Still a Mystery: Why Do Some People Get Leprosy?

Nearly 95 percent of the world's population is naturally immune to leprosy. What happens to that unlucky five percent? Researchers are exploring why some people get leprosy while others remain healthy. Leprosy appears to involve a conflict between the body's cell-mediated immune (CMI) system and the bacillus. CMI offers protection through the interaction of highly specialized cells, particularly T cell lymphocytes and macrophages, whose task it is to recognize and destroy materials foreign to the body (see the 1996 Holiday Lectures on Science). In tuberculoid leprosy, which affects about 75 percent of the world's sufferers, a strong CMI reaction helps confine the bacterium to a patch of skin or a nerve trunk. The intense response of the body's defenses to the presence of the leprosy bacilli and their antigens causes the macrophages, helped by T cells, to aggregate at the sites of infection, engulf the organisms and their antigens, and destroy them.

Lepromatous leprosy arises in patients with little or no immune resistance to the M. leprae organism. These patients cannot mount an immune response because of the lack of CMI. In such cases, the very cells charged with leading the defense—the macrophages—fail to destroy the bacillus by physically engulfing and digesting it. Rather, the macrophages become home to the bacilli as they multiply within the cell. As many as 300 bacilli may be crowded into one single macrophage, causing the cell to swell up like a balloon instead of retaining its amoeba-like shape. The macrophage then takes the bacilli for a spin through the bloodstream to all parts of the body. Wherever the M. leprae are deposited by the macrophages, perhaps after they have ruptured, the bacilli colonize the locality, grow there, and produce lesions. They also remain free to be taken up by other macrophages and transported further.

Putting the immune system on the defensive

How does the leprosy bacterium tinker with the immune system to produce these effects? Why do T cells in lepromatous patients stop cooperating with macrophages to recognize the bacterium and its antigens? Part of the answer may reside in the building blocks that make up the organism. The cell wall lipids of M. leprae, for example, appear to exert direct biological effects on macrophages and possibly T cells, altering some functions that may result in suppression of immunity. Terminal sugars on a leprosy-specific glycolipid induce suppressor T cells that can inhibit other T cells from responding specifically to M. leprae antigens. Unusual lipids containing phthiocerol and phenolphthiocerol are exposed at the surface and found only in the cell walls of slow-growing pathogenic mycobacteria. These lipids are also suspected of catalyzing host-pathogen reactions.

Secreted proteins represent another distinct group of agents and are probably important for affecting immune responses of the host after infection. Studying these proteins has proven difficult because they are lost when the bacilli are isolated from tissues.

Taking an alternative approach, therefore, some researchers are examining DNA sequences that code for secreted proteins, identifying the genes by the secretion signals typical of M. leprae that are encoded in them. Progress in the characterization of these proteins is offset somewhat by less knowledge about the proteins found in the cell wall, on which some researchers are now focusing. Another group of proteins that appear when the organism is heat-shocked are being examined to see what immune responses they affect.

Other operatives in the immune system such as lymphokines—agents released by activated T cells—and interleukins—proteins produced by activated macrophages and lymphocytes—are also being checked for their ability to enhance or suppress immune function during a leprosy infection. Parts of the human genome that control immunity such as the HLA genes of the major histocompatibility complex are also under scrutiny.

Exactly how the bacillus cleverly exploits these differences also requires considerably more research. Through better understanding of the bacterial components and their biological impacts, researchers may at last solve the final mysteries surrounding this long standing disease.

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