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)

We generated transgenic mice with DRB1*0401 gene with mutation in the beta2 domain (aa 110 and 139) for better interaction with mCD4. The DR4 transgene was introduced into H2-Aq (B10RQB3) and H2-Af (B10RFB3) to examine the role of DR4 in collagen arthritis. The HLA-DR molecules in these mice were found to be functional on the basis of their positive/negative selection of the Vbeta T cell repertoire. H2-Aq mice are resistant to porcine CII-induced arthritis. The RQB3/DR4 mice (H2Aq/DR4) developed severe collagen induced arthritis (CIA) when immunized with Porcine type II collagen while the negative littermates were resistant. RQB3.DR4 mice were also highly susceptible to CIA induced by Human CII while negative littermates got only mild disease. However, RFB3/DR4 mice (H2Af/ DR4) did not get CIA with any type II collagen. Therefore, the DR4 gene in the context of H2-Aq predisposes to severe arthritis but not in the context of H2-Af. Antibodies to renatured cyanogen bromide (CB) cleaved fragments of PII in RQB3/DR4 mice and negative littermates suggest that the presence of DR4 does not result in any differences in specificity of antibody response to CB fragments. These results indicate that a specific gene complementation occurring between DR4 and H2.Aq but not DR4 and H2Af promotes the induction of arthritis with PII and HII in these mice. A similar interaction may be involved between DR and DQ molecules in human RA.
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PMID:Complementation between HLA-DR4 (DRB1*0401) and specific H2-A molecule in transgenic mice leads to collagen-induced arthritis. 1052 88

It has been well established that many diseases are linked to HLA antigens. Two of the most interesting HLA associations may provide some insight into the pathogenesis of rheumatic inflammatory conditions. In ankylosing spondylitis (AS), 96% of patients possess HLA-B27, whilst the frequency of this marker in the general population is c. 8%. In rheumatoid arthritis (RA), >90% of patients possess either HLA-DR1 or some subtypes of HLA-DR4, whilst the frequency of this marker in the general population is c. 35%. The association between HLA-B27 and reactive arthritis (ReA) has also been well established. Furthermore, it has been shown that ReA is triggered by infection via the gastrointestinal tract due to Yersinia, Salmonella or Campylobacter spp. and in the genitourinary tract due to chlamydia. In a similar way, microbiological and immunological studies have revealed an association between Klebsiella pneumoniae in AS and Proteus mirabilis in RA. This article reviews the possible pathological implications of the associations between HLA-B27, K. pneumoniae and AS, as well as HLA-DR1/DR4, P. mirabilis and RA.
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PMID:HLA molecules, bacteria and autoimmunity. 1075 23

Inherited susceptibility to rheumatoid arthritis (RA) is associated with the DRB1 genes encoding the human leukocyte antigen (HLA)-DR4 and HLA-DR1 molecules. Transgenic mice expressing these major histocompatibility complex (MHC) class II molecules have been developed to generate humanized models for RA. The relevance of these models for understanding RA will be discussed.
Arthritis Res 2000
PMID:Association of MHC and rheumatoid arthritis. HLA-DR4 and rheumatoid arthritis: studies in mice and men. 1109 29

Antibiotic treatment-resistant Lyme arthritis is a chronic inflammatory joint disease that follows infection with Borrelia burgdorferi (BB:). A marked Ab and T cell response to BB: outer surface protein A (OspA) often develops during prolonged episodes of arthritis. Furthermore, cross-reaction between the bacterial OspA and human LFA-1alpha(L) at the T cell level and the inability to detect BB: in the joint implicate an autoimmune mechanism. To analyze the nature of response to OspA and LFA-1alpha(L), we used OspA-specific T cell hybrids from DR4 transgenic mice, as well as cloned human cells specific for OspA(165-184), the immunodominant epitope, from five DRB1*0401(+) patients, using OspA-MHC class II tetramers. Although OspA(165-184) stimulated nearly all OspA-specific human T cell clones tested to proliferate and secrete IFN-gamma and IL-13, LFA-1alpha(L326-345) stimulated approximately 10% of these clones to proliferate and a greater percentage to secrete IL-13. Assays with LFA- or OspA-DR4 monomers revealed that higher concentrations of LFA-DR4 were needed to stimulate dual-reactive T cell hybrids. Our analysis at the clonal level demonstrates that human LFA-1alpha(L326-345) behaves as a partial agonist, perhaps playing a role in perpetuating symptoms of arthritis.
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PMID:Molecular mimicry in Lyme arthritis demonstrated at the single cell level: LFA-1 alpha L is a partial agonist for outer surface protein A-reactive T cells. 1129 Aug 15

