AUTOIMMUNITY

Erwin Taher

DEFINISI
Autoimmune diseases result from the breakdown of immune tolerance to selfantigens. The loss of self-tolerance may result from one or more of several mechanisms, including the lack of elimination of self-reactive clones, the activation of anergic self-reactive cells, and the release of sequestered self-antigens that are normally inaccessible to the immune system, including the genetic constitution of the host and infection with certain microorganisms.

KLASIFIKASI
Autoimmune diseases are classified either as organ specific or as systemic (i.e., non-organ specific) on the basis of the primary location of the injury.

Targets of Antibodies in Selected Autoimmune Diseases

Disease Mixed connective tissue Disease Polymyositis Rheumatic fever Rheumatoid arthritis Scleroderma Systemic lupus Erythematosus Goodpastures syndrome Wegeners granulomatosis Sjgrens syndrome Target of Antibody Nuclear ribonucleoproteins Nuclei, Jo-1, PL-7, histadyl-tRNA synthetase, threonyl-tRNA synthetase, PM-1, Mi-2 Myocardium, heart valves, Choroid plexus g-Globulin, Epstein-Barr virusrelated antigens, types II and III collagen Nuclei, Scl-70, SS-A (Ro), SS-B (La), centromere DNA, ribonucleoproteins, histones, nuclear antigens Basement membranes Neutrophils g-Globulin, SS-A (Ro), SS-B (La)

Disease Addisons disease Graves disease

Hashimotos thyroiditis

Target of Antibody Adrenal cells Thyroid-stimulating hormone (TSH) receptor Thyroglobulin, TSH receptor Interstitial cells, corpus luteum Cells Sperm cells
b2-adrenergic receptors Basement membrane zone of skin and mucosa Intercellular substance of skin and mucosa Erythrocytes Platelets

Premature ovarian failure

Spontaneous infertility Allergic rhinitis, asthma, and autoimmune abnormalities Bullous pemphigoid Pemphigus

Autoimmune hemolytic Anemia Idiopathic thrombocytopenic purpura

PATHOGENESIS OF TISSUE INJURY

1. circulating autoantibodies react with modified or unmodified antigens on cell surfaces. The bound antibodies then stimulate the release of mediators of inflammation, trigger the complement pathway, or activate cytotoxic cells of the immune system that have receptors for the Fc portion of IgG, such as macrophages and a subpopulation of large granular lymphocytes known as K cells. The last two processes mentioned lead to cell lysis.

2. complexes between autoantibodies and antigens form in the circulation or in intercellular fluids. These immune complexes then deposit in various tissues, including glomeruli, joints, and blood vessels; they subsequently fix compl ement and cause inflammation and tissue injury. The site of deposition is determined by the physical properties of the immune complex, such as its size and charge.

3. sensitized T cells either injure cells directly or release lymphokines that amplify the inflammatory response (e.g., by augmenting the influx of other inflammatory cells). Although tissue injury caused by cell-mediated mechanisms may be important in autoimmune disease, its role is currently unclear.

Mechanisms of Autoimmunity
Autoimmune diseases result from abnormalities in lymphocyte function. Abnormalities in T cell function can be responsible for disease through cell-mediated immunity and through the activity of helper T cells to stimulate autoantibody formation. There are several possible mechanisms for autoimmunity, stemming from failure of one or more steps in the maintenance of tolerance .

Tolerance Tolerance is defined as a state of immunologic unresponsiveness to antigens. Recognition of antigens takes place on specific receptors on T and B cells of the immune system. These encounters result in either inhibition or activation of lymphocytes, depending on several conditions at the time of encounter. Tolerance may be acquired to foreign antigens; self-tolerance is a special form that applies to self-antigens.

MECHANISMS OF TOLERANCE Tolerance is a consequence of one of two effects on T and B cells: (1) clonal deletion, in which encounters with antigens result in the elimination or programmed cell death (apoptosis) of specific lymphocytes, or (2) clonal anergy, in which the lymphocytes are not killed but are rendered unresponsive to a specific antigen.

