Chapter category: Signal Transduction
Role of Nramp Family in Pro-Inflammatory Diseases
The Nramp Family
Edited by: Mathieu Cellier and Philippe GrosISBN: 0-306-47841-2
» Get more information about this book at landesbioscience.com «
Chapter authors:
Jenefer M. Blackwell, Hui-Rong Jiang and Jacqueline K. White
Early observations on the multiple pleiotropic effects of murine Slc11a1 (formerly Nramp1) on macrophage activation and pro-inflammatory responses prompted us to look for human SLC11A1 association with autoimmune diseases (rheumatoid arthritis (RA)). Since then, multiple studies have replicated and extended the linkage and/or association data to include: rheumatoid arthritis in UK, Canada, Korea and Spain; juvenile rheumatoid arthritis in Latvia; type 1 diabetes in the sibs of RA patients in the UK; early onset type 1 diabetes in Japan; inflammatory bowel disease, including CrohnÕs disease in USA and CrohnÕs disease and ulcerative colitis in Japan and Colored South Africans; primary biliary cirrhosis in the UK; sarcoidosis in African Americans; and multiple sclerosis in Caucasian South Africans. This growing number of reports attests to the potential global importance that polymorphism at SLC11A1 has in determining susceptibility to autoimmune diseases. The association is interesting in relation to the primary role of SLC11A1 in regulating infectious disease susceptibility, in particular to the frequently proposed infectious (especially mycobacterial) etiology or trigger for autoimmune diseases. A role for anti-mycobacterial immunity has also been proposed in modulating susceptibility to atopic disorder, such that in Sweden polymorphism at SLC11A1 influences susceptibility to atopy following BCG vaccination, but not in unvaccinated children. The common association between exposure to mycobacteria and susceptibility to pro-inflammatory autoimmune diseases and atopic disorders suggests that this group of pathogenic organisms has had a major impact in shaping the human immune system. Frequencies of polymorphic variants at SLC11A1 likely provide a genetic signature for the selective forces imposed by exposure to mycobacteria. To date the only functional polymorphism identified at the SLC11A1 locus is a GTn repeat in the promoter, which is further modulated in function by a variant C¡÷T allele at position -237bp. No studies in man have yet determined whether association with autoimmune disease and atopic disorder is related to the direct action of SLC11A1 protein as a divalent cation transporter in late endosomes/lysosomes of macrophage, or is due to one or more of the multiple pleiotropic effects of SLC11A1 on the pro-inflammatory response of macrophages and subsequent development of antigen-specific type 1 versus type 2 T cell responses. Development of murine models to study related autoimmune and atopic disease phenotypes, in particular the development of new congenic mouse strains that carry gene disruptions for proteins pleiotropically regulated by Slc11a1, should prove more tractable in determining the underlying mechanisms of disease.
Additional chapters from this book:
Plant Metal Transporters with Homology to Proteins of the NRAMP Family
Sebastien Thomine and Julian I. Schroeder
Plants need metal transporters to fulfill many essential functions ranging from metal absorption to metal sequestration and storage. In some cases, plants also have to deal with toxic heavy metals s...
Genetic Susceptibility to Infectious Diseases Linked to NRAMP1 Gene in Farm Animals
Judith Caron, Danielle Malo, Christopher Schutta, Joe W. Templeton and L. Garry Adams
Comparative genomics is playing a pivotal role in the genetic dissection of complex traits such as infectious diseases resistance. Using mouse models of infection, natural resistance associated macr...
Manganese and Iron Transport by Prokaryotic Nramp Family Transporters
Krisztina M. Papp, David G. Kehres and Michael E. Maguire
Initially identified in the mouse, the Nramp class of transport proteins is present in the majority of Eukaryota and Bacteria thus far investigated. In contrast very few Archaea appear to possess Nr...
