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Query: UMLS:C0003864 (arthritis)
 69,039 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A chance observation has led to the development of a new murine model for inflammatory arthritis. Arthritis is induced, and transferred, by T-cell-dependent antibodies to glucose-6-phosphate isomerase. This enzyme is expressed in all cells, and is detectable in serum. There are several similarities to rheumatoid arthritis (RA) in the murine disease. This elegant model raises several questions as to how and why a systemic response focuses inflammation so strongly on synovial joints. The model also re-introduces the possibility that antibodies to widely expressed self-proteins may play a role in the pathogenesis of RA.
Arthritis Res 2000
PMID:A new model for rheumatoid arthritis? 1109 17

In K/BxN T cell receptor-transgenic mice, spontaneous inflammatory arthritis exhibiting many of the features of human rheumatoid arthritis (RA) is initiated by T cells, but is almost entirely sustained by antibodies to the self-antigen glucose-6-phosphate isomerase (GPI). The relevance of these observations to human disease has been questioned. Here we show that 64% of humans with RA, but not controls, had increased concentrations of anti-GPI immunoglobulin G (IgG) in serum and synovial fluid. In addition, the concentrations of soluble GPI in the sera and synovial fluids of RA patients were also elevated, which led to immune complex formation. Using phage-display methods, we cloned a panel of specific high-affinity human monoclonal anti-GPI IgGs from a patient with RA. These antibodies were highly somatically mutated, which was indicative of an affinity-matured response that was antigen driven. Immunohistochemistry of RA synovium showed high concentrations of GPI on the surface of the synovial lining and on the endothelial cell surface of arterioles; this indicated a mechanism by which antibodies to GPI may precipitate joint disease. The results indicate that the immunological events that lead to the development of autoimmune disease in the K/BxN mouse model may also occur in human RA. This data may be used to develop new strategies for therapeutic intervention.
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PMID:Autoantibodies to GPI in rheumatoid arthritis: linkage between an animal model and human disease. 1197 12

K/BxN T cell receptor transgenic mice are a model of inflammatory arthritis, similar to rheumatoid arthritis. Disease in these animals is focused specifically on the joints but stems from autoreactivity to a ubiquitously expressed antigen, glucose-6-phosphate isomerase (GPI). T and B cells are both required for disease initiation, but anti-GPI immunoglobulins (Igs), alone, can induce arthritis in lymphocyte-deficient recipients. Here, we show that the arthritogenic Igs act through both Fc receptors (in particular, FcgammaRIII) and the complement network (C5a). Surprisingly, the alternative pathway of complement activation is critical, while classical pathway components are entirely dispensable. We suggest that autoimmune disease, even one that is organ specific, can occur when mobilization of an adaptive immune response results in runaway activation of the innate response.
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PMID:Arthritis critically dependent on innate immune system players. 1186 78

Arthritis in the K/BxN mouse model results from pathogenic immunoglobulins (Igs) that recognize the ubiquitous cytoplasmic enzyme glucose-6-phosphate isomerase (GPI). But how is a joint-specific disease of autoimmune and inflammatory nature induced by systemic self-reactivity? No unusual amounts or sequence, splice or modification variants of GPI expression were found in joints. Instead, immunohistological examination revealed the accumulation of extracellular GPI on the lining of the normal articular cavity, most visibly along the cartilage surface. In arthritic mice, these GPI deposits were amplified and localized with IgG and C3 complement. Similar deposits were found in human arthritic joints. We propose that GPI-anti-GPI complexes on articular surfaces initiate an inflammatory cascade via the alternative complement pathway, which is unbridled because the cartilage surface lacks the usual cellular inhibitors. This may constitute a generic scenario of arthritogenesis, in which extra-articular proteins coat the cartilage or joint extracellular matrix.
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PMID:How antibodies to a ubiquitous cytoplasmic enzyme may provoke joint-specific autoimmune disease. 1191 76

Arthritis in the K/BxN mouse model is provoked by pathogenic antibodies (Abs) directed against a ubiquitously expressed protein, glucose-6-phosphate isomerase (GPI). To begin dissecting the repertoire of arthritogenic immunoglobulins (Igs) in the K/BxN model, and to provide a basis for comparison with RA patients we have generated anti-GPI monoclonal Abs (mAbs) from spontaneously activated B cells in the lymphoid organs of arthritic mice. B cell clones with anti-GPI specificities were present at extraordinarily high frequencies in the spleen, and less frequently in other lymphoid organs and in the synovial fluid. None of the anti-GPI mAbs induced arthritis when injected individually into healthy recipients, but most were effective when combined in pairs or larger pools. Arthritogenic combinations depended on mAbs of the IgG1 isotype, which bound to GPI with Kd in the 10(-9) M range, with no indication of cooperative binding between complementing pairs. Pathogenicity was not associated with recognition of a particular epitope, but the ability to form mAb/GPI multimers by simultaneous recognition of different epitopes was clearly required, consistent with the known role of complement and FcRs in this model. Sequence analysis revealed structural similarities amongst the mAbs, indicating that a particular subset of B cells may evade tolerance in K/BxN mice, and that affinity maturation by somatic mutation likely takes place. These results confirm that GPI itself, rather than a cross-reactive molecule, is the target of pathogenic Igs.
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PMID:Arthritogenic monoclonal antibodies from K/BxN mice. 1195 98

