Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0003864 (arthritis)
 69,039 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Immunization with type II collagen (CII) induces collagen-induced arthritis (CIA) in animals, and B cells reactive with CII are involved in the induction and manifestation of the disease. In this study, B cell hybridomas producing IgG antibodies specific for a major epitope on mouse CII (the "C1" epitope, amino acid 316-333), were isolated 11 days after immunization from draining lymph nodes in DBA/1 mice. Injection into neonatal mice of purified and biotinylated monoclonal antibodies binding the C1 epitope led to a specific binding to joint cartilage, demonstrating that the antibodies interact with native antigen in vivo. cDNA sequencing of the B cell clones revealed that they all expressed the same combination of a variable heavy chain (VH J558 family) and light chain (V kappa 21 family) germ-line gene, apparently lacking somatic mutations. The presence of isotype-switched B cells expressing a certain combination of V genes encoding antibodies that bind epitopes in vivo, indicates that this B cell population has been peripherally selected.
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PMID:Variable region gene selection of immunoglobulin G-expressing B cells with specificity for a defined epitope on type II collagen. 769 8

The arthritis-predisposing HLA-B27 consists of a heavy chain, a small peptide, and the monomorphic beta 2-microglobulin (beta 2-m). CTLs and a mAb, Ye-2, which recognize the complex with specificities both for the heavy chain and for the peptide, are available. The beta 2-m is in noncovalent association with the heavy chain at multiple points and is exchangeable with free beta 2-m outside of the complex. The purpose of our experiments was to test whether mutant beta 2-m capable of modulating HLA-B27 activity could be created. Eighteen recombinant mutants of the human beta 2-m were experimentally generated. In 14 of these, mutations were at or near residues that are either contact residues or interface residues with the heavy chain. Relative to the parent beta 2-m, two-thirds of the mutants showed reduced ability to exchange into HLA-B27 complexes. However, at least four of them induced more than 80% decrease in Ye-2 Ab reactivity. Two mutants were able to induce a minor decrease in susceptibility to lysis by four CTL clones. One of the CTL clones was autoreactive. Two of the CTL clones were specific for HLA-B27 cells experimentally infected with arthritis-causing Yersinia enterocolitica. These results indicate that certain beta 2-m residues play an indirect role in peptide presentation, although they are not directly associated with the peptide residues.
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PMID:The effect of mutant beta 2-microglobulins on the conformation of HLA-B27 detected by antibody and by CTL. 793 May 76

The mechanism by which PG of the E series (PGE) promote murine B lymphocyte IgE production was investigated. We previously reported that PGE, and other agents that increase intracellular cAMP, synergize with IL-4 and LPS to induce IgE and IgG1 production while inhibiting IgM and IgG3 synthesis. These data suggested that PGE may promote IL-4-induced class switching, but the mechanism by which PGE increases IgE synthesis remained obscure. We report here that 1) PGE increases (up to 14-fold) the number of splenic B cells secreting IgE, even though PGE mildly inhibits proliferation. 2) PGE acts on sorted surface IgM positive B cells, consistent with PGE acting on uncommitted B cells to promote class switching to IgE. 3) PGE synergizes with IL-4 to induce germline epsilon transcripts, demonstrating that PGE acts at the level of transcription in cells that have not yet switched to IgE. 4) In the presence of PGE, rearranged mature V(D)J epsilon mRNA transcripts can be detected earlier and at higher levels than with IL-4 and LPS alone. Taken together, these data provide strong evidence that PGE synergizes with IL-4 and LPS to direct isotype switching to the epsilon heavy chain gene in purified B lymphocytes. PGE is a potentially important in vivo immunoregulator, particularly with regard to IgE production and the genesis of allergy. In support of this hypothesis, there are numerous clinical conditions (hyper-IgE, trauma, sepsis, Hodgkin's lymphoma, arthritis) in which overproduction of PGE is coincident with elevated IgE titers.
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PMID:Prostaglandin E2 promotes B lymphocyte Ig isotype switching to IgE. 799 35

