IMMUNOGENETICS OF LEISHMANIAL AND MYCOBACTERIAL INFECTIONS - THE BELEM FAMILY STUDY

In the 1970s and 1980s, analysis of recombinant inbred, congenic and r ecombinant 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 impli cated in the control of infections caused by different Leishmania spec ies which, because they show conserved synteny with regions of the hum an genome, immediately provides candidate gene regions for human disea se susceptibility genes. A common intramacrophage niche for leishmania l and mycobacterial pathogens, and a similar spectrum of immune respon se and disease phenotypes, also led to the prediction that the same ge nes/candidate gene regions might be responsible for genetic susceptibi lity to mycobacterial infections such as leprosy and tuberculosis. Ind eed, one of the murine genes (Nramp1) was identified for its role in c ontrolling 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 Brazi l and analysed to determine the role of these candidate genes/regions in determining disease susceptibility. Complex segregation analysis pr ovides evidence for one or two major genes controlling susceptibility to tuberculosis in this population. Family-based linkage analyses (com bined segregation and linkage analysis; sib-pair analysis), which have the power to detect linkage between marker loci in candidate gene reg ions and the putative disease susceptibility genes over 10-20 centimor gans, and transmission disequilibrium testing, which detects allelic a ssociations over 1 centimorgan (ca. 1 megabase), have been used to exa mine the role of four regions in determining disease susceptibility an d/or immune response phenotype. Our results demonstrate: (i) the major histocompatibility complex (MHC: H-2 in mouse, HLA in man: mouse chro mosome 17/human 6p; candidates class II and class III including TNF al pha/beta genes) shows both linkage to, and allelic association with, l eprosy per se, but is only weakly associated with visceral leishmanias is and shows neither linkage to nor allelic association with tuberculo sis; (ii) no evidence for linkage between NRAMP1, the positionally clo ned candidate for the murine macrophage resistance gene Ity/Lsh/Bcg (m ouse chromosome 1/human 2q35), and susceptibility to tuberculosis or v isceral leishmaniasis could be demonstrated in this Brazilian populati on; (iii) the region of human chromosome 17q (candidates NOS2A, SCYA2- 5) homologous with distal mouse chromosome 11, originally identified a s carrying the Sell gene controlling healing versus nonhealing respons es to Leishmania major, is linked to tuberculosis susceptibility; and (iv) the 'T helper 2' cytokine gene cluster (proximal murine chromosom e 11/human 5q; candidates IL4, IL5, IL9, IRF1, CD14) controlling later phases of murine L. major infection, is not linked to human disease s usceptibility for any of the three infections, but shows linkage to an d highly significant allelic association with ability to mount an immu ne response to mycobacterial antigens. These studies demonstrate that the 'mouse-to-man' strategy, refined by our knowledge of the human imm une response to infection, can lead to the identification of important candidate gene regions in man.