Causes Of Hypersensitivity Diseases

Immune responses against antigens from different sources can be the underlying cause of hypersensitivity disorders.

• Autoimmunity. Failure of the normal mechanisms of self-tolerance results in reactions against one's own cells and tissues that are called autoimmunity (see Chapter 14). The diseases caused by autoimmunity are referred to as autoimmune diseases. Autoimmune diseases are estimated to affect 2% to 5% of the population in developed countries, and the incidence of these disorders is rising. Many of these diseases are common in individuals in the 20- to 40-year age group. They are also more common in women than in men, for reasons that remain obscure. Autoimmune diseases are chronic and debilitating and an enormous medical and economic burden. In the early part of the 21st century, many new treatments for these disorders have been developed based on scientific principles; these are among the most impressive successes in medicine. The mechanisms of autoimmunity were described in Chapter 14; in this chapter, we will refer to various autoimmune diseases to illustrate how autoimmunity can cause disease.

• Reactions against microbes. Immune responses against microbial antigens may cause disease if the reactions are excessive or the microbes are unusually persistent. T cell responses against persistent microbes may give rise to severe inflammation, sometimes with the formation of granulomas; this is the cause of tissue injury in tuberculosis and some other chronic infections. If antibodies are produced against microbial antigens, the antibodies may bind to the antigens to produce immune complexes, which deposit in tissues and trigger inflammation. Rarely, antibodies or T cells against a microbe may cross-react with a host tissue. In some diseases involving the intestinal tract, called inflammatory bowel disease, the immune response is directed against commensal bacteria that normally reside in the gut and cause no harm. Sometimes the disease-causing immune response may be entirely normal, but in the process of eradicating the infection, host tissues are injured. In viral hepatitis, the virus that infects liver cells is not cytopathic, but it is recognized as foreign by the immune system. Cytotoxic T lymphocytes (CTLs) try to eliminate infected cells, and this normal immune response damages liver cells. This type of normal reaction is not considered hypersensitivity. • Reactions against environmental antigens. Most healthy individuals do not react against common, generally harmless environmental substances, but almost 20% of the population is abnormally responsive to one or more of these substances. These individuals produce immunoglobulin E (IgE) antibodies that cause allergic diseases (see Chapter 19). Some individuals become sensitized to environmental antigens and chemicals that contact the skin and develop T cell reactions that lead to cytokine-mediated inflammation, resulting in contact sensitivity.

In all these conditions, the mechanisms of tissue injury are the same as those that normally function to eliminate infectious pathogens. These mechanisms include innate immune responses, T lymphocytes, various other effector cells, and mediators of inflammation. The problem in hypersensitivity diseases is that the response is triggered and maintained inappropriately. Because the stimuli for these abnormal immune responses are difficult or impossible to eliminate (e.g., self antigens, commensal microbes, and environmental antigens) and the immune system has many built-in positive feedback loops (amplification mechanisms), once a pathologic immune response starts, it is difficult to control or to terminate it. Therefore, these hypersensitivity diseases tend to be chronic and progressive and are major therapeutic challenges in clinical medicine.

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