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W J Koopman

Publications and source records attributed to W J Koopman.

At least 55 records · Page 3Linked to original sources
PubMed1995

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↗
PubMed1995

Mapping the gene for acetazolamide responsive hereditary paryoxysmal cerebellar ataxia to chromosome 19p.

Acetazolamide responsive hereditary paroxysmal cerebellar ataxia (APCA) is a rare autosomal dominant disorder characterized by attacks of cerebellar ataxia and dysarthria with normal or near normal neurologic function between attacks. A genome-wide search using polymorphic di- and tri-nucleotide repeats was initiated and the APCA locus was found to be linked to the short arm of chromosome 19 in two large kindreds. The microsatellite marker UT705 was found to be linked to the APCA locus with two point analysis yielding a maximum lod score of 8.20 at theta max = 0.000 in a five generation pedigree. Linkage to this region was confirmed in a second kindred. The absence of known candidate genes in the region may necessitate a positional cloning approach in order to identify the gene for this disorder.

Acetazolamide↗
PubMed1995

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↗
PubMed1995

Molecular characterization of monoclonal IgM derived from human B cell lines expressing the 4C9 rheumatoid factor associated idiotype.

Ten human monoclonal B cell lines that express the RF associated Id 4C9 were analyzed using an immunogenetic approach. Five of eight tested lines were also strongly positive for the 6B6.6 Id. We found that all the 4C9/6B6.6 positive lines expressed VkIIIa light chain genes. In contrast, 4C9 reactivity was also found on a cell line expressing a VkIIIb light chain gene and on a line expressing a V light chain gene. The two anti-Ids recognized a linear light chain determinant on Humkv328 encoded light chains but also a conformational determinant on Vg encoded light chains that appeared to be dependent on the presence of a heavy chain. Idiotypic reactivity occurred on both RF positive and RF negative antibodies. Within this idiotypic system, the basis for idiotypic reactivity and RF reactivity is complex, subject to both heavy and light chain gene usage and sensitive to small numbers of somatic mutations.

Amino Acid Sequence↗
PubMed1994

Supplementation with folic acid during methotrexate therapy for rheumatoid arthritis. A double-blind, placebo-controlled trial.

OBJECTIVE: To determine the effect of two different weekly doses of folic acid on the toxicity and efficacy of low-dose methotrexate therapy for rheumatoid arthritis. DESIGN: Randomized, double-blind, placebo-controlled study. PATIENTS: 79 persons between 19 and 78 years of age who fulfilled the American Rheumatism Association's criteria for rheumatoid arthritis. INTERVENTION: Participants were randomly assigned to visually identical placebo or to 5 mg or 27.5 mg of folic acid each week. MEASUREMENTS: Duration, intensity, and clinical severity of toxic events; efficacy (indices of joint tenderness and swelling and grip strength); plasma and erythrocyte folate levels; and other laboratory variables. RESULTS: Folic acid supplementation at either dose did not affect the efficacy of methotrexate therapy as judged by joint indices and patient and physician assessments of disease. Patients given folic acid supplements had lower toxicity scores than did participants given placebo (P < or = 0.001). Low blood folate levels and increased mean corpuscular volumes were associated with substantial methotrexate toxicity, whereas daily dietary intakes of more than 900 nmol (400 micrograms) of folic acid were associated with little methotrexate toxicity. CONCLUSIONS: Folic acid, an inexpensive vitamin, is safe in a broad range of doses and protects patients with rheumatoid arthritis who are taking methotrexate from toxicity while preserving the efficacy of methotrexate.

Adult↗
PubMed1994

Human rheumatoid factors with restrictive specificity for rabbit immunoglobulin G: auto- and multi-reactivity, diverse VH gene segment usage and preferential usage of V lambda IIIb.

To determine the molecular and functional properties of human rheumatoid factors (RF), we established stable hybridomas and Epstein-Barr virus-transformed B cell lines from the synovial fluid or peripheral blood of three patients with rheumatoid arthritis and one patient with systemic lupus erythematosus. 17 cell lines were obtained that produced high-titer immunoglobulin M (IgM) RF that reacted exclusively with rabbit but not human IgG or IgG of other mammalian species. Certain anti-rabbit IgG RF also had specificity for other mammalian antigens (Ag), including cytoskeletal proteins and intracellular proteins found in HeLa cells, as well as for Ag present in an extract prepared from the cell wall of group A streptococci. 13 of the 17 RF contained lambda-type light (L) chains, of which 12 were classified serologically as members of the lambda-L chain variable region (V lambda) subgroup, designated V lambda III. The heavy chain V region (VH) and V lambda sequences of nine of these IgM lambda RF were determined at the cDNA level. Five VH genes in three VH families were used by these antibodies (Ab), including VH1 (dp21/1-4b and dp10 [51p1]/hv1051), VH3 (dp38/3-15 and dp77/13-21), and VH4 (dp70/4-4b). The deduced V gene-encoded amino acid sequences of the lambda chains of these IgM lambda RF confirmed their serological classification as lambda III, and they were further classified as members of the relatively uncommon V lambda III subgroup, designated V lambda IIIb. Based on cDNA analyses, nine were the product of three different V lambda III b germline genes. Two such genes, designated hsiggll150 and hsiggll295, were cloned and sequenced from genomic DNA. Unique combinations of these VH and V lambda III b genes could be related to distinctive patterns of reactivity among the IgM lambda RF. Although the VH and V lambda regions of these Abs were expressed primarily as germline-encoded sequences, four of nine multireactive Abs had extensive V region mutation, indicative of an Ag-driven process. The finding that lambda IIIb L chains are preferentially found among anti-rabbit IgG RF, and that some of these Ab have specificity for other protein, cellular, and bacterial Ag, provides new insight into the pathogenesis of RA and related diseases.

