Leprosy, or Hansen disease, is a slowly progressive infection caused by Mycobacterium leprae, affecting the skin and peripheral nerves and resulting in disabling deformities. M. leprae is, for the most part, contained within the skin, but leprosy is likely to be transmitted from person to person through aerosols from lesions in the upper respiratory tract. Inhaled M. leprae, like M. tuberculosis, is taken up by alveolar macrophages and disseminates through the blood, but grows only in relatively cool tissues of the skin and extremities. Despite its low communicability, leprosy remains endemic among an estimated 10 to 15 million people living in poor tropical countries.
Pathogenesis. M. leprae is an acid-fast obligate intracellular organism that grows very poorly in culture but can be grown in the armadillo. It grows more slowly than other mycobacteria and grows best at 32° to 34°C, the temperature of the human skin and the core temperature of armadillos. Like M. tuberculosis, M. leprae secretes no toxins, and its virulence is based on properties of its cell wall. The cell wall is similar enough to that of M. tuberculosis that immunization with bacille Calmette-Guérin confers some protection against M. leprae infection. Cell-mediated immunity is reflected by delayed type hypersensitivity reactions to dermal injections of a bacterial extract called lepromin.
Leprosy has two strikingly different patterns of disease. Patients with the less severe form, tuberculoid leprosy, have dry, scaly skin lesions that lack sensation. They often have large, asymmetric peripheral nerve involvement. The more severe form of leprosy, lepromatous leprosy, includes symmetric skin thickening and nodules. This is also called anergic leprosy, because of the unresponsiveness (anergy) of the host immune system. Cooler areas of skin, including the earlobes and feet, are more severely affected than warmer areas, such as the axilla and groin. In lepromatous leprosy, damage to the nervous system comes from widespread invasion of the mycobacteria into Schwann cells and into endoneural and perineural macrophages. In advanced cases of lepromatous leprosy, M. leprae is present in sputum and blood. People can also have intermediate forms of disease, called borderline leprosy.
The T-helper lymphocyte response to M. leprae determines whether an individual has tuberculoid or lepromatous leprosy.109 Patients with tuberculoid leprosy have a TH1 response, with production of IL-2 and IFN-γ. As with M. tuberculosis, IFN-γ is critical to mobilizing an effective host macrophage response. IL-12, which is produced by antigen presenting cells, is important to the generation of TH1 cells.
Low levels of IL-12 or unresponsiveness of T cells to this cytokine may reduce the TH1 response, leading to lepromatous leprosy. In addition to TH1 cells, lymphocytes bearing the γ/δ T-cell receptor infiltrate the lesions of leprosy and produce IFN-γ in patients with tuberculoid leprosy. Patients with lepromatous leprosy have a defective TH1 response or a dominant TH2 response, with production of IL-4, IL-5, and IL-10, which may suppress macrophage activation in response to M. leprae.
In some cases, antibodies are produced against M. leprae antigens. Paradoxically, these antibodies are usually not protective, but they may form immune complexes with free antigens that can lead to erythema nodosum, vasculitis and glomerulonephritis.
Morphology
Tuberculoid leprosy begins with localized skin lesions that are at first flat and red but enlarge and develop irregular shapes with indurated, elevated, hyperpigmented margins and depressed pale centers (central healing). Neuronal involvement dominates tuberculoid leprosy. Nerves become enclosed within granulomatous inflammatory reactions and, if small enough (e.g., the peripheral twigs), are destroyed.
Nerve degeneration causes skin anesthesias and skin and muscle atrophy that render the patient liable to trauma of the affected parts, with the development of indolent skin ulcers. Contractures, paralyses, and autoamputation of fingers or toes may ensue. Facial nerve involvement can lead to paralysis of the eyelids, with keratitis and corneal ulcerations.
On microscopic examination, all sites of involvement disclose granulomatous lesions closely resembling those found in tuberculosis, and bacilli are almost never found. The presence of granulomas and absence of bacteria reflect strong T-cell immunity. Because leprosy pursues an extremely slow course, spanning decades, most patients die with leprosy rather than of it.
Lepromatous leprosy involves the skin, peripheral nerves, anterior chamber of the eye, upper airways (down to the larynx), testes, hands, and feet. The vital organs and central nervous system are rarely affected, presumably because the core temperature is too high for growth of M. leprae. Lepromatous lesions contain large aggregates of lipid-laden macrophages (lepra cells), often filled with masses of acid-fast bacilli (globi).
The failure to contain the infection and to form granulomas reflects failure of the TH1 response. Macular, papular, or nodular lesions form on the face, ears, wrists, elbows, and knees. With progression, the nodular lesions coalesce to yield a distinctive leonine facies. Most skin lesions are hypoesthetic or anesthetic. Lesions in the nose may cause persistent inflammation and bacilli-laden discharge.
The peripheral nerves, particularly the ulnar and peroneal nerves where they approach the skin surface, are symmetrically invaded with mycobacteria, with minimal inflammation. Loss of sensation and trophic changes in the hands and feet follow the nerve lesions.
Lymph nodes show aggregation of foamy macrophages in the paracortical (T-cell) areas, with enlargement of germinal centers. In advanced disease, aggregates of macrophages are also present in the splenic red pulp and the liver. The testes are usually extensively involved, with destruction of the seminiferous tubules and consequent sterility.