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Jenefer M Blackwell - One of the best experts on this subject based on the ideXlab platform.
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SLC11A1 formerly nramp1 is expressed in dendritic cells and influences major histocompatibility complex class ii expression and antigen presenting cell function
Infection and Immunity, 2007Co-Authors: Carmel B Stober, Jacqueline K. White, Jean-francois Popoff, Sven Brode, Jenefer M BlackwellAbstract:Solute carrier family 11 member a1 (SLC11A1; formerly Nramp1) encodes a late endosomal/lysosomal protein/divalent cation transporter that regulates iron homeostasis in macrophages. During macrophage activation, SLC11A1 has multiple pleiotropic effects on gene regulation and function, including gamma interferon-induced class II expression and antigen-presenting cell function. The wild-type allele at SLC11A1 has been associated with a bias in Th1 cell function in vivo, which is beneficial in resistance to infection against intracellular macrophage pathogens but detrimental in contributing to development of type 1 diabetes. The extent to which this depends on macrophage versus dendritic cell (DC) function is not known. Here we show that SLC11A1 is expressed in late endosomes and/or lysosomes of CD11c(+) DCs. DCs from mutant and congenic wild-type mice upregulate interleukin-12 (IL-12) and IL-10 mRNA in response to lipopolysaccharide (LPS) stimulation, but the ratio of IL-10 to IL-12 is higher in unstimulated DCs and DCs stimulated for 15 h with LPS from mutant mice than from wild-type mice. DCs from wild-type mice upregulate major histocompatibility complex class II in response to LPS more efficiently than DCs from mutant mice. Unstimulated DCs from wild-type and mutant mice present ovalbumin (OVA) peptide with an efficiency equivalent to that of an OVA-specific CD4 T-cell line, but DCs from wild-type mice are more efficient at processing and presenting OVA or Leishmania activator of cell kinase (LACK) protein to OVA- and LACK-specific T cells. These data indicate that wild-type SLC11A1 expressed in DCs may play a role both in determining resistance to infectious disease and in susceptibility to autoimmune disease such as type 1 diabetes.
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SLC11A1 nramp1 but not slc11a2 nramp2 polymorphisms are associated with susceptibility to tuberculosis in a high incidence community in south africa
International Journal of Tuberculosis and Lung Disease, 2004Co-Authors: Eileen G Hoal, Sarra E. Jamieson, Leeanne Lewis, F Tanzer, Manda Rossouw, T C Victor, R Hillerman, N Beyers, Jenefer M Blackwell, P D Van HeldenAbstract:CONTEXTE : Faculte des Sciences de Sante de l'Universite Stellenbosch et la ville de Cape Town, West Cape, Afrique du Sud. OBJECTIF: Investiguer dans quelle mesure l'association signalee entre les polymorphismes de SLC11A1 (ou NRAMP1) et la sensibilite a la tuberculose (TB) peuvent etre confirmes dans une population differente et dans quelle mesure les polymorphismes de SLC11A2 (ou NRAMP2, DCT1, DMT1) sont en association avec la TB. SCHEMA: On a utilise un schema d'etude cas-controle pour comparer les frequences de cinq polymorphismes de SLC11A1 et trois de SLC11A2 entre un groupe de patients TB confirmes par l'examen bacteriologique et des sujets-controle bien portants provenant de la collectivite. RESULTATS : L'allele 5' (GT)9 du promoteur de SLC11A1 se retrouve a des frequences significativement moins elevees parmi les 224 patients TB pulmonaires (TBP) que chez les 265 controles (P = 0,002 ; OR 0,6 ; IC95% 0.43-0,83). Les homozygotes pour la deletion de TGTG (1726+55del4) dans le 3'UTR de SLC11A1 sont representes de facon excessive parmi les patients TBP (P = 0,013 ; OR 5,19 ; IC95% 1.42-18.94). Une analyse de regression logistique par etapes a indique que les polymorphismes 5' et 3' contribuent a des effets principaux separes. Chez les patients atteints de meningite tuberculeuse (n = 22), on a trouve la meme frequence de genotype et le meme allele que chez les patients atteints de TBP. Aucun des polymorphismes de SLC11A2 testes n'a ete en association avec la TB. CONCLUSION: L'allele 5' (GT) n , poussant au plus haut taux de transcription de SLC11A1, semble associe a une protection contre la TB dans la majorite des populations etudiees.
