules (B7) . o Multiple sclerosis, rheumatoid arthritis and psoriasis • Failure of AICD- Failure of the auto reactive activated T cells to undergo activation induced cell death (AICD) o SLE (systemic lupus erythematosus) MECHANISMS OF AUTOIMMUNITY • Loss of Treg cells. • Providing T cell help to stimulate self-reacting B cells: o Antibody response to self-antigens occurs only when potentially self-reactive B cells receive help from T cells. MECHANISMS OF AUTOIMMUNITY • Release of Sequestered Antigens: o Sequestered antigens -never been exposed to the tolerance mechanisms during development of immune system. o Injury to the organs leads to release of such sequestered antigens which are very well capable of mounting an immune response. o Spermatozoa and ocular antigens release can cause post vasectomy orchitis and post-traumatic uveitis. MECHANISMS OF AUTOIMMUNITY • Molecular Mimicry: o Some microorganisms share antigenic determinants (epitopes) with self-antigens. o Immune response against such microbes would produce antibodies that can cross-react with self-antigen. o Example: Acute rheumatic fever and multiple sclerosis (molecular mimicry involving T-cell epitopes). MECHANISMS OF AUTOIMMUNITY • Polyclonal Lymphocyte Activation o Polyclonal T cell activation - Superantigens released from microbes (e.g. Staphylococcus aureus), polyclonally activate the T cells directly by binding to antigen non-specific Vβ region of T cell receptors. o Polyclonal B cell activation can be induced by products of various microbes such as Epstein Barr virus, HIV, etc. MECHANISMS OF AUTOIMMUNITY • Bystander activation: o Nonspecific activation of bystander self-reactive TH1 cells. o Leads to cytokine influx which causes an increased infiltration of various non-specific T cells at the site of infection. AUTOIMMUNE DISEASES Disease Autoimmune anemias Autoimmune hemolytic anemia Drug induced hemolytic anemia Pernicious anemia Idiopathic Thrombocytopenic Purpura Single Organ or Cell Type Autoimmune Diseases Self-antigen present on Type of immune response & Important features RBC membrane proteins Auto-antibodies to RBC antigens triggers complement mediated lysis or antibody-mediated opsonization of the RBCs Drugs alter the red cell membrane Drugs such as penicillin or methyldopa interact antigens with RBCs so that the cells become antigenic Intrinsic factor (a membrane-bound Auto-antibodies to intrinsic factor block the protein on gastric parietal cells) uptake of vitamin B 12; leads to megaloblastic anemia Platelet membrane proteins Auto-antibodies against platelet membrane (glycoproteins IIb-IIIa or Ib-IX) antigens leads to ↓platelet count AUTOIMMUNE DISEASES Disease Goodpasture syndrome Single Organ or Cell Type Autoimmune Diseases Self-antigen present Type of immune response & Important features on Auto-antibodies bind to basement-membrane antigens on kidney Renal and lung basement glomeruli and the alveoli of the membranes lungs followed by complement mediated injury leads to progressive kidney damage and pulmonary haemorrhage Myasthenia gravis Acetylcholine receptors Blocking type of auto-antibody directed against Ach receptors present on motor nerve endings, leads to progressive weakening of the skeletal muscles Graves’ disease Thyroid-stimulating hormone (TSH) receptor Anti TSH- auto-antibody (stimulates thyroid follicles, leads to hyperthyroid state) AUTOIMMUNE DISEASES Disease Self-antigen present Type of immune response & Important features on Hashimoto’s thyroiditis Thyroid proteins and Auto-antibodies and TDTH cells targeted against thyroid antigen cells leads to suppression of thyroid gland. • Seen in middle aged females • Hypothyroid state is produced (↓ production of thyroid hormones) Post-streptococcal Kidney Streptococcal antigen- antibody complexes are deposited on glomerulonephritis glomerular basement membrane Insulin-dependent Beta cells present in TDTH cells and auto-antibodies directed against pancreatic beta diabetes mellitus islets of Langerhans cells cause ↓ production of insulin of pancreas AUTOIMMUNE DISEASES Disease Systemic lupus erythematosus Single Organ or Cell Type Autoimmune Diseases Systemic Autoimmune Diseases Self-antigen present on Type of immune response & Important features Auto-antibodies are produced • Age & sex- Women (20-40 years of age) are against various tissue antigens commonly affected; female to male ratio is-10:1. such as DNA, nuclear protein, • Immune complexes (self Ag- auto Ab) are RBC and platelet membranes. formed; which are deposited in various organs • Major symptoms- Fever, butterfly rash over the cheeks, arthritis, pleurisy, and kidney dysfunction AUTOIMMUNE DISEASES Disease Rheumatoid arthritis Single Organ or Cell Type Autoimmune Diseases Systemic Autoimmune Diseases Self-antigen present on Type of immune response & Important features Here, a group of