Autoimmune Diseases
Manifestations of autoimmunity are found in a large number of pathologic conditions. However, their presence does not necessarily imply that the pathologic process is an autoimmune disease. A number of attempts to establish formal criteria for the diagnosis of autoimmune diseases have been made, but none is universally accepted. One set of criteria is shown in Table 3-4; however, this should be viewed merely as a guide in consideration of the problem.
TABLE 3-4
HUMAN AUTOIMMUNE DISEASE: PRESUMPTIVE EVIDENCE FOR AN IMMUNOLOGIC PATHOGENESIS |
Major Criteria |
1. Presence of autoantibodies or evidence of cellular reactivity to self |
2. Documentation of relevant autoantibody or lymphocytic infiltrate in the pathologic lesion |
3. Demonstration that relevant autoantibody or T cells can cause tissue pathology |
a. Transplacental transmission |
b. Adaptive transfer into animals c. In vitro impact on cellular function |
Supportive Evidence |
1. Reasonable animal model |
2. Beneficial effect from immunosuppressive agents |
3. Association with other evidence of autoimmunity |
4. No evidence of infection or other obvious cause |
To classify a disease as autoimmune, it is necessary to demonstrate that the immune response to a self-antigen causes the observed pathology. Initially, the demonstration that antibodies against the affected tissue could be detected in the serum of patients suffering from various diseases was taken as evidence that these diseases had an autoimmune basis. However, such autoantibodies are also found when tissue damage is caused by trauma or infection, and the autoantibody is secondary to tissue damage. Thus, it is necessary to show that autoimmunity is pathogenic before classifying a disease as autoimmune.
If the autoantibodies are pathogenic, it may be possible to transfer disease to experimental animals by the administration of autoantibodies, with the subsequent development of pathology in the recipient similar to that seen in the patient from whom the antibodies were obtained. This has been shown, for example, in Graves’ disease. Some autoimmune diseases can be transferred from mother to fetus and are observed in the newborn babies of diseased mothers. The symptoms of the disease in the newborn usually disappear as the levels of the maternal antibody decrease. An exception is congenital heart block, in which damage to the developing conducting system of the heart as a result of transfer of antiRo antibody from the mother results in permanent heart block.
In most situations, the critical factors that determine when the development of autoimmunity results in autoimmune disease have not been delineated. The relationship of autoimmunity to the development of autoimmune disease may relate to the fine specificity of the antibodies or T cells or their specific effector capabilities. In many circumstances, a mechanistic understanding of the pathogenic potential of autoantibodies has not been established. In some autoimmune diseases, biased production of cytokines by helper T (TH) cells may play a role in pathogenesis. In this regard, T cells can differentiate into specialized effector cells that predominantly produce interferon γ (TH1) or IL-4 (TH2) (Chap. 1). The former facilitate macrophage activation and classic cell-mediated immunity, whereas the latter are thought to have regulatory functions and are involved in the resolution of normal immune responses and also the development of responses to a variety of parasites. In a number of autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, Type 1 diabetes mellitus, and Crohn’s disease, there appears to be biased differentiation of TH1 cells, with resultant organ damage.
Organ-Specific Versus Systemic Autoimmune Diseases
Autoimmune diseases form a spectrum, from those specifically affecting a single organ to systemic disorders with involvement of many organs (Table 3-5). Hashimoto’s autoimmune thyroiditis is an example of an organ-specific autoimmune disease. In this disorder, there is a specific lesion in the thyroid associated with infiltration of mononuclear cells and damage to follicular cells. Antibody to thyroid constituents can be demonstrated in nearly all cases.
TABLE 3-5
SOME AUTOIMMUNE DISEASES |
|
Organ Specific |
|
Graves’ disease |
Vitiligo |
Hashimoto’s thyroiditis |
Autoimmune hemolytic anemia |
Autoimmune polyglandular syndrome |
|
Autoimmune |
|
Type 1 diabetes mellitus |
thrombocytopenic purpura |
Insulin-resistant diabetes |
Pernicious anemia |
mellitus |
Myasthenia gravis |
Immune-mediated infertility |
Multiple sclerosis |
Autoimmune Addison’s disease |
Guillain-Barré syndrome |
Stiff-man syndrome |
|
Pemphigus vulgaris |
Acute rheumatic fever |
Pemphigus foliaceus |
Sympathetic ophthalmia |
Dermatitis herpetiformis |
Goodpasture’s syndrome |
Autoimmune alopecia |
|
Organ Nonspecific (Systemic) |
|
Systemic lupus erythematosus |
Wegener’s granulomatosis |
Antiphospholipid syndrome |
|
Rheumatoid arthritis |
Sjögren’s syndrome |
Systemic necrotizing vasculitis |
Other organ- or tissue-specific autoimmune disorders include pemphigus vulgaris, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, Goodpasture’s syndrome, myasthenia gravis, and sympathetic ophthalmia. One important feature of some organ-specific autoimmune diseases is the tendency for overlap, such that an individual with one specific syndrome is more likely to develop a second syndrome. For example, there is a high incidence of pernicious anemia in individuals with autoimmune thyroiditis. More striking is the tendency for individuals with an organ-specific autoimmune disease to develop multiple other manifestations of autoimmunity without the development of associated organ pathology. Thus, as many as 50% of individuals with pernicious anemia have non-crossreacting antibodies to thyroid constituents, whereas patients with myasthenia gravis may develop antinuclear antibodies, antithyroid antibodies, rheumatoid factor, antilymphocyte antibodies, and polyclonal hypergammaglobulinemia. Part of the explanation for this may relate to the genetic elements shared by individuals with these different diseases.
Systemic autoimmune diseases differ from organ-specific diseases in that pathologic lesions are found in multiple diverse organs and tissues. The hallmark of these conditions is the demonstration of associated relevant autoimmune manifestations that are likely to be etiologic in the organ pathology. SLE represents the prototype of these disorders because of its abundance of autoimmune manifestations.
SLE is a disease of protein manifestations that characteristically involves the kidneys, joints, skin, serosal surfaces, blood vessels, and central nervous system (Chap. 4). The disease is associated with a vast array of autoantibodies whose production appears to be a part of a generalized hyperreactivity of the humoral immune system. Other features of SLE include generalized B cell hyperresponsiveness, polyclonal hypergammaglobulinemia, and increased titers of antibodies to commonly encountered viral antigens.
Treatment:
Autoimmune Diseases
Treatment of autoimmune diseases can focus on either suppressing the induction of autoimmunity, restoring normal regulatory mechanisms, or inhibiting the effector mechanisms. To eliminate autoreactive cells, immunosuppressive or ablative therapies are most commonly used. In recent years,cytokine blockade has been demonstrated to be effective in preventing immune activation in some diseases. New therapies are currently in clinical trials to target lymphoid cells more specifically, either by blocking a costimulatory signal needed for T or B cell activation, by eliminating the effector T cells or B cells, or by using autoantigen itself to induce tolerance. One major advance in inhibiting effector mechanisms has been the introduction of cytokine blockade,targeting TNF or IL-1 receptor,which appears to limit organ damage in some diseases. Biologicals that interface with T cell activation (abatacept) or deplete B cells (rituximab) have also recently been approved for the treatment of rheumatoid arthritis. Therapies that prevent target organ damage or support target organ function remain an important therapeutic approach to autoimmune disease.