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Incomplete glycosylation and defective intracellular targeting of mutant solute carrier family 11 member 1 (SLC11A1)
Biochemical Journal, 2004Co-Authors: Jacqueline K. White, Abigail Stewart, Jean-francois Popoff, Shona Wilson, Jenefer M BlackwellAbstract:Solute carrier family 11 member 1 (SLC11A1, formerly Nramp1) is a highly glycosylated, 12 transmembrane domain protein expressed in macrophages. It resides in the membrane of late endosomes and lysosomes, where it functions as a bivalent cation transporter. Mice susceptible to infection by various intracellular pathogens including Leishmania donovani and Salmonella typhimurium carry a glycine to aspartic acid substitution at position 169 (G169D, Gly169→Asp), within transmembrane domain 4 of SLC11A1. To investigate the molecular pathogenesis of infectious disease susceptibility, we compared the behaviour of heterologously and endogenously expressed wild-type and mutant SLC11A1 by immunofluorescence, immunoelectron microscopy and Western-blot analysis. We found occasional late endosome/lysosome staining of mutant protein using immunoelectron microscopy, but most of the mutant SLC11A1 was retained within the ER (endoplasmic reticulum). Using glycosylation as a marker for protein maturation in two independent heterologous expression systems, we found that most mutant SLC11A1 existed as an ER-dependent, partially glycosylated intermediate species. Correct endosomal targeting of wild-type SLC11A1 continued despite disruption of N-glycosylation sites, indicating that glycosylation did not influence folding or sorting. We propose that the G169D mutation causes localized misfolding of SLC11A1, resulting in its retention in the ER and manifestation of the loss of function phenotype.
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divalent cation transport and susceptibility to infectious and autoimmune disease continuation of the ity lsh bcg nramp1 SLC11A1 gene story
Immunology Letters, 2003Co-Authors: Jenefer M Blackwell, Susan Searle, H.s. Mohamed, Jacqueline K. WhiteAbstract:Solute carrier family 11 member a1 (SLC11A1), formerly known as Nramp1/Ity/Lsh/Bcg, is a proton/divalent cation antiporter that regulates susceptibility to infectious and autoimmune disease. Here we review recent studies on (1) the role of SLC11A1 in iron metabolism and iron recycling in macrophages; (2) the use of mouse breeding and introgression of knockouts onto SLC11A1 congenic backgrounds for genes encoding the multiple pleiotropic functions associated with SLC11A1; and (3) associations/linkages of SLC11A1 with human disease and how these relate to functional promoter region polymorphisms.
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solute carrier 11a1 SLC11A1 formerly nramp1 regulates metabolism and release of iron acquired by phagocytic but not transferrin receptor mediated iron uptake
Biochemical Journal, 2002Co-Authors: Jenefer M Blackwell, Susan Searle, Victoriano Mulero, J H BrockAbstract:Solute carrier 11a1 (SLC11A1; formerly Nramp1; where Nramp stands for natural-resistance-associated macrophage protein) is a proton/bivalent cation antiporter that localizes to late endosomes/lysosomes and controls resistance to pathogens. In the present study the role of SLC11A1 in iron turnover is examined in macrophages transfected with SLC11A1(Gly169) (wild-type) or SLC11A1(Asp169) (mutant=functional null) alleles. Following direct acquisition of transferrin (Tf)-bound iron via the Tf receptor, iron uptake and release was equivalent in wild-type and mutant macrophages and was not influenced by interferon-gamma/lipopolysaccharide activation. Following phagocytosis of [(59)Fe]Tf-anti-Tf immune complexes, iron uptake was equivalent and up-regulated similarly with activation, but intracellular distribution was markedly different. In wild-type macrophages most iron was in the soluble (60%) rather than insoluble (12%) fraction, with 28% ferritin (Ft)-bound. With activation, the soluble component increased to 82% at the expense of Ft-bound iron (<5%). In mutant macrophages, 40-50% of iron was in insoluble form, 50-60% was soluble and <5% was Ft-bound. Western-blot analysis confirmed failure of mutant macrophages to degrade complexes 24 h after phagocytic uptake. Confocal microscopy showed that complexes were within lysosome-associated membrane protein 1-positive vesicles in wild-type and mutant macrophages at 30 min and 24 h, implying failure in the degradative process in mature phagosomes in mutant macrophages. NO-mediated iron release was 2.4-fold higher in activated wild-type macrophages compared with mutant macrophages. Overall, our data suggest that iron acquired by phagocytosis and degradation is retained within the phagosomal compartment in wild-type macrophages, and that NO triggers iron release by direct secretion of phagosomal contents rather than via the cytoplasm.