Animals↗
PubMed1994

T cell influence on superantigen-induced arthritis in MRL-lpr/lpr mice.

OBJECTIVE: To define the influence of the T cell receptor (TCR) and the lpr autoimmune gene on the induction and progression of superantigen-induced arthritis in V beta 8 transgenic MRL-lpr/lpr mice. METHODS: The time to onset and the extent of synovial hyperplasia after the induction of arthritis by intraarticular injection of staphylococcal enterotoxin B (SEB) were compared in mice having T cells that bear the V beta 8 transgene alone (V beta 8 TCR transgenic MRL-+/+), the lpr gene without the V beta 8 gene (nontransgenic MRL-lpr/lpr), both the V beta 8 gene and the lpr gene (V beta 8 transgenic MRL-lpr/lpr), or neither gene (nontransgenic MRL-+/+). Synovial hyperplasia was compared in SEB-injected V beta 8 transgenic MRL-lpr/lpr mice after treatment with cyclosporin A (CSA), anti-V beta 8 and anti-CD4 monoclonal antibodies, and in V beta 8 transgenic MRL-lpr/lpr mice after injection of a non-V beta 8-reactive superantigen, staphylococcal enterotoxin A (SEA). RESULTS: At day 30, increased synovial cells were observed in all SEB-treated mice, but the increase was greatest in the V beta 8 transgenic MRL-lpr/lpr mice. T cell involvement was indicated by the inability of either heat-denatured SEB or SEA to induce severe arthritis, the reduction in the severity of the arthritis on systemic treatment with CSA or anti-V beta 8, and the correlation of synovial hyperplasia with in vitro SEB reactivity of T cells. CONCLUSION: These observations suggest that superantigens can induce chronic arthritis and that the induction and progression of the arthritis requires an underlying T cell defect in anergy induction in addition to exposure to the superantigen.

Animals↗
PubMed1994

Treatment of refractory rheumatoid arthritis with a chimeric anti-CD4 monoclonal antibody. Long-term followup of CD4+ T cell counts.

OBJECTIVE: To evaluate CD4+ T cell counts of rheumatoid arthritis (RA) patients at 18 and 30 months after treatment with a chimeric anti-CD4 monoclonal antibody (MAb), cM-T412, in a phase I trial. METHODS: Of the 25 RA patients who received the MAb, 23 were available for followup at 18 and 30 months. Levels of circulating CD4+ T cells were measured by flow cytometry. RESULTS: Circulating CD4+ T cell levels in these 23 RA patients remained below normal at 18 and 30 months posttreatment. More profound CD4+ T cell depletion was noted in the higher-dose groups (300 and 700 mg). CONCLUSION: Prolonged suppression of circulating CD4+ T cells was noted both in single-infusion and multiple-infusion groups 18 and 30 months after cM-T412 treatment. The depression was more pronounced in patients who received multiple infusions of cM-T412. The prolonged decrease in CD4+ T cell numbers suggests that the capacity to reconstitute CD4+ T cells in this patient population (treated with methotrexate) is limited. One patient, who was also receiving methotrexate and prednisone, died 18 months after receiving 100 mg of cM-T412. No other significant adverse effects, in particular, no opportunistic infections, were reported in these 23 RA patients at 18 and 30 months of followup.

Adult↗
PubMed1994

HLA in ankylosing spondylitis: is HLA-B27 the only MHC gene involved in disease pathogenesis?

