Leprosy

The spectrum of leprosy

M. leprae cannot yet be cultivated in vitro. It will infect primates and armadillos, and give limited proliferation in mice after infection with small numbers of organisms. It enters numerous different cell types in vivo, and is found inside Schwann cells, neurons, endothelial cells, muscles and fibroblasts. It proliferates within the cytoplasm, rather than within phagosomes, and this may shield it from protective pathways. It is the predilection for nerves that is responsible for most of the pathology.

Leprosy patients can be classified on a 'spectrum' according to the apparent efficacy of the cell-mediated response. The problems that require explanation are quite different at the two extremes of this spectrum.

Tuberculoid leprosy In tuberculoid disease, the in vivo and in vitro correlates of T cell-mediated responsiveness, such as skin-test responsiveness and lymphoproliferation in response to antigens of M. leprae, appear to be intact, bacilli are few and histologically the lesions are classical T lymphocyte-dependent granulomata containing CD4+ T cells, activated macrophages, and epithelioid cells, with a few CD8+ cells round the periphery. The lesions are largely due to nerve damage secondary to expansion of the granulomata and inflammation within nerve sheaths. There is evidence of TH1 cytokine production in these lesions. Without treatment, many of these individuals will downgrade towards the lepro-matous pole, where the TH1 response is compromised (see below). Since the T cell-mediated responses appear to be functioning, it is not clear why this type of leprosy frequently fails to be self-limiting.

Theoretically, two types of explanation seem possible. First, the T cells responding may be the wrong type. This cannot be resolved at present because we do not known what effector mechanisms are required for the elimination of M. leprae, though as for tuberculosis, immunity is likely to depend upon macrophage activation and cytotoxic T cells mobilized by a Th1 response. There is a TH1 response in tuberculoid leprosy so why do the patients have a disease?

An alternative hypothesis is that the response in tuberculoid patients is adequate in mechanism, but is directed towards the wrong antigens. Again this cannot be resolved until protective antigens can be identified, but one possibility is that the critical antigens are the secreted ones. These would presumably be the first to be available for presentation to T cells, and would therefore allow a rapid response to infection. They would also allow recognition of live organisms. Thus it is possible that tuberculoid leprosy patients have a chronic granulomatous response to persistent cell wall fragments derived from dead organisms which are difficult to metabolize, while their lymphocytes fail to recognize the live organisms proliferating elsewhere.

Lepromatous leprosy In contrast, lepromatous patients show minimal evidence of T cell-mediated immunity either in vivo or in vitro, and their lesions consist of large numbers of macrophages filled with bacilli, showing no signs of activation. Often these patients remain unresponsive to the organisms even after years of treatment when the antigen load has been drastically reduced. Thus in this form of leprosy we need to explain the persistent absence of a response, whereas in tuberculoid leprosy the problem is the paradoxical failure of a superficially intact one. The meaningful study of this type of leprosy is hampered by the fact that the organism is nontoxic, and in the absence of a strong inflammatory response it can proliferate within the patient's tissues for many years before its presence becomes apparent. Thus much of what has been revealed by immunologists may be the consequence of prolonged heavy antigen load, rather than the actual basis for the failure to eliminate the organisms in the first place. It is now clear that the lack of an apparent T cell-mediated response to M. leprae in lepromatous leprosy is not due to a lack of T cells recognizing this organism. However the T cells present tend to express Tn2 cytokines. Moreover peripheral blood leukocytes from some (but not all) patients give a proliferative response to M. leprae if the cultures are supplemented with IL-2 or other lymphokines.

Several groups have been able to demonstrate T cells that suppress lymphoproliferation in the presence of M. leprae. These may represent some type of 'suppressor' cell, or the effects seen may be attributable to Th2 cytokine production. It remains possible that these phenomena are secondary to the presence of a large antigen load for many years before diagnosis. It may be significant that once the organism has become established within nerves (which do not have lymphatics) and endothelial cells, antigens will be released directly into the circulation which is likely to evoke suppression of cell-mediated responses, and high antibody levels.

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