Jacqueline K. White - One of the best experts on this subject based on the ideXlab platform.
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SLC11A1 formerly nramp1 is expressed in dendritic cells and influences major histocompatibility complex class ii expression and antigen presenting cell function
Infection and Immunity, 2007Co-Authors: Carmel B Stober, Jacqueline K. White, Jean-francois Popoff, Sven Brode, Jenefer M BlackwellAbstract:Solute carrier family 11 member a1 (SLC11A1; formerly Nramp1) encodes a late endosomal/lysosomal protein/divalent cation transporter that regulates iron homeostasis in macrophages. During macrophage activation, SLC11A1 has multiple pleiotropic effects on gene regulation and function, including gamma interferon-induced class II expression and antigen-presenting cell function. The wild-type allele at SLC11A1 has been associated with a bias in Th1 cell function in vivo, which is beneficial in resistance to infection against intracellular macrophage pathogens but detrimental in contributing to development of type 1 diabetes. The extent to which this depends on macrophage versus dendritic cell (DC) function is not known. Here we show that SLC11A1 is expressed in late endosomes and/or lysosomes of CD11c(+) DCs. DCs from mutant and congenic wild-type mice upregulate interleukin-12 (IL-12) and IL-10 mRNA in response to lipopolysaccharide (LPS) stimulation, but the ratio of IL-10 to IL-12 is higher in unstimulated DCs and DCs stimulated for 15 h with LPS from mutant mice than from wild-type mice. DCs from wild-type mice upregulate major histocompatibility complex class II in response to LPS more efficiently than DCs from mutant mice. Unstimulated DCs from wild-type and mutant mice present ovalbumin (OVA) peptide with an efficiency equivalent to that of an OVA-specific CD4 T-cell line, but DCs from wild-type mice are more efficient at processing and presenting OVA or Leishmania activator of cell kinase (LACK) protein to OVA- and LACK-specific T cells. These data indicate that wild-type SLC11A1 expressed in DCs may play a role both in determining resistance to infectious disease and in susceptibility to autoimmune disease such as type 1 diabetes.
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Candidate gene association study of solute carrier family 11a members 1 (SLC11A1) and 2 (SLC11A2) genes in Alzheimer's disease.
Neuroscience Letters, 2005Co-Authors: Sarra E. Jamieson, Jacqueline K. White, Joanna M. M. Howson, Rebecca Pask, Anne Smith, Carol Brayne, John Grimley Evans, John H. Xuereb, Nigel J. Cairns, David C. RubinszteinAbstract:Divalent cations are strongly implicated in Alzheimer's disease (AD) pathogenesis, and can regulate amyloid beta-peptide aggregation. The proton-divalent cation transporters encoded by SLC11A1 (formerly NRAMP1) on chromosome 2q35, and SLC11A2 (also known as DCT1 and DMT1) on chromosome 12q13, are expressed in the brain and regulate ion homeostasis from endosomal compartments. SLC11A1 also has pleiotropic effects on pro-inflammatory responses that may be important in AD. We analyzed seven informative polymorphisms in the SLC11A1 and SLC11A2 genes encoding these divalent cation transporters in a sample of 216 late-onset AD cases and 323 age-matched controls. We found only borderline evidence (p=0.08) for an allelic association between SNP rs407135 at SLC11A2 and AD, in which the variant allele was protective (odd ratio (OR) 0.77; 95% CI 0.56-1.04) relative to the more common allele. There was no interaction with apolipoprotein E (APOE) varepsilon4, but stratification by gender showed that all of the effect of SLC11A2 was in the male patient group. No other associations with AD were observed at SLC11A1 or SLC11A2, indicating no major effect of either gene for the occurrence of AD.