auto-antibodies • Age & sex- Women (40-60 years of age) affected against the host IgG antibodies • Auto-antibodies bind to circulating IgG, forming are produced called RA factor. It IgM-IgG complexes that are deposited in the is an IgM antibody directed joints and can activate the complement cascade. against the Fc region of IgG. • Major symptomsACPA (Anti citrullinated peptide Main feature-Arthritis (chronic inflammation of the antibodies) are also produced joints, begins at synovium; most common joints involved are-small joints of the hands, feet and cervical spine) Other features-hematologic, cardiovascular, and respiratory systems are also frequently affected AUTOIMMUNE DISEASES Single Organ or Cell Type Autoimmune Diseases Systemic Autoimmune Diseases Disease Self-antigen present on Type of immune response & Important features Sjögren syndrome Ribonucleoprotein (RNP) antigens SS-A (Ro) and SS-B (La) present on salivary gland, lacrimal gland, liver, kidney, thyroid Auto-antibodies to the RNP antigens SS-A (Ro) and SS-B (La); leads to immune-mediated destruction of the lacrimal and salivary glands resulting in dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia) AUTOIMMUNE DISEASES Disease Scleroderma (Systemic Sclerosis) Single Organ or Cell Type Autoimmune Diseases Systemic Autoimmune Diseases Self-antigen present on Type of immune response & Important features Nuclear antigens such as DNA Helper T cell (mainly) and auto-antibody mediated. topoisomerase and centromere Excessive fibrosis of the skin, throughout the body Two typespresent in heart, lungs, GIT, 1.Diffuse scleroderma- Auto-antibodies against kidney, etc DNA topoisomerase I (anti-Scl 70) is elevated 2.Limited scleroderma- ↑Anticentromere antibody, characterized by CREST syndrome-calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia AUTOIMMUNE DISEASES Disease Seronegative Spondyloarthropathies Single Organ or Cell Type Autoimmune Diseases Systemic Autoimmune Diseases Self-antigen present on Type of immune response & Important features Common characteristics- They present as rheumatoid Sacroiliac joints & other arthritis like features, but differ from it byvertebrae • Association with HLA-B27 Several types• Pathologic changes begin in the ligamentous • Ankylosing spondylitis attachments to the bone rather than in the • Reiter Syndrome synovium • Psoriatic Arthritis • Involvement of the sacroiliac joints, and/or • Spondylitis With arthritis in other peripheral joints Inflammatory Bowel Disease • Absence of RFs (hence the name "seronegative") • Reactive arthritis • Auto-Ab and immune complex mediated AUTOIMMUNE DISEASES Single Organ or Cell Type Autoimmune Diseases Systemic Autoimmune Diseases Disease Self-antigen present on Type of immune response & Important features Multiple sclerosis Brain (white matter) Self-reactive T cells produce characteristic inflammatory lesions in brain that destroys the myelin sheath of nerve fibers; leads to numerous neurologic dysfunctions LABORATORY DIAGNOSIS OF AUTOIMMUNE DISEASES Autoimmune diseases Autoimmune hemolytic anemias Goodpasture syndrome Laboratory diagnosis oCoombs test - red cells are incubated with an anti– human IgG antiserum  IgG auto-antibodies are present on the red cells, the cells are agglutinated by the antiserum Biopsies from patients are stained with fluorescent-labeled anti-IgG and anti-C3b reveal linear deposits of IgG and C3b along the basement membranes. LABORATORY DIAGNOSIS OF AUTOIMMUNE DISEASES Autoimmune diseases Laboratory diagnosis SLE (Systemic lupus erythematosus) Detection of autoantibodies by indirect immunofluorescence assay (most widely used) and ELISA based techniques. • ANA (antinuclear antibody)- Positive in >90% cases (screening test). • Anti-double stranded DNA (dsDNA)-Highly specific (Confirmation). • Anti-Sm antibodies Lupus band test- Direct immunofluorescence test - detect deposits of immunoglobulins and complement proteins in the patient's skin. LE cell test- No longer used because the LE cells are only found in 50– 75% of SLE cases. LABORATORY DIAGNOSIS OF AUTOIMMUNE DISEASES Autoimmune diseases Laboratory diagnosis Scleroderma Anti-Scl 70 antibody is raised, detected by indirect immunofluorescence assay Sjögren’s syndrome Detection of SS-A (or anti-Ro) and SS-B (or anti-La) antibodies by indirect immunofluorescence assay. LABORATORY DIAGNOSIS OF AUTOIMMUNE DISEASES Autoimmune diseases Laboratory diagnosis Rheumatoid arthritis RA factor (by latex agglutination test)- RA factor is an IgM autoantibody directed against Fc portion of IgG, good sensitivity. False positive - seen in other autoimmune diseases. ACPA (Anti-citrullinated peptide antibodies) is an auto-antibody to citrullin protein. It is positive only in 67% of cases; but is highly specific. Rose-Waaler test to detect RA factor is of historical importance, no longer used now.