FAILURE OF CENTRAL TOLERANCE

The elimination of self-reactive T cells in the thymus is a major mechanism for self-tolerance, and failure of this negative selection may allow self-reactive T cells to survive.

FAILURE OF PERIPHERAL TOLERANCE

Activation of Self-Antigen-Specific T Cells One mechanism for peripheral tolerance is the presentation of self-antigen by APCs lacking costimulators such as B7. Under some conditions (e.g., inflammation), APCs may become activated to express costimulators, thereby providing the conditions necessary for activation of self-antigen-specific T cells.

Antigenic Epitopes

Complex antigens may present two or more antigenic epitopes to the immune system. In an example of self-tolerance (a), a self-antigen presents its two self-epitopes to a specific B cell. The B cell is potentially reactive and recognizes one of the epitopes, but tolerance is maintained because the processed antigen fails to elicit T cell help (T cells recognizing the self-antigen have been either deleted or rendered anergic). In an example of molecular mimicry, a hypothetical mechanism for autoimmunity (b), one of two epitopes presented by a foreign antigen to a B cell mimics a self-epitope because of an amino acid sequence identical to an amino acid sequence of the specific self-antigen. The second, foreign epitope is processed by the B cell and presented to a helper T cell that recognizes the processed foreign antigen. The activated T cell then stimulates the B cell to produce antibodies to the self-epitope.

THE ROLE OF AUTOANTIBODIES

Although autoantibodies are frequently present in autoimmune diseases, it may be difficult to establish that these antibodies contribute significantly to the pathogenesis of autoimmune diseases.

Autoantibodies to Cell Surface Molecules Pemphigus is a bullous skin disease related to acantholysis, or loss of epidermal cell adhesion associated with antibodies to desmosomes (epidermal cell surface molecules involved in intercellular adhesion). patients with myasthenia gravis have autoantibodies to acetylcholine receptors (ACRs) on skeletal muscle

Autoimmune disease of the thyroid is associated with antibodies directed toward three antigens: microsomal thyroid peroxidase, thyroglobulin, and the thyroid receptor for thyroid-stimulating hormone (TSH).

Neuromuscular Junction

At a normal neuromuscular junction, synaptic vesicles release acetylcholine when the nerve cell is stimulated. Acetylcholine crosses the synaptic cleft and binds to the acetylcholine receptor (ACR), which leads to contraction of the muscle. Patients with myasthenia gravis produce autoantibodies against the ACR, which reduces the number of receptors present on the muscle cell membrane and leads to muscle weakness and, sometimes, death.

 Autoantibodies to Extracellular Molecules The antiphospholipid syndrome (APS) consists of recurrent thrombosis, fetal loss, thrombocytopenia in association with antibodies to cardiolipin or other negatively charged phospholipids, and abnormalities of certain clotting tests, referred to as the lupus anticoagulant -APS is either primary, in the absence of associated disease, or secondary, usually with SLE or its variants.

Autoantibodies to Intracellular Molecules Autoantibodies may react with intracellular proteins that also appear on cell surfaces or in extracellular locations. Antibodies to ribosomal P proteins occur in SLE and are commonly seen in patients with depression or psychosis. It is intriguing that th ese antibodies also react with a protein on cell surfaces that is similar in size to its ribosomal protein antigen. It is unclear yet whether the cell surface protein is the ribosomal protein that has been transported to the cell surface or is another, similar protein.

-Nevertheless, the presence of the antigen on the cell surface suggests that antibodies to ribosomal P proteins may contribute to the neurologic manifestations of SLE. Antibodies to the small nucleoprotein antigen SS-A, which is also called Ro, and to SS-B, or La, are found in patients with SLE and Sjogren's syndrome, as well as in neonatal lupus and congenital heart block.