Polymicrobial septic arthritis in a patient with Wilson's disease.
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Adult↗
Biomedical subjects
S L Bridges
Publications and source records attributed to S L Bridges.
Early rheumatoid arthritis: a medical emergency?
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Anti-Inflammatory Agents, Non-Steroidal↗
A genomewide screen in multiplex rheumatoid arthritis families suggests genetic overlap with other autoimmune diseases.
Rheumatoid arthritis (RA) is an autoimmune/inflammatory disorder with a complex genetic component. We report the first major genomewide screen of multiplex families with RA gathered in the United States. The North American Rheumatoid Arthritis Consortium, using well-defined clinical criteria, has collected 257 families containing 301 affected sibling pairs with RA. A genome screen for allele sharing was performed, using 379 microsatellite markers. A nonparametric analysis using SIBPAL confirmed linkage of the HLA locus to RA (P < .00005), with lambdaHLA = 1.79. However, the analysis also revealed a number of non-HLA loci on chromosomes 1 (D1S235), 4 (D4S1647), 12 (D12S373), 16 (D16S403), and 17 (D17S1301), with evidence for linkage at a significance level of P<.005. Analysis of X-linked markers using the MLOD method from ASPEX also suggests linkage to the telomeric marker DXS6807. Stratifying the families into white or seropositive subgroups revealed some additional markers that showed improvement in significance over the full data set. Several of the regions that showed evidence for nominal significance (P < .05) in our data set had previously been implicated in RA (D16S516 and D17S1301) or in other diseases of an autoimmune nature, including systemic lupus erythematosus (D1S235), inflammatory bowel disease (D4S1647, D5S1462, and D16S516), multiple sclerosis (D12S1052), and ankylosing spondylitis (D16S516). Therefore, genes in the HLA complex play a major role in RA susceptibility, but several other regions also contribute significantly to overall genetic risk.
Alleles↗
Expression of recombination-activating genes and terminal deoxynucleotidyl transferase and secondary rearrangement of immunoglobulin kappa light chains in rheumatoid arthritis synovial tissue.
OBJECTIVE: Lymphocytic infiltrates in rheumatoid arthritis (RA) synovium often resemble lymphoid follicles and contain clonally related Ig transcripts, suggesting in situ antigen-dependent B cell selection. Recent reports have shown expression of recombination-activating genes (RAGs) and concurrent secondary rearrangement of Ig genes in normal peripheral lymphoid organs (receptor revision). We sought to determine if RAG-mediated receptor revision of Ig kappa light chains occurs in B cells within the RA synovium. Because we previously reported enhanced N-region addition at V(L)-J(L) joins in clonally expanded light-chain transcripts from RA synovium, we also sought expression of terminal deoxynucleotidyl transferase (TdT), which is normally expressed only in B cell precursors or immature B cells. METHODS: Reverse transcription-polymerase chain reaction (PCR) was used to detect RAG and TdT transcripts from unselected and B cell-enriched synovial and peripheral blood mononuclear cells obtained from 12 RA patients. Activity of RAG protein was sought using ligation-mediated PCR to detect recombination intermediates, and immunohistochemistry was performed to identify RAG+ cells within synovia. RESULTS: We found evidence of RAG-mediated secondary Ig kappa light chain rearrangements in about one-third of RA synovia. TdT expression was found in several samples, but did not correlate with RAG expression. CONCLUSION: RAG-mediated secondary Ig rearrangements of kappa light chains may contribute to the local production of antibodies to autoantigens (e.g., rheumatoid factor) or exogenous antigens, or it may represent a failed attempt at immune tolerance. TdT expression suggests the presence of immature B cells in RA synovia. These findings have important implications for the local generation of antibodies in RA and other chronic inflammatory diseases.
Adult↗
Pathogenesis of rheumatoid arthritis. Role of B lymphocytes.
Despite many years of investigation, there remain many unanswered fundamental questions on the role of B cells in RA. Why is RF found in the sera of 80% of patients with RA and often in other chronic inflammatory diseases? What signals lead B lymphocytes to migrate into the subsynovial lining of joints? Does receptor revision in synovium play a role in the generation of autoantibodies in RA? What is the relative contribution of B-cell inhibition on the salutary effect of medications for RA? Can targeting autoreactive B cells, in conjunction with other therapies, provide therapeutic benefit in RA? We are hopeful that through continued basic, clinical, and translational research, these questions can be answered.
