Autoimmune diseases cannot be explained by a solitary cause or mechanism. Small amounts of autoantibodies are normally produced and may have physiologic roles in cellular interactions. Positive serologic findings may be found years before the development of pathogenic autoimmunity or clinical illness, and in some cases, they represent normal immunity or “benign autoimmunity” without disease. The major theories regarding the development of autoimmune disease are (1) release of normally sequestered antigens; (2) escape from anergy or defective apoptosis (programmed cell death) leading to abnormal autoreactive cellular clones; (3) shared antigens between the host and microorganisms, ie, “molecular mimicry”; and (4) defects in helper or suppressor T cell function. A genetic susceptibility is also a likely determinant of autoimmune disease. In nearly all autoimmune diseases, multiple mechanisms of autoimmunity are operative.
Certain autoimmune diseases are mediated by T cells that have become specifically immunized to autologous tissues. Cytotoxic or killer T cells generated by this aberrant immune response injure specific organs in the absence of serum autoantibodies. Diminished suppressor T cell activity or loss of clonal anergy results in disordered regulation of immune function and consequent autoreactivity. The immune damage in systemic (non-organ-specific) diseases such as systemic lupus erythematosus may be due to such a mechanism.
Several autoimmune diseases have been shown to be caused by autoantibodies in the absence of cell-mediated autoimmunity. The autoimmune hemolytic anemias, idiopathic thrombocytopenia, and Goodpasture’s syndrome appear to be mediated solely by autoantibodies directed against autologous cell membrane constituents. In these diseases, antibody attaches to cell membranes and fixes complement; the ensuing inflammatory reaction injures the cells.
Anti-receptor antibodies that compete with or mimic physiologic agonists for cellular receptors cause several diseases. In Graves’ disease, antibodies are present that bind to thyroid cells’ TSH receptors and thereby stimulate thyroid hormone production. In rare instances of type 1 diabetes mellitus, anti-insulin receptor antibodies cause insulin resistance in peripheral target tissues. Antibodies to acetylcholine receptors of the myoneural junction in myasthenia gravis block neuromuscular transmission and produce muscle weakness.
Immune Complex Disease
In this group of diseases (systemic lupus erythematosus, lupus nephritis, rheumatoid arthritis, some drug-induced hemolytic anemias, and thrombocytopenias), autologous tissues are injured as “innocent bystanders.” Autoantibodies are not directed against cellular components of the target organ but rather against autologous or heterologous antigens in the serum. The resultant antigen-antibody complexes bind nonspecifically to autologous membranes (eg, glomerular basement membrane) and fix complement. Fixation and subsequent activation of complement components produce a local inflammatory response resulting in tissue injury.
Revision date: June 20, 2011
Last revised: by Janet A. Staessen, MD, PhD