Pathogenesis And Immunity

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In humans, direct skin-to-skin contact or fomites may transmit leprosy,55 but the nasorespiratory route is believed to be most common.56 Secretions from the nasal mucosa of untreated lepromatous patients contain large numbers of viable leprosy bacilli.57 M. leprae bacilli, after drying in the shade, in India, remain viable for up to 5 months, and in wet soil for 46 days.58 Thus, the leprosy bacilli could be carried in aerosols and contaminate the nasal mucosa, perhaps first binding to fibronectin and then to fibronectin receptors on mucosal cells.59 Transmission through mother's milk or transplacental infection is plausible. Breast tissue and mother's milk of multibacillary patients may contain large numbers of M. leprae, putting their nursing infants at risk.60 There is increasing evidence for placental transmission of leprosy. Cord blood contains M. leprae-specific IgA and IgM antibodies,

FIGURE 38-14 Lucio's lepromatous leprosy in a Mexican patient. Punched-out irregular ulcers are at sites with infarcts caused by obliter-ative vasculitis of dermal and subcutaneous vessels.

FIGURE 38-16 Erythema nodosum leprosum in a Filipino patient with lepromatous leprosy. Some of the numerous tender, soft nodules will rupture and discharge pus.

and titers of these antibodies rise in some infants of lepro-matous mothers over 3 to 24 months after birth.61-62 Leprosy in infants under 1 year of age is well known. In one series of 49 such infants, the youngest patient was 2 months old at diagnosis,21 and the mother had clinical leprosy in only about half of these infants. This implies that during gestation the mother had a transient subclinical M. leprae bacteremia.

Bacteremia is common in multibacillary leprosy and in up to 15% of paucibacillary patients.63-64 Invasion and multiplication of M. leprae in dermal lymphatic and vascular endothelial cells probably plays a major role in the hematogenous spread of the bacillus.65,66 Scollard and associates have demonstrated that M. leprae invades peripheral nerves via the blood (and possibly lymphatic) vessels of the perineurium, gaining access to the endoneurial compartment.67 Infection of endothelial cells by M. leprae may lead to ischemia of nerve, contributing to peripheral neuritis. The Schwann cell of peripheral nerves is the classic target for M. leprae. Rambukkana and coworkers have shown that laminin-2 in the basal lamina of the Schwann cell-axon unit binds to M. leprae, and ultimately that the a-dystroglycan receptor of the Schwann cells binds with laminin-2.68 This may be one mechanism by which Schwann cells become infected.

Disturbances in the modulation of T lymphocyte-macrophage function in the different forms of leprosy are well known. Total numbers of circulating T lymphocytes may be decreased in advanced lepromatous disease, but T-cell subset ratio variations are not consistent.69 In lesions, however, T helper (CD4+) cells predominate in tuberculoid leprosy, and T suppressor (CD8+) lymphocytes predominate in lepromatous disease.70,71 Increased suppressor cell activity in lepromatous leprosy may be induced by lepromin72 or PGL-1,73and may in part be related to infiltration of paracortical areas of lymph nodes by M. leprae-laden macrophages.74

Much is known about the immunologic perturbations in leprosy, which have been extensively reviewed.75 Protective mechanisms against leprosy, the contribution of the T-cell subsets, cytokine networks, and macrophage bactericidal mechanisms, for example, remain unresolved.76

Classically, CD4+ T lymphocytes recognize specific antigens when associated with HLA and produce interferon-y (IFN-y), which activates macrophages. Macrophages from lepromatous patients, once activated by cytokines, have the capacity to kill and clear M. leprae.77 Production of inter-leukin-2 (IL-2) and IFN-y, however, is deficient in leproma-tous patients. This suppression may represent an effect of CD8+ T suppressor cells by reducing proliferation of sensitized T cells and inhibiting activation of macrophages. IL-2 restores proliferation of lymphocytes and IFN-y production in response to specific stimulation.75,78,79 Injection of IL-2 and IFN-y into lepromatous lesions increases the influx of CD4+ T cells, activating macrophages and reducing bacillary load.80,81 These cytokines may have therapeutic value but do provoke tumor necrosis factor-a (TNF-a), which may be associated with reversal reactions in skin and peripheral nerves.82

The immune response, as it may relate to the spectrum of disease forms in leprosy, may be summarized as follows: In tuberculoid leprosy the response is that of Th1-like T cells, and in lepromatous leprosy there is a Th2 response producing cytokines IL-4 and IL-10.83 These different immunologic responses of the host determine, in large measure, the different clinical and histopathologic forms in the spectrum of leprosy (see Table 38-1).

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