Arthritis, Rheumatoid↗
The genetics of rheumatoid arthritis: influences on susceptibility, severity, and treatment response.
There has been an explosion of knowledge of genetic variations among different populations and the influence of genetics on complex diseases such as rheumatoid arthritis (RA). Although class II major histocompatibility complex (MHC) alleles are important contributors, there are likely multiple other genes that modulate the disease phenotype. Genetic markers may allow prediction of response to particular treatments. Given the recent approval of tumor necrosis factors (TNF) inhibitors and the large number of biologic agents currently undergoing clinical trials, pharmacogenetic markers may prove to be clinically useful.
Antirheumatic Agents↗
A novel single nucleotide polymorphism and five probable haplotypes in the 5' flanking region of the IL-6 gene in African-Americans.
In order to identify novel single nucleotide polymorphisms (SNPs), we sequenced a 940 bp region of the 5' flanking region of the IL-6 gene in 63 normal African-Americans. We identified a biallelic (G/C) SNP at position -573 relative to the transcription start site (-573C allele frequency 0.095). This SNP, together with SNPs at -598 and -174, allows identification of five probable haplotypes. Haplotypes containing the -174C allele, which has been associated with lower plasma IL-6 levels, were uncommon (4%). These haplotypes may influence IL-6 gene transcription and thus may contribute to racial differences in the prevalence of inflammatory diseases.
Black People↗
T-cell receptor peptide vaccination in the treatment of rheumatoid arthritis.
In several human T-cell-mediated autoimmune diseases and animal models of such illnesses, T-cell receptors (TCR) specific for antigens that initiate or perpetuate the disease share a limited number of variable region determinants. Vaccinations with peptides derived from over-represented TCRs are effective treatment for some of these disorders. RA is a chronic inflammatory disease in which there is prominent T-cell infiltration in the synovial lining layer. TCR V beta 3, V beta 14, and V beta 17 have been found to be over-represented among IL-2 receptor-positive T-cells from patients with RA. A phase II clinical trial in RA, using a combination of three peptides derived from V beta 3, V beta 14, and V beta 17, has yielded promising results. Larger clinical efficacy and safety studies must be performed to determine if TCR peptide vaccination will become a viable treatment alternative for patients with RA.
Antibody Formation↗
Clonally-related immunoglobulin VH domains and nonrandom use of DH gene segments in rheumatoid arthritis synovium.
BACKGROUND: Synovia of patients with long-standing rheumatoid arthritis (RA) are typically infiltrated with B lymphocytes and plasma cells that secrete large amounts of immunoglobulin. The CDR3 of an immunoglobulin heavy chain is composed of the VH-DH-JH join, with interposed N region addition, and thus defines clonal relatedness. Furthermore, the CDR3 lies at the center of the antigen binding site, so its length and composition influence antigen binding. We sought definitive evidence of an antigen-driven B cell response (i.e., clones derived from the same VH, DH, and JH gene segments with shared somatic mutations) in RA synovial mRNA transcripts, and to characterize CDR3 intervals at the target of inflammation in this autoimmune disease. MATERIALS AND METHODS: We screened a cDNA library generated from unselected cells from the knee joint of a 62-year-old white female with long-standing RA. This technique does not have the potential bias of selecting for antibodies that express a particular reactivity such as rheumatoid factor. C gamma recombinants were sequenced and progenitor VH, DH, and JH gene segments were assigned and somatic mutations determined by comparison to germline sequences. Analyses of DH reading frame utilization and hydropathy characteristics of CDR3s were performed. RESULTS: Two of 67 recombinants were derived from the same VH (V3-11) and JH gene segments, demonstrated shared mutations, and contained nearly identical VH-DH-JH joins, including N region addition. Three other recombinants contained identical sequence throughout the variable domain. We also found preferential utilization of a limited number of VH and DH gene segments and marked preference for a DH reading frame encoding predominantly hydrophilic residues. CONCLUSIONS: Analysis of expressed heavy chain variable domains strongly supports the hypothesis that the B cell response in RA synovium is at least in part antigen driven and oligoclonal.
