Genetic regulation of macrophage activation: understanding the function ofNramp1 (= Ity/Lsh/Bcg)

The Nramp 1 gene was originally described as Ity/Lsh/Bcg, a single gene con trolling resistance and susceptibility of inbred mice to a range of intrama crophage pathogens. Functional studies demonstrated that Ity/Lsh/Bcg had mu ltiple pleiotropic effects on macrophage activation pathways, broadening in terest in the gene to include its candidacy as an autoimmune disease suscep tibility gene. In 1993 the gene was positionally cloned and found to encode a polytopic integral membrane protein of unknown function. Subsequent stud ies have localized the protein to late endosomal and lysosomal compartments , and demonstrated that it functions as an iron transporter. Precisely how this function influences macrophage activation pathways is still under inve stigation, but is likely to include direct effects on pathogen survival in the endosomal/lysosomal compartment as well as influences on intracellular signalling pathways and in regulating mRNA stability. Several studies now p rovide evidence for a role for NRAMP1 in determining human susceptibility t o autoimmune (rheumatoid arthritis, juvenile rheumatoid arthritis, diabetes , Crohn's disease) and infectious (tuberculosis. leprosy) diseases. Amongst these, data are accumulating to support the hypothesis that a functional Z -DNA forming repeat polymorphism in the promoter region of human NRAMP1 con tributes directly to disease susceptibility. Four alleles have been observe d, alleles 1 and 4 are rare (gene frequencies similar to 0.001), alleles 2 and 3 occur at gene frequencies similar to 0.25 and similar to 0.75, respec tively. In the absence of exogenous stimuli, alleles 1, 2 and 4 are poor pr omoters of gene expression in a luciferase reporter gene system; allele 3 d rives high expression. Allele 3 shows allelic association with autoimmune d isease susceptibility, allele 2 with infectious disease susceptibility. Hen ce, balancing selection is likely to be maintaining these two alleles in hu man populations. Although the association of NRAMP1 with autoimmune disease susceptibility may be related to any one of the multiple pleiotropic effec ts associated with macrophage activation, the function of NRAMP1 as an iron transporter now prompts more interesting speculation that regulation of ir on transport may contribute directly to the disease phenotype in arthritic disease. Patients suffering from rheumatoid arthritis show increased deposi tion of iron in the synovial membrane, which may contribute to free radical generation and local inflammation. Further analysis of NRAMP1 function wil l continue to be of importance in understanding the molecular basis to auto immune and infectious disease susceptibility. (C) 1999 Elsevier Science B.V . All rights reserved.