Quantitative photometrical assessment of iron deposits in synovial membranes in different joint diseases

Fritz, Péter; Saal, J. G.; Wicherek, C; König, A.; Laschner, W; Rautenstrauch, H

doi:10.1007/bf00290523

Cited by 15 publications

(12 citation statements)

References 33 publications

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“…Patients with RA show a statistically significant increase in iron deposits in the synovial membrane compared with osteoarthritis patients (46), with an inverse correlation between the hemoglobin concentration and serum erythrocyte levels and the amount of iron in the synovial membrane. In a collaborative study (Mulero V, Wei X, Liew FY, Barton CH, Blackwell JM, and Brock J: manuscript submitted), it has been shown that iron delivered as insoluble 59 FE-labeled transferrin-antitransferrin accumulates in macrophages transfected with mutant Nramp1, but is efficiently recycled to the medium in wild-type transfectants.…”

Section: Discussionmentioning

confidence: 94%

Polymorphism at NRAMP1 and D2S1471 loci associated with juvenile rheumatoid arthritis

Sanjeevi

Miller

Dabadghao

et al. 2000

Arthritis & Rheumatism

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Objective. To examine the role of NRAMP1 in susceptibility to juvenile rheumatoid arthritis (JRA).Methods. DNA from 119 JRA patients (72 pauciarticular, 47 polyarticular) and 111 healthy controls from Latvia was genotyped for a functional repeat polymorphism in the promoter of NRAMP1 and a linked (<150 kb) microsatellite D2S1471. The findings were compared with those from HLA-DQ alleles typed previously. Chi-square analyses were performed using the Mantel-Haenszel test and stratification according to pure Latvian or pure Russian descent. Haplotype analysis was performed using the Associate program to implement the expectation-maximization algorithm based on the gene-counting technique.Results. Allele 3 at NRAMP1 conferred increased risk (odds ratios [ORs] 2.26, 2.31, and 2.19; P ‫؍‬ 0.0006, 0.003, and 0.019) of disease in the JRA, pauciarticular, and polyarticular patient groups, respectively. Allele 2 conferred protection (OR 0.44, 0.43, and 0.46). Alleles at D2S1471 that conferred susceptibility (6 and 12) or protection (11) did so only when on a haplotype with alleles 3 or 2, respectively, at NRAMP1. Allele 3 at NRAMP1 was additive with HLA-DQ7 for susceptibility (OR 3.71, 3.71, and 4.02), and allele 2 at NRAMP1 was additive with HLA-DQ5 for protection (OR 0.19, 0.08, and 0.12).Conclusion. The NRAMP1 allele conferring susceptibility to JRA drives high levels of NRAMP1 expression, while the allele associated with protection drives low levels. These 2 alleles are inversely associated with susceptibility to infectious disease, consistent with their maintenance in populations through balancing selection.

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Section: Discussionmentioning

confidence: 94%

Polymorphism at NRAMP1 and D2S1471 loci associated with juvenile rheumatoid arthritis

Sanjeevi

Miller

Dabadghao

et al. 2000

Arthritis & Rheumatism

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“…[2,3]) in determining susceptibility to inflammatory and autoimmune diseases, and indeed, different pleiotropic effects might play different roles in each disease (reviewed in ref. Patients suffering from rheumatoid arthritis, for example, show a statistically significant increase in iron deposits in the synovial membrane compared with osteoarthritis patients [39], with an inverse correlation between the hemaglobin concentration and erythrocytes in the serum and the amount of iron in the synovial membrane. A direct role for divalent cation transport function in pathogenesis is also an attractive hypothesis.…”

Section: Discussionmentioning

confidence: 99%

“…A direct role for divalent cation transport function in pathogenesis is also an attractive hypothesis. Patients suffering from rheumatoid arthritis, for example, show a statistically significant increase in iron deposits in the synovial membrane compared with osteoarthritis patients [39], with an inverse correlation between the hemaglobin concentration and erythrocytes in the serum and the amount of iron in the synovial membrane. This could relate to the direct role Slc11a1 has in regulating cytoplasmic iron content and iron recycling [40,41].…”