Amino Acid Sequence↗
Enhanced expression of immunoglobulin kappa light chains with unusually long CDR3 regions in patients with rheumatoid arthritis.
OBJECTIVE: Our previous sequence analysis of immunoglobulin kappa light chains revealed that some patients with rheumatoid arthritis (RA) expressed repertoires enriched for transcripts containing unusually long CDR3 lengths of 11 amino acid codons. This was due, in part, to N region addition at the Vkappa-Jkappa joins. In this study, we analyzed a larger number of individuals to determine how often enrichment of kappa light chain repertoires for 11 amino acid CDR3 occurs in synovial lymphocytes and peripheral blood lymphocytes (PBL) of individuals with RA. METHODS: To measure length variability of kappa chain CDR3 regions, we performed a 2 stage polymerase chain reaction amplification and polyacrylamide gel electrophoresis. We sampled PBL and synovial lymphocytes of 9 patients with longstanding RA, and used PBL of 9 age and sex matched healthy individuals as controls. RESULTS: In PBL of healthy individuals, there was low level but consistent expression of kappa chains containing CDR3 with 11 amino acids. In patients, there was enhanced expression of kappa chains containing CDR3 with 11 amino acids compared to healthy individuals. This enhanced expression of kappa chains containing CDR3 of 11 amino acids was more pronounced in synovial lymphocytes compared to PBL of the same patients. CONCLUSION: These findings suggest that there is antigenic selection of B cells bearing antibodies with unusually long kappa light chain CDR3 in RA.
Adult↗
Frequent N addition and clonal relatedness among immunoglobulin lambda light chains expressed in rheumatoid arthritis synovia and PBL, and the influence of V lambda gene segment utilization on CDR3 length.
BACKGROUND: In rheumatoid arthritis (RA), B-lineage cells in the synovial membrane secrete large amounts of immunoglobulin that contribute to tissue destruction. The CDR3 of an immunoglobulin light chain is formed by rearrangements of VL and JL gene segments. Addition of non-germline-encoded (N) nucleotides at V(D)J joins by the enzyme terminal deoxynucleotidyl transferase (TdT) enhances antibody diversity. TdT was previously thought to be active in B cells only during heavy chain rearrangement, but we and others reported unexpectedly high levels of N addition in kappa light chains. We also found clonally related kappa chains bearing unusually long CDR3 intervals in RA synovium, suggesting oligoclonal expansion of a set of atypical B lymphocytes. In this study, we analyzed lambda light chain expression to determine if N addition occurs throughout immunoglobulin gene rearrangement and to compare CDR3 lengths of lambda and kappa light chains in RA patients and normal individuals. MATERIALS AND METHODS: Reverse transcription-polymerase chain reaction (RT-PCR) amplification of V lambda III transcripts was performed on RA synovia and peripheral blood lymphocytes (PBL) and normal PBL for which kappa repertoires were previously analyzed. Representative lambda + PCR products were cloned and sequenced. RESULTS: Analysis of 161 cDNA clones revealed that N addition occurs in lambda light chains of RA patients and normal controls. The lambda light chain repertoires in RA were enriched for long CDR3 intervals. In both RA and controls, CDR3 lengths were strongly influenced by which V lambda gene segment was present in the rearrangement. Five sets of clonally related sequences were found in RA synovia and PBL; one set was found in normal PBL. CONCLUSIONS: In humans, unlike mice, N addition enhances antibody diversity at all stages of immunoglobulin assembly, and the structural diversity of lambda CDR3 intervals is greater than that of kappa light chains. Clonally related V lambda gene segments in RA support an antigen-driven B-cell response.
Amino Acid Sequence↗
CDR3 fingerprinting of immunoglobulin kappa light chains expressed in rheumatoid arthritis. Evidence of antigenic selection or dysregulation of gene rearrangement in B cells.
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Adult↗
Perioperative use of methotrexate in patients with rheumatoid arthritis undergoing orthopedic surgery.