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Incomplete glycosylation and defective intracellular targeting of mutant solute carrier family 11 member 1 (SLC11A1)
Biochemical Journal, 2004Co-Authors: Jacqueline K. White, Abigail Stewart, Jean-francois Popoff, Shona Wilson, Jenefer M BlackwellAbstract:Solute carrier family 11 member 1 (SLC11A1, formerly Nramp1) is a highly glycosylated, 12 transmembrane domain protein expressed in macrophages. It resides in the membrane of late endosomes and lysosomes, where it functions as a bivalent cation transporter. Mice susceptible to infection by various intracellular pathogens including Leishmania donovani and Salmonella typhimurium carry a glycine to aspartic acid substitution at position 169 (G169D, Gly169→Asp), within transmembrane domain 4 of SLC11A1. To investigate the molecular pathogenesis of infectious disease susceptibility, we compared the behaviour of heterologously and endogenously expressed wild-type and mutant SLC11A1 by immunofluorescence, immunoelectron microscopy and Western-blot analysis. We found occasional late endosome/lysosome staining of mutant protein using immunoelectron microscopy, but most of the mutant SLC11A1 was retained within the ER (endoplasmic reticulum). Using glycosylation as a marker for protein maturation in two independent heterologous expression systems, we found that most mutant SLC11A1 existed as an ER-dependent, partially glycosylated intermediate species. Correct endosomal targeting of wild-type SLC11A1 continued despite disruption of N-glycosylation sites, indicating that glycosylation did not influence folding or sorting. We propose that the G169D mutation causes localized misfolding of SLC11A1, resulting in its retention in the ER and manifestation of the loss of function phenotype.
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divalent cation transport and susceptibility to infectious and autoimmune disease continuation of the ity lsh bcg nramp1 SLC11A1 gene story
Immunology Letters, 2003Co-Authors: Jenefer M Blackwell, Susan Searle, H.s. Mohamed, Jacqueline K. WhiteAbstract:Solute carrier family 11 member a1 (SLC11A1), formerly known as Nramp1/Ity/Lsh/Bcg, is a proton/divalent cation antiporter that regulates susceptibility to infectious and autoimmune disease. Here we review recent studies on (1) the role of SLC11A1 in iron metabolism and iron recycling in macrophages; (2) the use of mouse breeding and introgression of knockouts onto SLC11A1 congenic backgrounds for genes encoding the multiple pleiotropic functions associated with SLC11A1; and (3) associations/linkages of SLC11A1 with human disease and how these relate to functional promoter region polymorphisms.
Nancy Starobinas - One of the best experts on this subject based on the ideXlab platform.
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SLC11A1 nramp 1 gene modulates immune inflammation genes in macrophages during pristane induced arthritis in mice
Inflammation Research, 2017Co-Authors: Mara A Correa, Tatiane Canhamero, Andrea Borrego, Jose Ricardo Jensen, Wafa Hanna Koury Cabrera, Nancy Starobinas, Jussara Gonçalves Fernandes, Iana Suly Santos Katz, Jose Luiz Guerra, Orlando Garcia RibeiroAbstract:Objective and design Pristane-induced arthritis (PIA) in AIRmax mice homozygous for SLC11A1 R and S alleles was used to characterize the influence of SLC11A1 gene polymorphism on immune responses during disease manifestation. Previous reports demonstrated that the presence of the SLC11A1 S allele increased the incidence and severity of PIA in AIRmax SS , suggesting that this gene could interact with inflammatory loci to modulate PIA. We investigated the effects of SLC11A1 alleles on the activation of phagocytes during PIA.
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pristane induced arthritis loci interact with the SLC11A1 gene to determine susceptibility in mice selected for high inflammation
PLOS ONE, 2014Co-Authors: Marcelo Franco, Luciana C Peters, Mara A Correa, Antonella Galvan, Tatiane Canhamero, Andrea Borrego, Jose Ricardo Jensen, Jussara Goncalves, Wafa Hanna Koury Cabrera, Nancy StarobinasAbstract:AIRmax (maximal inflammation) and AIRmin (minimal inflammation) mice show distinct susceptibilities to pristane-induced arthritis (PIA). The SLC11A1 gene, which regulates macrophage and neutrophil activity, is involved in this infirmity. AIRmaxSS mice homozygous for the non-functional SLC11A1 S (gly169asp) allele obtained by genotype-assisted crosses from AIRmax and AIRmin mice are more susceptible than mice homozygous for the SLC11A1 resistant (R) allele. The present work sought to identify the quantitative trait loci (QTL) regulating PIA and to examine the interactions of these QTL with SLC11A1 alleles in modulating PIA. Mice were given two ip injections of 0.5 mL pristane at 60 day intervals, and the incidence and severity of PIA was scored up to 160 days. Genome-wide linkage studies were performed to search for arthritis QTL in an F2 (AIRmax × AIRmin, n = 290) population. Significant arthritis QTL (LODscore>4) were detected on chromosomes 5 and 8, and suggestive QTL on chromosomes 7, 17 and 19. Global gene expression analyses performed on Affymetrix mouse 1.0 ST bioarrays (27k genes) using RNA from arthritic or control mice paws showed 419 differentially expressed genes between AIRmax and AIRmin mice and demonstrated significantly (P<0.001) over-represented genes related to inflammatory responses and chemotaxis. Up-regulation of the chemokine genes Cxcl1, Cxcl9, Cxcl5, Cxcl13 on chromosome 5 was higher in AIRmaxSS than in the other lines. Macrophage scavenger receptor 1 and hemeoxigenase (decycling) 1 genes on chromosome 8 were also expressed at higher levels in AIRmaxSS mice. Our results show that the gene expression profiles of the two arthritis QTL (on chromosomes 5 and 8) correlate with SLC11A1 alleles, resulting in enhanced AIRmaxSS mice susceptibility to PIA.