Mouse Natural Resistance Associated Macrophage Protein 1 (Nramp1): A Key Master Player in Host Innate Immunity Against Infections
Nada Jabado, Steven Lam-Yuk-Tseung, John R. Forbes and Philippe Gros
Nramp1 is one of the few host resistance genes that have been well characterized at the molecular and functional level. This protein is an integral transmembrane protein expressed in the lysosomal c...
Role of Nramp Family in Pro-Inflammatory Diseases
Jenefer M. Blackwell, Hui-Rong Jiang and Jacqueline K. White
Early observations on the multiple pleiotropic effects of murine Slc11a1 (formerly Nramp1) on macrophage activation and pro-inflammatory responses prompted us to look for human SLC11A1 association w...
The Role of Yeast Nramp Metal Transporters in Manganese and Iron Homeostasis
Edward Luk, Laran Jensen and Valeria Culotta
The bakers yeast S. cerevisiae expresses three distinct Nramp metal transporters, namely Smf1p, Smf2p and Smf3p. Smf1p and Smf2p primarily function in manganese homeostasis, however these transporte...
Molecular Evolutionary Analysis of Nramp Family
Etienne Richer, Pascal Courville and Mathieu FM Cellier
The natural resistance-associated macrophage protein (Nramp) belongs to a family of ion permeases highly conserved in eukaryotes that originated in prokaryotes. Three phylogenetic groups of homologs...
Role of Nramp2 (DMT1) in Iron Homeostasis
Nancy C. Andrews
Nramp2 (DMT1) plays several important roles in iron metabolism. Investigations of animals carrying mutations in the Nramp2 (DMT1) gene have shown that the protein is critically important for absorpt...
Regulation of Bacterial MntH Genes
John D. Helmann
Bacterial NRAMP-like transporters, generically referred to as MntH proteins, appear to function primarily as Mn(II) uptake systems induced under conditions of manganese limitation. Regulation of mnt...
Molecular Physiology of the H+-coupled Iron Transporter DMT1
Bryan Mackenzie • Matthias A. Hediger
The mammalian DMT1 is a widely-expressed divalent metal-ion transporter that is energized by the H+ electrochemical gradient. Among the broad range of transition metal ions accepted as substrates, F...
Metal-ion Transporters— From Yeast to Human Diseases
Adiel Cohen, Hannah Nelson and Nathan Nelson
Transition metal ions such as copper, iron, manganese and zinc serve as essential cofac tors for a variety of biological processes including cell energetics, gene regulation and control of free radi...
Role of the Nramp Orthologue, MntH, in the Virulence of Mycobacterium Tuberculosis
P. Domenech and S.T. Cole
Mycobacterium tuberculosis is the causative agent of tuberculosis. The natural habitat of this pathogen is the alveolar macrophage where it modulates the maturation of the phagosome, inhibiting the ...
Tissue Distribution and Subcellular Localization of Nramp Proteins
François Canonne-Hergaux and Philippe Gros
The NRAMP family regroups divalent metal transporters highly conserved throughout evolution. In mammals, these membrane carriers play key roles in resistance to intracellular pathogens and in iron h...
Pleiotropic Effects of Nramp (Bcg/Lsh/Ity) Gene Expression on Macrophage Functions
Luis F. Barrera and Martin Olivier
Expression of Nramp1 gene in phagocytes has been correlated with resistance toward infections, restricting growth of various intracellular microbes within the phagolysosome environment. This gene co...
The NRAMP Genes and Human Susceptibility to Common Diseases
Audrey Poon and Erwin Schurr
Results obtained in murine models have raised the hope that human NRAMP genes could be important determinants of susceptibility for common human diseases. There is good agreement among studies condu...
Cellular and Tissue Expression of Rat DMT1 / Nramp 2
Evan H. Morgan
Evidence that rat DMT1 functions as a membrane transporter of iron was established by expression cloning in Xenopus laevis oocytes and by investigations in the Belgrade rat in which iron metabol...