This study analyzed the distribution of an idiotype, B3-Id, in patients with active SLE, classified according to organ involvement, normal controls, and other autoimmune rheumatic diseases. A polyclonal anti-idiotype was raised by immunizing a rabbit with a monoclonal IgG anti-double-stranded (ds) DNA antibody, B3, generated from a patient with SLE who had active arthritis. The idiotype is present on the lambda chain and is at or near the binding site for double-stranded DNA. The lambda chain, which was characterized by nucleotide sequencing, was 90% homologous to the V lambda 2.1 germline, which is known to be involved in coding for nephritogenic anti-DNA antibodies carrying the 8.12 idiotype. There were four changes to positively charged amino acids, known to be involved in DNA binding, in the complementarity determining regions of B3 lambda chain compared with a non-DNA binding, 8.12 positive antibody, PV11. Only one change to a positively charged amino acid occurs in the heavy chain of B3, which is 93.5% homologous to VH-26. The B3-Id was present on IgG antibodies in the serum of 20% of patients with SLE but was not found in the normal controls. Within the SLE group, there is a statistically significant association of B3-Id on IgG in the arthritis group (42%) compared to the other manifestations (9%) (P < 0.001). In four B3-Id-positive SLE patients tested serially, the level of B3-Id reflected the arthritis disease activity more closely than the overall disease activity (P < 0.05). The B3-Id was also present on IgM antibodies in one third of patients with rheumatoid arthritis. This idiotype is the first to be derived from a human monoclonal anti-DNA antibody of the IgG class, the isotype associated with active disease. Sequence analysis shows that positively charged amino acids on the lambda chain may contribute to DNA binding.
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PMID:Serological and genetic characterization of a human monoclonal immunoglobulin G anti-DNA idiotype. 816 78

The increased amounts of agalactosyl IgG (N-linked oligosaccharides terminating with N-acetylglucosamine (GlcNAc) in the serum of patients with rheumatoid arthritis (RA) and other chronic inflammatory diseases have suggested that agalactosyl IgG may be involved in the pathogenesis of RA. We have now evaluated the incidence of agalactosyl IgG in the Lewis rat during the course of adjuvant arthritis (AA). The modification in glycosylation of IgG was measured by means of polyclonal and monoclonal anti GlcNAc antibodies as well as by the lectin concanavalin A (Con A). The results show that Lewis rats undergo a change in serum IgG glycosylation during the course of AA. As in human RA patients, rats with AA lack terminal galactose on IgG heavy chain oligosaccharides, and the terminal GlcNAc or mannose residues are thus exposed. The degree of agalactosyl IgG was positively correlated with the incidence of disease, peaked 20 days after disease induction, and the IgG gradually reverted to the fully glycosylated form thereafter. The post-arthritic glycosylation profile was very similar to that characteristic of the naive animal. Purified IgG was shown to contain two IgG subclasses, IgG1 and IgG2b, which underwent changes in glycosylation. Western blot analysis revealed that IgG1 expressed a higher degree of terminal mannose, whereas IgG2b expressed a higher degree of terminal GlcNAc. These findings raise the question of the possible involvement of agalactosyl IgG in immune complex-mediated inflammation.
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PMID:Adjuvant arthritis is associated with changes in the glycosylation of serum IgG1 and IgG2b. 825 6

In summary, we suggest that the following statements regarding lupus nephritis are best supported by the existing data. 1) Lupus nephritis is an immunologically complex disorder. Autoantibodies directed against multiple epitopes on chromatin, including but not limited to dsDNA, may contribute to nephritis. 2) The presence of charged residues within autoantibody heavy chain CDR regions, particularly CDR3, may be essential to the property of nephritogenicity. 3) Chromatin/antichromatin immune complexes (formed either in the circulation or in situ in the GBM) are likely the proximal cause of lupus nephritis. Cross-reactive autoantibodies or antibodies reacting directly to glomerular antigens are less likely to play a major pathogenic role. 4) The induction of lupus nephritis may relate to the propensity of chromatin or its components to bind to the GBM by virtue of the interactions of histones with type IV collagen and heparan-sulfated glycosaminoglycans. Nonetheless, as indicated above, there are numerous issues that remain to be addressed and clarified with respect to lupus nephritis. Insight into these issues is not only of theoretical interest, but may lead to new approaches to diagnostic testing and more specific therapies to replace currently use nonspecific immunosuppressive drugs, which have substantial toxicities.
Arthritis Rheum 1996 Jun
PMID:Nephritogenic autoantibodies in lupus: current concepts and continuing controversies. 865 82