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SLC11A1 formerly nramp1 gene modulates both acute inflammatory reactions and pristane induced arthritis in mice
Genes and Immunity, 2007Co-Authors: Luciana C Peters, Andrea Borrego, Jose Ricardo Jensen, Wafa Hanna Koury Cabrera, Nancy Starobinas, Olga M. Ibañez, Orlando Garcia Ribeiro, N. Baker, Marcelo FrancoAbstract:Mice selected for the maximum acute inflammatory reaction (AIRmax) are highly susceptible to pristane-induced arthritis (PIA), whereas mice selected for the minimum response (AIRmin) are resistant. These lines show distinct patterns of leukocyte infiltration and R and S allele frequency disequilibrium of the solute carrier family 11a member 1 (SLC11A1) gene. In order to study the interactions of the SLC11A1 R and S alleles with the inflammation modulating Quantitative Trait Loci (QTL) during PIA development, homozygous AIRmaxRR, AIRmaxSS, AIRminRR and AIRminSS lines were produced by genotype-assisted breedings. These mice received two intraperitoneal injections of 0.5 ml pristane at 60-day intervals, and the subsequent development of arthritis was assessed for 210 days. Cytokine-secreting cell profiles were investigated using enzyme-linked immunospot. Arthritis incidence in AIRmaxRR mice reached 29%, whereas PIA incidence in AIRmaxSS mice was 70% by day 180. AIRminRR mice were resistant, whereas 13.3% of AIRminSS mice became arthritic. The presence of the defective S allele also increased arthritis severity, although acute inflammation was higher in mice bearing the R allele. A predominant Th0/Th2-type response in SLC11A1SS mice was observed. These results indicate that SLC11A1 is a strong candidate for the QTL modulating acute inflammation and for PIA.
John Ikonomopoulos - One of the best experts on this subject based on the ideXlab platform.
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investigation of the association of the SLC11A1 gene with resistance sensitivity of goats capra hircus to paratuberculosis
Veterinary Microbiology, 2010Co-Authors: Laskarina Maria Korou, Maria Gazouli, Emmanouil Liandris, John IkonomopoulosAbstract:Abstract SLC11A1 (solute carrier family 11 member A1) protein is located on the phagolysosome membrane of macrophages and participates in bacterial killing. Here we have extended our previous work on the investigation of the potential association of polymorphisms of the 3′untranslated region (UTR) of SLC11A1 gene with test-positivity of goats to Mycobacterium avium subsp. paratuberculosis (MAP). Blood, serum and faeces were collected from 223 adult goats, from nine goat farms from Greece with a long-term record of paratuberculosis but no vaccination or tuberculin testing. The samples were subjected to sequence and structure analysis of the SLC11A1 gene and were evaluated by ELISA, culture and real time polymerase chain reaction. The 3′UTR region of the targeted gene revealed 2 microsatellites consisting of a variable number of guanine-thymine repeats named regions A and B. Statistically significant association was recorded between genotypes of region B and ELISA results, whereas the presence of B 7 allele was found to contribute to ELISA negativity. The comparison of the SLC11A1 mRNA level pre- and post-exposure to MAP shows elevated gene expression especially at the 3-h time point, in all macrophages tested regardless of their genotype. Unfortunately the latter could not be linked at a statistically significant level with any of the targeted genetic polymorphisms separately. In conclusion it can be stated that the evidence reported here provide the first indications on the association of B genotypes of the SLC11A1 gene and the detection of MAP-specific antibody by ELISA in goats.
