Pathogenesis of nerve damage in leprosy: genetic polymorphism regulates the production of TNF alpha

Studies carried out over the last decade have strongly suggested that TNF a lpha both overtly participates in the cell-mediated immune response against Mycobacterium leprae, and is overproduced during reaction. In addition, re actions are intimately related to the onset of nerve damage. Finally, TNF a lpha has been implicated in the pathogenesis of many human and experimental autoimmune peripheral neuropathies that, as in leprosy, result in demyelin ation and axonal lesions. Because of recent findings associating human TNF alpha mutant alleles at the -308 position with increased production of TNF alpha in many immunological and infectious diseases, an investigation of th e role of TNF2 in predisposing leprosy patients to reaction has been undert aken. Analysis of 300 patients with leprosy-210 multibacillary and 90 pauci bacillary-has shown that the percentage of reactional patients was similar among both carriers and non-carriers of the TNF2 allele. However, a separat e analysis of 57 carriers of TNF2 found that reactions occurred much more f requently among heterozygous than among homozygous patients. Moreover, the frequency of neuritis was somewhat greater among the heterozygous patients than among the non-carriers. Enhanced serum levels of TNF alpha have been n oted in both TNF-1 and TNF-2 mutant patients in the course of leprosy react ion. Our observations to date suggest that other factors not related to the presence of the mutant gene may lead to the TNF alpha hyper-responsiveness observed during reaction.