Antiphospholipid antibodies (aPL) are recognized increasingly as a probable cause of clinical features such as thrombosis and recurrent miscarriages, particularly in a subset of patients with systemic lupus erythematosus (SLE) and those with the antiphospholipid antibody syndrome (APS). A powerful method of studying the origin of these antibodies and delineating their binding sites is to sequence monoclonal aPL. The few reports of mouse aPL sequences suggest that gene families J558 and Vk23 may be used preferentially but without extensive mutation of complementarity determining regions (CDR). Polyreactive human aPL, which bind DNA as well as phospholipids, generally use germline genes with few mutations. Specific immunoglobulin (Ig) M aPL also tend to use relatively unmutated genes but often have high concentrations of positive residues in CDR, which may enhance binding to anionic phospholipids. IgG aPL show many more antigen-selected mutations, particularly in heavy chain CDR. This difference between isotypes is similar to that seen in anti-DNA antibodies, but the role of positively charged residues in aPL is less evident, and additional motifs are likely to be important in antigen binding.
Semin Arthritis Rheum 1996 Oct
PMID:Sequences of monoclonal antiphospholipid antibodies: variations on an anti-DNA antibody theme. 891 96

HLA-B27 has a striking association with inflammatory arthritis. We show that free HLA-B27 heavy chains can form a disulfide-bonded homodimer, dependent on residue Cys67 in their extracellular alpha 1 domain. Despite the absence of beta 2-microglobulin, HLA-B27 heavy chain homodimers (termed HC-B27) were stabilized by a known peptide epitope. HC-B27 complexes were recognized by the conformation-specific Ab W6/32, but not the ME1 Ab. Surface labeling and immunoprecipitation demonstrated the presence of similar W6/32-reactive free heavy chains at the surface of HLA-B27-transfected T2 cells. HC-B27 homodimer formation might explain the ability of HLA-B27 to induce spondyloarthropathy in beta 2-microglobulin-deficient mice.
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PMID:Cutting edge: HLA-B27 can form a novel beta 2-microglobulin-free heavy chain homodimer structure. 1022 70

In 1991, gamma heavy chain disease was diagnosed in a 43-year-old female, who 3 years earlier had contracted an erosive seronegative chronic arthropathy. In 1996, her lymphoproliferative disorder required treatment with melphalan and prednisolone. Laboratory studies revealed a gamma3 heavy chain monoclonal component in serum and urine. Massive localization of plasma cells and blasts with cytoplasmic or cell membrane staining for gamma3 chains, but no staining for light chains, was observed by immunohistochemical studies of bone marrow as well as affected synovial tissue. Large amounts of extracellular gamma3-chains were also deposited in the synovial membrane. This is the first documentation of gamma heavy chain deposition disease directly affecting articular structures. Whether it represents the primary pathogenic event followed by reactive inflammatory changes in the joints, or another example of gamma heavy chain disease preceded by chronic arthritis, remains elusive. Regardless, several common cellular and molecular mechanisms discussed here suggest a pathogenic link between the two disease processes.
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PMID:Is there a pathogenic link between gamma heavy chain disease and chronic arthritis? 1064 57

HLA-B27 is highly linked with a group of human diseases called spondyloarthropathies (SpA). Many of these disorders begin after an infection with an enterobacteria. The symptoms seen in patients with spondyloarthropathies are inflammatory pain in the spine and asymmetrical arthritis of lower limbs. Additional symptoms related to SpA include inflammation in the eyes, bowel, and skin. The autoantigen(s) in SpA are not known. Proteins such as collagen and proteoglycans have been thought to be potent autoantigens in arthritidis including B27-associated human diseases. Type II collagen is a common denominator among eyes and joints, affected tissues in B27-linked diseases. Moreover, a few reports indicated CII specific T cells and antibodies in patients with spondyloarthropathies. We and others have previously described development of spontaneous arthritis and nail disease in HLA-B27 transgenic animals. To determine whether CII may be a target antigen in the B27-linked diseases, B27 + m beta 2 m% (HLA-B27) transgenic mice lacking mouse beta 2m with and without human beta 2m) mice were immunized with type II collagen inside the barrier facility. Male HLA-B27 transgenic mice developed collagen-induced arthritis compared to transgene negative littermates or female counterparts. There was no difference in the incidence of arthritis in HLA-B27 transgenic mice with and without human beta 2m. Our data suggest that beta 2m free heavy chain of HLA-B27 may present soluble antigens such as type II collagen to trigger specific T cells contributing in the development of arthritis. Our data also suggest that CII may be a potential target antigen in the cartilage during the disease process.
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PMID:HLA-B27 transgenic mice are susceptible to collagen-induced arthritis: type II collagen as a potential target in human disease. 1071 6


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