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relationship between crohn s disease infection with mycobacterium avium subspecies paratuberculosis and SLC11A1 gene polymorphisms in sardinian patients
World Journal of Gastroenterology, 2006Co-Authors: Leonardo Antonio Sechi, Daniela Paccagnini, Lee E. Sieswerda, Maria Gazouli, John Ikonomopoulos, Niyaz Ahmed, Paola Molicotti, Antonio Mario Scanu, Stefania Anna Lucia ZanettiAbstract:AIM: To study the association between Crohn’s disease (CD), Mycobacterium avium subspecies paratuberculosis (MAP), and genetic factors by examining the role of natural resistance-associated macrophage protein 1 (NRAMP1) gene polymorphisms (now SLC11A1) in Sardinian patients with CD and controls. METHODS: Thirty-seven CD patients and 34 controls with no inflammatory bowel disease (IBD) were recruited at the University of Sassari after giving written consent. Six SCL11A1 polymorphisms previously reported to be the most significantly associated with IBD were searched. M. paratuberculosis was identified by IS900 PCR and sequencing. Logistic regression was used to calculate odds ratios (OR) for the associations among CD, presence of MAP, and 6 loci described above. RESULTS: For the first time, a strong association was observed between polymorphisms at NRAMP1 locus 823C/T and CD. While CD was strongly associated with both NRAMP1 and MAP, NRAMP1 polymorphisms and MAP themselves were not correlated. CONCLUSION: Combined with previous work on the NOD2/CARD15 gene, it is clear that the interplay of genetic, infectious, and immunologic factors in the etiology of CD is complex.
Orlando Garcia Ribeiro - One of the best experts on this subject based on the ideXlab platform.
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SLC11A1 nramp 1 gene modulates immune inflammation genes in macrophages during pristane induced arthritis in mice
Inflammation Research, 2017Co-Authors: Mara A Correa, Tatiane Canhamero, Andrea Borrego, Jose Ricardo Jensen, Wafa Hanna Koury Cabrera, Nancy Starobinas, Jussara Gonçalves Fernandes, Iana Suly Santos Katz, Jose Luiz Guerra, Orlando Garcia RibeiroAbstract:Objective and design Pristane-induced arthritis (PIA) in AIRmax mice homozygous for SLC11A1 R and S alleles was used to characterize the influence of SLC11A1 gene polymorphism on immune responses during disease manifestation. Previous reports demonstrated that the presence of the SLC11A1 S allele increased the incidence and severity of PIA in AIRmax SS , suggesting that this gene could interact with inflammatory loci to modulate PIA. We investigated the effects of SLC11A1 alleles on the activation of phagocytes during PIA.
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SLC11A1 formerly nramp1 gene modulates both acute inflammatory reactions and pristane induced arthritis in mice
Genes and Immunity, 2007Co-Authors: Luciana C Peters, Andrea Borrego, Jose Ricardo Jensen, Wafa Hanna Koury Cabrera, Nancy Starobinas, Olga M. Ibañez, Orlando Garcia Ribeiro, N. Baker, Marcelo FrancoAbstract:Mice selected for the maximum acute inflammatory reaction (AIRmax) are highly susceptible to pristane-induced arthritis (PIA), whereas mice selected for the minimum response (AIRmin) are resistant. These lines show distinct patterns of leukocyte infiltration and R and S allele frequency disequilibrium of the solute carrier family 11a member 1 (SLC11A1) gene. In order to study the interactions of the SLC11A1 R and S alleles with the inflammation modulating Quantitative Trait Loci (QTL) during PIA development, homozygous AIRmaxRR, AIRmaxSS, AIRminRR and AIRminSS lines were produced by genotype-assisted breedings. These mice received two intraperitoneal injections of 0.5 ml pristane at 60-day intervals, and the subsequent development of arthritis was assessed for 210 days. Cytokine-secreting cell profiles were investigated using enzyme-linked immunospot. Arthritis incidence in AIRmaxRR mice reached 29%, whereas PIA incidence in AIRmaxSS mice was 70% by day 180. AIRminRR mice were resistant, whereas 13.3% of AIRminSS mice became arthritic. The presence of the defective S allele also increased arthritis severity, although acute inflammation was higher in mice bearing the R allele. A predominant Th0/Th2-type response in SLC11A1SS mice was observed. These results indicate that SLC11A1 is a strong candidate for the QTL modulating acute inflammation and for PIA.