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

Abstract

Summary. 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 vilro 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.

An RFLP map for 2q33‐q37 from multicase mycobacterial and leishmanial disease families: no evidence for an Lsh/Ity/Bcg gene homologue influencing susceptibility to leprosy

“…The major method of two-point linkage analysis used in this study of genetic susceptibility to leprosy bears some comparison with earlier studies on the influence of HLA on susceptibility to disease p e r se and different disease phenotypes. It is of interest, for example, that although many studies have shown an association between disease phenotypes and polymorphism for particular HLA class I and I1 genes a t the population level (reviewed Blackwell, 1988), it has proved much more difficult to demonstrate linkage between HLA and disease (Rawlinson et al 1988;Abel et al 1989) using classical LOD score linkage analysis, even when large numbers of families are examined. Indeed, close linkage ( < 5-10 cM) between HLA markers and disease phenotypes of clinical leprosy, clinical subtype of leprosy, or lymphocyte proliferative response was excluded (LOD scores < -2) in two separate studies involving 27 (953 individuals ;Abel et al 1989) and 10 (87 individuals; Rawlinson et al 1988) multicase families.…”

“…It is of interest, for example, that although many studies have shown an association between disease phenotypes and polymorphism for particular HLA class I and I1 genes a t the population level (reviewed Blackwell, 1988), it has proved much more difficult to demonstrate linkage between HLA and disease (Rawlinson et al 1988;Abel et al 1989) using classical LOD score linkage analysis, even when large numbers of families are examined. Indeed, close linkage ( < 5-10 cM) between HLA markers and disease phenotypes of clinical leprosy, clinical subtype of leprosy, or lymphocyte proliferative response was excluded (LOD scores < -2) in two separate studies involving 27 (953 individuals ;Abel et al 1989) and 10 (87 individuals; Rawlinson et al 1988) multicase families. One reason for this may be that linkage analysis is too exacting a mode of analysis for complex diseases ( a ) when precise assumptions have to be made about the mode of inheritance of disease susceptibility or associated immune phenotypes, levels of penetrance for the susceptibility allele, and frequency of phenocopies; and/or ( b ) where several genes may contribute to an overall disease phenotype.…”

“…Although associations between disease phenotypes and particular HLA class I and I1 antigens have been observed a t the population level for both leprosy (reviewed by Serjeantson, 1983;Van Eden & De Vries, 1984;Blackwell, 1988) and TB (e.g. Selby et al'1978;Al-Arif et al 1979;Singh et al 1983a;Hwang et al 1985;Cox et al 1988; reviewed Blackwell, 1988), it has been difficult to demonstrate linkage between susceptibility to disease per se or particular disease phenotypes and HLA when familial sib-pair haplotype segregation or linkage analyses are performed (De Vries et al 1976Fine et al 1979;Singh et al 19836, 1984;Haile et al 1985; Van Eden et al 1985;Rawlinson et al 1988;Abel et al 1989). For leprosy in particular, susceptibility to disease per se has been shown by several workers not to come under MHC control (Van Eden et al 1985;Rawlinson et al 1988;Abel et al 1989), and it has been suggested (e.g.…”

“…Selby et al'1978;Al-Arif et al 1979;Singh et al 1983a;Hwang et al 1985;Cox et al 1988; reviewed Blackwell, 1988), it has been difficult to demonstrate linkage between susceptibility to disease per se or particular disease phenotypes and HLA when familial sib-pair haplotype segregation or linkage analyses are performed (De Vries et al 1976Fine et al 1979;Singh et al 19836, 1984;Haile et al 1985; Van Eden et al 1985;Rawlinson et al 1988;Abel et al 1989). For leprosy in particular, susceptibility to disease per se has been shown by several workers not to come under MHC control (Van Eden et al 1985;Rawlinson et al 1988;Abel et al 1989), and it has been suggested (e.g. Abel & Demenais, 1988;Jazwinska & Serjeantson, 1988;Abel et al 1989) that a human homologue for the murine chromosome 1 macrophage resistance gene Lsh/lty/Bcg would provide a plausible candidate for this non-MHC control.…”

Sequential Designs for Genetic Epidemiological Linkage or Association Studies A Review of the Literature

“…Seven studies were identified that explicitly reported the application of formal classical sequential test procedures. Of these, five (Chadda et al, 1986;Goedde et al, 1976;Rawlinson et al, 1988;Rosen-Bronson et al, 1988;Sasaki et al, 1987) allegedly used the sequential test by Morton (1955). However, data was not collected sequentially, and the LOD scores were not calculated repeatedly on increasing samples.…”