The balance between interleukin-1 (IL-1) and its competitive antagonist IL-1 receptor antagonist (IL-1Ra) may contribute to the pathogenesis of rheumatoid arthritis (RA). We analysed the frequency of different alleles in the IL-1B gene (at -511 and at +3954) as well as in the IL-1Ra gene (at +2018) in an association study involving 297 RA patients and 112 healthy controls from the same geographic area. We tested associations with RA susceptibility or severity, and with circulating levels of IL-1Ra and IL-1beta. Carriage of the rare IL-1B (+3954) allele 2 was increased in destructive arthritis (DRA) as compared to non-destructive arthritis (NDRA) (OR 1.7, 95% CI 1.1-2.8, 49.0% vs 35.9%) and controls (OR 1.7, 95% CI 1.1-2.8, 35.8%). Patients carrying this allele had a more destructive (Larsen wrist radiological index: mean +/- s.e.m., 2.1 +/- 0.2 vs 1.6 +/- 0.1, P = 0.005; Steinbrocker functional index: 2.4 +/- 0.1 vs 1.9 +/- 0.1, P = 0.002) and active disease (Ritchie articular index: 8.1 +/- 0.8 vs 5.3 +/- 0.6, P = 0.002; erythrocyte sedimentation rate (ESR): 36.6 +/- 2.9 mm/h vs 25.3 +/- 1.8 mm/h, P = 0.002). This contribution was independent from that of HLA DR4/DR1 to severity. IL-1Ra plasma levels adjusted to ESR values were significantly lower in IL-1B2 (+3954) positive than negative RA patients (1.0 +/- 0.1 vs 1.2 +/- 0.1 ng/ml, P = 0.01). This IL-1B (+3954) gene polymorphism may be an important marker for the severity of joint destruction in RA and is associated with an imbalance in IL-1Ra production. As this genetic association was independent and additive to the risk of HLA DR4/DR1 status, it could be a useful addition to HLA-DR4/1 as a genetic prognostic marker early in the course of the disease.
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PMID:IL-1B and IL-1Ra gene polymorphisms and disease severity in rheumatoid arthritis: interaction with their plasma levels. 1147 78

Rheumatoid arthritis is an autoimmune disease in which susceptibility is strongly associated with the expression of specific HLA-DR haplotypes, including DR1 (DRB1*0101) and DR4 (DRB1*0401). As transgenes, both of these class II molecules mediate susceptibility to an autoimmune arthritis induced by immunization with human type II collagen (hCII). The dominant T cell response of both the DR1 and DR4 transgenic mice to hCII is focused on the same determinant core, CII(263-270). Peptide binding studies revealed that the affinity of DR1 and DR4 for CII(263-270) was at least 10 times less than that of the model Ag HA(307-319), and that the affinity of DR4 for the CII peptide is 3-fold less than that of DR1. As predicted based on the crystal structures, the majority of the CII-peptide binding affinity for DR1 and DR4 is controlled by the Phe(263); however, unexpectedly the adjacent Lys(264) also contributed significantly to the binding affinity of the peptide. Only these two CII amino acids were found to provide binding anchors. Amino acid substitutions at the remaining positions had either no effect or significantly increased the affinity of the hCII peptide. Affinity-enhancing substitutions frequently involved replacement of a negative charge, or Gly or Pro, hallmark amino acids of CII structure. These data indicate that DR1 and DR4 bind this CII peptide in a nearly identical manner and that the primary structure of CII may dictate a different binding motif for DR1 and DR4 than has been described for other peptides that bind to these alleles.
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PMID:HLA-DR1 (DRB1*0101) and DR4 (DRB1*0401) use the same anchor residues for binding an immunodominant peptide derived from human type II collagen. 1175 69