There is increasing thought that autoantibodies to systemic self-antigens may provide a principal effector mechanism for the initiation and propagation of joint inflammation. The recent identification of arthritis transfer with antibodies to the self-antigen glucose-6-phosphate isomerase has boosted this interest. Fc receptor involvement in arthritis has been evaluated, identifying pro-inflammatory and inhibitory Fc gamma receptor subtypes, and demonstrating a link between Fc gamma receptor expression, cytokine production, cartilage destruction, and mouse strain susceptibility to immune complex arthritis. Further proof of a key role of interleukin (IL)-1 in arthritis was provided by the occurrence of spontaneous arthritis in IL-1 receptor antagonist knockout mice and elicitation of full-blown arthritis in tumor necrosis factor (TNF)-deficient mice. IL-18 (part of the IL-1 family) is a crucial upstream cytokine that, with IL-12, induces IL-1 and TNF and promotes arthritis and T-cell differentiation. IL-18 neutralization improved arthritis outcome, but its central role in host defense against bacterial infections may complicate therapeutic IL-18 targeting. T helper 1 (Th1) cells may aggravate arthritis and joint destruction through the production of IL-17, which shows joint destructive potential independent of IL-1. Studies have also focused on the control of receptor activator of nuclear factor kappaB ligand, modulation with IL-4, and regulation of downstream mediators in tissue destruction. Gene therapeutic approaches proved efficacious and will provide future ways to control arthritis.
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PMID:Lessons from animal models of arthritis. 1201 Jun 8

Patients with rheumatoid arthritis (RA) have several options for treatment nowadays, although we do not know what types of therapies are effective for these patients because RA is a very heterogenous disease. We discuss several possible mechanisms of RA in this review and explain one possible scenario of autoantibodies dependent arthritis confirmed by anti-glucose-6-phosphate isomerase antibodies. We also propose several efficacious treatments for treating these patients as made-to-order therapies.
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PMID:B cells and immunoglobulins dependent mechanisms in rheumatoid arthritis: a possible rationale of the extracorporeal immunomodulation for rheumatoid arthritis. 1216 3

Spontaneous arthritis in the KRN transgenic mouse (K/BxN) model is due to the autoreactivity of the transgenic TCR and subsequent induction of autoantibodies directed against glucose-6-phosphate isomerase. These autoantibodies transfer clinically apparent arthritis into most recipient mouse strains and systemic catabolism of the transferred Abs attenuates paw swelling. Although mice deficient in the common gamma-chain of the FcgammaR did not show clinical synovitis after receiving K/BxN sera, erosive lesions in the bone still developed. Further analysis demonstrated that FcgammaRII(-/-) mice manifested accelerated arthritis whereas the FcgammaRIII(-/-) mice had a more slowly progressing arthritis. Paw swelling required FcgammaR expression by bone marrow-derived cells and mast cells substantially contributed to the acute phase of paw swelling. In the K/BxN serum transfer model of arthritis, there is a clinically apparent acute phase, which is modulated by FcgammaRII and FcgammaRIII, and a subacute component, which results in bone erosion, even in the absence of FcgammaR signaling.
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PMID:The role of FcgammaR signaling in the K/B x N serum transfer model of arthritis. 1244 73

Intra-articular hypoxia in the inflamed rheumatoid joint is associated with increased cell proliferation, enhanced metabolism and compromised vascular perfusion. Recent clinical studies using direct measurements of hypoxia in rheumatoid joints have delineated up to 20% of soft tissue pO(2) readings as below 10mm Hg. Increased markers for glycolysis exist in rheumatoid synovial fluid and upregulation of tissue glycolytic enzymes occurs in a rat model of synovitis. Recent reports show arthritis is provoked by linked T and B cell lymphocyte recognition of the glycolytic enzyme glucose-6-phosphate isomerase (GPI). This suggests an unusual physiological feature of rheumatoid joints leads to autoimmune destruction. In this report I suggest that hypoxia, within the rheumatoid joint, leads to upregulation of the glycolytic enzyme GPI which in turn perpetuates rheumatoid arthritis.
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PMID:Hypoxia-induced upregulation of the glycolytic enzyme glucose-6-phosphate isomerase perpetuates rheumatoid arthritis. 1258 6

In 1996 a new murine model of spontaneous arthritis was described by the group of Benoist and Mathis. Mice transgenic for a T cell receptor recognizing an epitope of bovine RNase and bred onto a NOD background developed severe destructive arthritis, which resembles human rheumatoid arthritis in many respects. The development of disease requires the presence of T and B lymphocytes and is dependent on the MHC class II molecule I-A(g7). B cell activation by antigen and an additional CD40-CD40 ligand interaction was found to give rise to the production of autoantibodies. Glucose-6-phosphate isomerase was identified as the target of the autoantibodies; moreover, the transgenic T cells were demonstrated to exhibit a dual specificity for both bovine RNase and glucose-6-phosphate isomerase. Importantly, the arthritis is serum transferable to normal recipients, enabling the examination of the pathogenic mechanisms of joint inflammation and destruction. Recent studies suggest the crucial involvement of the innate immune system in the development of antibody-induced arthritis. Complement components, Fc receptors and neutrophils are indispensable for disease induction. An overview of the existing data is given and the emerging concepts of the pathogenesis of the K/BxN arthritis are discussed with respect to their relevance for human rheumatoid arthritis. Because of the reliable and robust induction of joint inflammation by serum transfer this new disease model has been and will be a valuable means to address the as-yet-unanswered key questions related to the development of arthritis.
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PMID:The KRN mouse model of inflammatory arthritis. 1290 93


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