Leprosy and immunity: genetics and immune function in multiple case families.

Genetic susceptibility to infection with M. leprae was studied in 10 multiple case families of Australian Aborigines. Of the 87 members available for study, 24 had proven stable clinical leprosy which had been or was still being treated with diamino diphenyl sulphone. Evidence of contact with M. leprae in the remaining 63 members as assessed by ELISA to M. leprae sonicate and phenolic glycolipid (PGL) or by indirect immunofluorescence antibody assay was found in 78%, 64% and 71%, respectively. By contrast, in vitro assays of T cell function (LMAT and LTT) were less reliable indicators of exposure. Evidence was sought for possible linkages between human leucocyte antigen (HLA) or non-HLA genes and four marker phenotypes including clinical leprosy, clinical subtype of leprosy and lymphocyte transformation or leucocyte migration inhibition factor (LIF) production in response to M. leprae antigen. No associations were found with any particular HLA or non-HLA gene. On the other hand, sequential analysis of the data from the 10 families was strongly suggestive of a linkage between HLA haplotype and non-responsiveness to M. leprae as manifest by lack of LIF production but not lymphocyte transformation. The model which best fits the data is for a gene on chromosome 6 in close linkage with the HLA haplotype, with two alleles, autosomal recessive inheritance and penetrance of 90%. On this basis, it can be suggested that disease type (lepromatous leprosy) rather than disease susceptibility may be controlled by genes within or closely linked to the major histocompatibility gene complex.