Section: Discussionmentioning

confidence: 99%

Influence ofSlc11a1(formerlyNramp1) on DSS-induced colitis in mice

Jiang

Gilchrist

Popoff

et al. 2008

Journal of Leukocyte Biology

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Multiple genetic studies in humans indicate a role for solute carrier family 11a member 1 [SLC11A1; formerly natural resistance-associated macrophage protein 1 (NRAMP1)] in autoimmune disease susceptibility, including ulcerative colitis. Murine Slc11a1 has many pleiotropic effects on macrophage activation and proinflammatory responses. To determine which of these are important in ulcerative colitis, we established a phenotype for oral dextran sulfate sodium (DSS)-induced acute colitis in congenic Slc11a1 wild-type (wt) and mutant (mt) mice on a B10 background. For over 7 days of treatment with 2% DSS in the drinking water, Slc11a1 wt mice showed enhanced acute ulcerative colitis, as demonstrated by significantly greater body weight loss and reduction in colon length, as well as a marked increase in monocyte/macrophage inflammatory infiltrates and histopathology changes in the colon. This was accompanied by a clear, inverse relationship between IFN-gamma and IL-10 responses in Slc11a1 wt compared with mt mice, resulting in a significantly higher ratio of IFN-gamma:IL-10 in wt compared with mt mice in lymph node and splenic T cells. RNase protection assays confirmed the presence of significantly higher IFN-gamma at the RNA level in the colons of wt compared with mt mice at Day 7 of treatment. Interestingly this was accompanied by significantly enhanced RNA levels for the acute-phase protein IL-6, which is known to inhibit the generation of forkhead box P3+ regulatory T cells and help to drive the differentiation of Th17 from naive T cells and not by differences in RNA for IL-12p35 or IL-12p40 molecules that dimerize to form the Th1-inducing cytokine IL-12.

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Section: Figure 6 Model Of Bivalent Cation Homoeostasis In Macrophagesmentioning

confidence: 99%

“…In the case of the regulation of arthritic diseases [5,7], NRAMP1 may contribute directly to the statistically significant increase in iron deposition observed in the synovial membrane of rheumatoid arthritis compared with osteoarthritis patients [47]. The inverse correlation between haemoglobin and erythrocytes in the serum and the amount of iron in the synovial membrane [47] also suggests a role in diseaseassociated anaemia. Indeed, polymorphism and the role of NRAMP1\2 should be examined more broadly in the context of both the anaemias of chronic disease, inflammatory, infectious or neoplastic disorders, and nutritionally related anaemias (reviewed in [48,49]).…”

Section: Figure 6 Model Of Bivalent Cation Homoeostasis In Macrophagesmentioning

confidence: 99%

Natural-resistance-associated macrophage protein 1 is an H+/bivalent cation antiporter

Goswami

Bhattacharjee

Babal

et al. 2001

Biochemical Journal

135

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In mammals, natural-resistance-associated macrophage protein 1 (Nramp1) regulates macrophage activation and is associated with infectious and autoimmune diseases. Nramp2 is associated with anaemia. Both belong to a highly conserved eukaryote/prokaryote protein family. We used Xenopus oocytes to demonstrate that, like Nramp2, Nramp1 is a bivalent cation (Fe2+, Zn2+ and Mn2+) transporter. Strikingly, however, where Nramp2 is a symporter of H+ and metal ions, Nramp1 is a highly pH-dependent antiporter that fluxes metal ions in either direction against a proton gradient. At pH9.0, oocytes injected with cRNA from wild-type murine Nramp1 with a glycine residue at position 169 (Nramp1G169; P = 3.22×10-6) and human NRAMP1 (P = 3.87×10-5) showed significantly enhanced uptake of radiolabelled Zn2+ compared with water-injected controls. At pH5.5, Nramp1G169 (P = 1.34×10-13) and NRAMP1 (P = 1.09×10-6) oocytes showed significant efflux of Zn2+. Zn2+ transport was abolished when the proton gradient was dissipated using carbonyl cyanide p-trifluoromethoxyphenylhydrazone. Using pre-acidified oocytes, currents of 130±57 nA were evoked by 100µM Zn2+ at pH7.5, and 139±47 nA by 100µM Fe2+ at pH7.0, in Nramp1G169 oocytes; currents of 254±49 nA and 242±26 nA were evoked, respectively, in NRAMP1 oocytes. Steady-state currents evoked by increasing concentrations of Zn2+ were saturable, with apparent affinity constants of approx. 614nM for Nramp1G169 and approx. 562nM for NRAMP1 oocytes, and a curvilinear voltage dependence of transporter activity (i.e. the data points approximate to a curve that approaches a linear asymptote). In the present study we propose a new model for metal ion homoeostasis in macrophages. Under normal physiological conditions, Nramp2, localized to early endosomal membranes, delivers extracellularly acquired bivalent cations into the cytosol. Nramp1, localized to late endosomal/lysosomal membranes, delivers bivalent cations from the cytosol into this acidic compartment where they may directly affect antimicrobial activity.

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Quantitative photometrical assessment of iron deposits in synovial membranes in different joint diseases

Cited by 15 publications

References 33 publications

Polymorphism at NRAMP1 and D2S1471 loci associated with juvenile rheumatoid arthritis

Polymorphism at NRAMP1 and D2S1471 loci associated with juvenile rheumatoid arthritis

Influence ofSlc11a1(formerlyNramp1) on DSS-induced colitis in mice

Natural-resistance-associated macrophage protein 1 is an H+/bivalent cation antiporter

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