Immunogenetics of leishmanial and mycobacterial infections: the Belem Family Study

In the 1970s and 1980s, analysis of recombinant inbred, congenic and recombinant haplotype mouse strains permitted us to effectively 'scan' the murine genome for genes controlling resistance and susceptibility to leishmanial infections. Five major regions of the genome were implicated in the control of infections caused by different Leishmania species which, because they show conserved synteny with regions of the human genome, immediately provides candidate gene regions for human disease susceptibility genes. A common intramacrophage niche for leishmanial and mycobacterial pathogens, and a similar spectrum of immune response and disease phenotypes, also led to the prediction that the same genes/candidate gene regions might be responsible for genetic susceptibility to mycobacterial infections such as leprosy and tuberculosis. Indeed, one of the murine genes (Nramp1) was identified for its role in controlling a range of intramacrophage pathogens including leishmania, salmonella and mycobacterium infections. In recent studies, multicase family data on visceral leishmaniasis and the mycobacterial diseases, tuberculosis and leprosy, have been collected from north-eastern Brazil and analysed to determine the role of these candidate genes/regions in determining disease susceptibility. Complex segregation analysis provides evidence for one or two major genes controlling susceptibility to tuberculosis in this population. Family-based linkage analyses (combined segregation and linkage analysis; sib-pair analysis), which have the power to detect linkage between marker loci in candidate gene regions and the putative disease susceptibility genes over 10-20 centimorgans, and transmission disequilibrium testing, which detects allelic associations over 1 centimorgan (ca. 1 megabase), have been used to examine the role of four regions in determining disease susceptibility and/or immune response phenotype. Our results demonstrate: (i) the major histocompatibility complex (MHC: H-2 in mouse, HLA in man: mouse chromosome 17/human 6p; candidates class II and class III including TNF alpha/beta genes) shows both linkage to, and allelic association with, leprosy per se, but is only weakly associated with visceral leishmaniasis and shows neither linkage to nor allelic association with tuberculosis; (ii) no evidence for linkage between NRAMP1, the positionally cloned candidate for the murine macrophage resistance gene Ity/Lsh/Bcg (mouse chromosome 1/human 2q35), and susceptibility to tuberculosis or visceral leishmaniasis could be demonstrated in this Brazilian population; (iii) the region of human chromosome 17q (candidates NOS2A, SCYA2-5) homologous with distal mouse chromosome 11, originally identified as carrying the Scl1 gene controlling healing versus nonhealing responses to Leishmania major, is linked to tuberculosis susceptibility; and (iv) the 'T helper 2' cytokine gene cluster (proximal murine chromosome 11/human 5q; candidates IL4, IL5, IL9, IRF1, CD14) controlling later phases of murine L. major infection, is not linked to human disease susceptibility for any of the three infections, but shows linkage to and highly significant allelic association with ability to mount an immune response to mycobacterial antigens. These studies demonstrate that the 'mouse-to-man' strategy, refined by our knowledge of the human immune response to infection, can lead to the identification of important candidate gene regions in man.