Seventeen children who met the criteria for juvenile chronic arthritis (JCA) were reviewed. Throughout the study, the clinical examination, HLA phenotyping, and radiological assessment of the hips were performed by separate authors who were blinded to other data. At the end of the study, the results were also compared with 25 healthy, age- and sex-matched children. Six of the children with JCA also had radiological signs of slipped capital femoral epiphysis (SCFE; five with minimal slip pattern, one with moderate slip), and five of them had DR4 in their genotypes, in contrast to the remaining 11 patients who did not (p < 0.001). On the other hand, only 2 of 25 children in the control group had DR4 (p < 0.01). The difference was not significant when the patients without SCFE were compared with the control group (p = 1.0). The relative risk of cases with DR4 antigen for SCFE was 57.5, while it was below I for the other antigens. These results suggest that although DR4 is not specific for JCA, it is the common HLA antigen for those who have SCFE, and patients with JCA and HLA-DR4 antigen should be examined for evidence of SCFE, which was not reported before to exist with JCA.
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PMID:The association of HLA-DR4 antigen with juvenile chronic arthritis and slipped capital femoral epiphysis. 1176 38

Collagen II arthritis (CIA) represents an animal model of human RA that can be induced in DBA/1J (H-2(q)) but not in C57BL/6 mice (H-2(b)). A vigorous CII specific CD4 Th1-cell response but not IgG2 anti-CII antibody or CIA could be induced in C57BL/6 mice made transgenic for the RA shared epitope DR4 (B1*0401). We developed CD4 Th1-cell clones specific for CII from these transgenic (tg) mice in order to determine if the adoptive transfer of these clones into syngeneic tg C57BL/6 recipients could induce CIA. Three bovine CII specific (bCII) CD4 Th1-cell clones and one T-cell line specific for an immunodominant region of bCII (p261-273) were generated. Among these only one clone that could up-regulate anti-CII, IgG2 antibody in the recipient mice was able to induce transient arthritis. However, this level of IgG2 anti-CII antibody was only one-third of that seen in CII immunized DBA/1J mice that develop persistent arthritis. These results confirm our previous observations that the induction of CIA requires a sustained IgG2 antibody response to CII, an effect difficult to achieve even in DR4 (B1*0401) tg mice reconstituted with CD4 Th1 cells. This suggests that a rate limiting step in the development of human RA among those individuals expressing the RA shared epitope may be the requirement to generate sustained levels of complement fixing antibody to arthritogenic antigens.
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PMID:Induction of transient arthritis by the adoptive transfer of a collagen II specific Th1 clone to HLA-DR4 (B1*0401) transgenic mice. 1236 57

Type II collagen (CII) is a candidate cartilage-specific autoantigen, which can become post-translationally modified by hydroxylation and glycosylation. T cell recognition of CII is essential for the development of murine collagen-induced arthritis (CIA) and also occurs in rheumatoid arthritis (RA). The common denominator of murine CIA and human RA is the presentation of an immunodominant CII-derived glycosylated peptide on murine Aq and human DR4 molecules, respectively. To investigate the importance of T cell recognition of glycosylated CII in CIA development after immunization with heterologous CII, we treated neonatal mice with different heterologous CII-peptides (non-modified, hydroxylated and galactosylated). Treatment with the galactosylated peptide (galactose at position 264) was superior in protecting mice from CIA. Protection was accompanied by a reduced antibody response to CII and by an impaired T cell response to the glycopeptide. To investigate the importance of glycopeptide recognition in an autologous CIA model, we treated MMC-transgenic mice, which express the heterologous CII epitope with a glutamic acid in position 266 in cartilage, with CII-peptides. Again, a strong vaccination potential of the glycopeptide was seen. Hence CII-glycopeptides may be the optimal choice of vaccination target in RA, since humans share the same epitope as the MMC mouse.
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PMID:Glycosylation of type II collagen is of major importance for T cell tolerance and pathology in collagen-induced arthritis. 1251 72

A 32-year-old Japanese man developed polyarthritis with mild fever and conjunctivitis. Clinical assessment indicated non-specific arthritis, aseptic pyuria induced by infection with Chlamydia, and conjunctivitis. He was diagnosed with reactive arthritis (Reiter's syndrome). Serotyping of human leucocyte antigen (HLA) class I and II revealed positivity for B51(5), A2, A33(19), B44(12), Cw1, DR4 and DR6, but B27 was negative. He was treated with a combination of doxycycline, oral prednisolone, diclofenac sodium and salazosulphapyridine. Fever and arthralgia improved and he became negative for anti-Chlamydia immunoglobulin (Ig) A and IgG antibodies. HLA-B51 may be involved in the pathogenesis of Reiter's syndrome in this Japanese patient.
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PMID:Reiter's syndrome associated with HLA-B51: a case report. 1263 35


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