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Immune tolerance and autoimmunity are important clinically. First, there are at least 40 known or suspected autoimmune diseases, and many are common (see box next page). Overall, 1 in every 31 persons is affected. 1 Moreover, autoimmune type 1 diabetes mellitus is the most common of all chronic diseases of children. Second, autoimmune disease is poorly diagnosed because the onset can be stealthy, and initial symptoms are often nonspecific: tiredness, fatigue, or fever. Third, patients with autoimmune disease expect their physician to interpret their illness. Fourth, new insights are set to revolutionize management by replacing blanket immunosuppression with new selective immunotherapies.
IMMUNE TOLERANCE AND THE IMMUNE RESPONSE
Figure 1 illustrates how tolerance is established and maintained, how it fails with ensuing autoimmunity, and how it can be restored. Specific immune and autoimmune responses involve the same elements. These include an antigen (or autoantigen); a response by interacting families and subsets of cells that include antigen-presenting cells, T lymphocytes, and B lymphocytes; messenger molecules, cytokines, chemokines, and their receptors; and signaling and costimulatory molecules on cell surfaces ( figure 2 ). Many of the functionally important cell surface molecules and their receptors are described by the cluster of differentiation (CD) nomenclature based on their identification by characterized monoclonal antibodies.
Table 1 Prevalence of autoimmune diseases Thyroid diseases (includes Hashimoto's thyroiditis and Graves' disease): more than 3% of adult women
Rheumatoid arthritis: 1% of general population, but female excess
Primary Sjögren's syndrome: 0.6% to 3% of adult women
Systemic lupus erythematosus: 0.12% of general population, but female excess
Multiple sclerosis: 0.1% of general population, but female excess
Type 1 diabetes mellitus: 0.1% of children
Primary biliary cirrhosis: 0.05% to 0.1% of middle-aged and elderly women
Myasthenia gravis: 0.01% of general population, but female excess
The immune system does not normally respond to self-antigens. This immunologic tolerance was postulated more than 50 years ago, but its multifactorial basis is still controversial. 2 , 3 , 4 Tolerance is generated at 2 levels. The "upper level" of central tolerance develops primarily in fetal life, and the "lower level" of peripheral tolerance develops postnatally as a back-up process. A faulty central tolerance sows the seeds for autoimmune disease, and faulty peripheral tolerance leads to its eruption.
Central tolerance
Lymphocytes...