THE IMMUNOGENETICS OF HUMAN INFECTIOUS-DISEASES

Twin and adoptee studies have indicated that host genetic factors are major determinants of susceptibility to infectious diseases in humans. Twin studies have also found high heritabilities for many humoral and cellular immune responses to pathogen antigens, with most of the gene tic component mapping outside of the major histocompatibility complex. Candidate gene studies have implicated several immunogenetic polymorp hisms in human infectious diseases. HLA variation has been associated with susceptibility or resistance to malaria, tuberculosis, leprosy, A IDS, and hepatitis virus persistence. Variation in the tumor necrosis factor gene promoter has also been associated with several infectious diseases. Chemokine receptor polymorphism affects both susceptibility to HIV-1 infection and the rate of progression to AIDS. Inactivating m utations of the gamma-interferon receptor lead to increased susceptibi lity to atypical mycobacteria and disseminated BCG infection in homozy gous children. The active form of vitamin D has immunomodulatory effec ts, and allelic variants of the vitamin D receptor appear to be associ ated with differential susceptibility to several infectious diseases. NRAMP1, a macrophage gene identified by positional cloning of its muri ne homologue, has been implicated in susceptibility to tuberculosis in Africans. Whole genome linkage analysis of multi-case families is now being used to map and identify new loci affecting susceptibility to i nfectious diseases. It is likely that susceptibility to most microorga nisms is determined by a large number of polymorphic genes, and identi fication of these should provide insights into protective and pathogen ic mechanisms in infectious diseases.