Methotrexate (MTX) is commonly prescribed for the treatment of rheumatoid arthritis. Its use seems to be an independent risk factor for infection with common pathogens and opportunistic organisms. Some rheumatologists and orthopedic surgeons hold the opinion that MTX should be temporarily withheld to lessen the likelihood of postoperative infection or poor wound healing. Alternatively, some clinicians believe that MTX should be continued throughout the perioperative period to avoid flares in rheumatoid arthritis disease activity. There are no definitive studies on which to rely in this decision-making process, but the authors believe that withholding MTX for 2 weeks of the perioperative period is a reasonable and prudent approach.
Antirheumatic Agents↗
Analysis of immunoglobulin gamma heavy chains from rheumatoid arthritis synovium. Evidence of antigen-driven selection.
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Amino Acid Sequence↗
Immunoglobulin gene expression in rheumatoid arthritis.
Rheumatoid arthritis (RA) is characterized by inflammation of synovium, in which immunoglobulin-secreting plasma cells are generally present. The forces driving immunoglobulin expression in RA synovium are unknown. Sequences of VH and VK transcripts from an RA synovial cDNA library demonstrate patterns of somatic mutation typical of an antigen-driven response. Moreover, 5% of the kappa repertoire appears to derive from the same B cell progenitor, suggesting an oligoclonal response. Immunoglobulin expression in this synovium thus appears to result from antigen stimulation. In addition, this patient's synovium is enriched for unusually long VK-JK joins (CDR3s), suggesting abnormal selection or regulation of the B cell response in RA.
Arthritis, Rheumatoid↗
Somatic mutation and CDR3 lengths of immunoglobulin kappa light chains expressed in patients with rheumatoid arthritis and in normal individuals.
Immunoglobulin secretion by plasma cells infiltrating synovial membranes is a prominent feature of RA. Previous analyses of a cDNA library generated from synovium of RA patient BC revealed immunoglobulin kappa light chain transcripts with extensive somatic mutation, frequent N region addition, and unexpected variation in the lengths of CDR3 regions which form the center of the antigen binding site. To determine if these characteristics are present in other individuals, we performed reverse transcription-polymerase chain reaction amplification and sequenced > or = 10 V kappa-containing amplicons from nine tissue samples: synovia of three individuals with long-standing RA (including patient BC), PBLs of two of these individuals, and PBLs or splenocytes of four normal individuals. Increased levels of somatic mutation in PBLs appeared to correlate with increased age, which may reflect accumulation of circulating memory cells and/or decreased bone marrow production of naive B lymphocytes. Two of three RA synovial samples and both RA PBL samples exhibited increased proportions of clones with unusual CDR3 lengths. Enrichment for these antibody binding sites could be due to abnormal regulation of the emerging repertoire or to selection for B lymphocytes bearing antibodies of unusual specificity, and may play a role in the pathogenesis of RA.
Adult↗
Overexpression of zinc-finger transcription factor Z-225/Egr-1 in synoviocytes from rheumatoid arthritis patients.
In rheumatoid arthritis (RA) the proliferation of synovial lining cells appears to be one of the initial pathologic changes that contributes to the destruction of articular joints. To understand the pathomechanisms involved in these functional changes, we analyzed the transcriptional regulation of the zinc-finger gene 225 (Z-225/Egr-1), a transcription factor expressed in the immediate early events of cellular activation. We found that Z-225 transcripts were significantly up-regulated in RA synoviocytes. In primary and long term culture Z-225 was spontaneously transcribed at elevated levels. In situ hybridization of zinc-finger probe showed characteristic Z-225 transcripts in RA synovial tissues. Identity of these signals to the Z-225 gene product were confirmed in freshly isolated synovial tissue by enzymatic amplification of cDNA by the PCR technique. Z-225 transcripts were also detected and characterized in a cDNA library established from a RA synovial explant. We therefore conclude that RA synoviocytes spontaneously produce Z-225 gene products at elevated levels. Because early growth response gene Z-225 is involved in the regulation of expression of other genes such as proto-oncogenes c-ras and c-sis, which are also up-regulated in the RA synovium, activation of Z-225 transcription in RA may represent a key event in articular joint destruction.
Arthritis, Rheumatoid↗