Linkage analysis of HLA haplotypes, HLA-B27 subtypes, and a 9.2-kb PvuII B7 restriction fragment length polymorphism (RFLP) (shown previously to be associated with peripheral arthritis in ankylosing spondylitis [AS]) in 115 relatives from 12 multiplex spondyloarthropathy (SNSA) and 2 B27-positive control families showed AS to be linked to HLA-B27 haplotypes. The RFLP segregated with HLA-A3- and HLA-A9-bearing haplotypes (lod score, 10.98; odds in favor of linkage, 9.2 x 10(10):1), although its linkage to AS or other SNSA per se was not seen. The association of HLA-A3/A9 with the RFLP was also seen in 52 AS patients and 92 controls, although no HLA-A, -B, -C, or -DR allele (other than HLA-B27) was significantly increased in frequency. The HLA-B27 subtype seen on all but one of the haplotypes studied was B*2705, the sole exception being HLA-B*2702. Although not ruling out a second HLA-A-linked gene influencing the clinical expression of AS, these data fail to support the role of a second MHC-associated gene in the pathogenesis of AS per se.

Alleles↗
PubMed1994

The future of biologics in the treatment of rheumatoid arthritis.

The development of highly effective biological therapies directed against T cells in several animal models of autoimmune disease has prompted trials of similar approaches in rheumatoid arthritis (RA). However, it is unlikely that these approaches will abrogate long-standing disease. Indeed, considerable evidence indicates that although T cells likely play a critical role in induction of RA, non-T-cell-dependent pathways become increasingly dominant as the disease progresses. According to this model, specific T-cell therapies are likely to be most effective in early disease, whereas individualized combinations of biologics targeted against pathways dominating in the recipient's synovium are more likely to be efficacious in established disease.

Animals↗
PubMed1994

Evidence of antigen receptor-influenced oligoclonal B lymphocyte expansion in the synovium of a patient with longstanding rheumatoid arthritis.

Plasma cell infiltration of synovium is common in longstanding rheumatoid arthritis (RA). The mechanism(s) underlying synovial B cell proliferation remains unclear. One theory invokes nonspecific polyclonal stimuli; another implicates antigen as the driving force. Antigen-driven repertoires are characteristically enriched for related sets of V gene segments containing similar sequence in the antigen binding site (complementarity-determining regions; CDRs). To study the forces shaping B cell proliferation, we analyzed V kappa transcripts expressed in the synovium of an RA patient. We found Humkv325, a developmentally regulated V kappa III gene segment associated with autoantibody reactivity, in > 10% of randomly-chosen synovial C kappa cDNAs. Two sets of sequences contained identical charged amino acid residues at the V kappa-J kappa join, apparently due to N region addition. We generated "signature" oligonucleotides from these CDR3s and probed PCR amplified V kappa products from the synovium and PBLs of the same patient, and from PBLs and spleen of individuals without rheumatic disease. Significant expression of transcripts containing these unique CDR3 sequences occurred only in the patient's synovium. Thus, in this synovium there is expansion of a limited set of B cell clones expressing antigen receptors that bear evidence of antigen selection.

Amino Acid Sequence↗
PubMed1994

Expression of rheumatoid factor idiotypes 17.109, 6B6.6 and 4C9 in the sera of Pima Indians.

This study was undertaken to determine whether the expression of 17.109, 6B6.6 and 4C9 rheumatoid factor (RF) idiotypes is predictive of the development of rheumatoid arthritis (RA) and whether the RF response is idiotypically restricted in an inbred population of Pima Indians who have a genetic predisposition for the disease. Serial sera were obtained from 25 subjects who developed RA and 25 RF-positive subjects who did not develop RA over the course of a longitudinal community health survey. RF titers and titers of the RF-associated idiotypes 17.109, 6B6.6 and 4C9 were determined by ELISA, and the relationship between 6B6.6 and 4C9 was analyzed by cross-absorption studies. Expression of the three RF-associated idiotypes was found in both the subjects who developed RA and those who did not. The amount of idiotype expressed was variable, but a few subjects in both groups had high levels indicative of an oligoclonal RF response. Reactivity with 6B6.6 and 4C9 antiidiotypes overlapped, with 4C9 appearing to mark a broader spectrum of RF than 6B6.6. Thus, even in an inbred and genetically predisposed population, the RF-associated antiidiotypes studied here did not identify a dominant idiotypic response and were no better markers for the development of RA than was RF itself.

Adult↗
PubMed1994

Survival impact of autoantibodies in systemic lupus erythematosus.

OBJECTIVE: To determine the frequency, the clinical and laboratory associations, and the impact on survival of anti-dsDNA, anti-Sm, anti-nRNP, anti-Ro, and anti-La in patients with systemic lupus erythematosus (SLE). METHODS: The clinical and laboratory features of 94 patients with SLE tested for anti-dsDNA, anti-nRNP, anti-Sm, anti-Ro and anti-La were studied. Survival analyses were performed by the Kaplan Meier method. RESULTS: Anti-Ro, anti-nRNP and anti-Sm were found with lower frequency in our patients compared to other reports. There was a higher frequency of anti-Sm (19.5 vs 10%, p = 0.0093) and anti-nRNP positivity (29.2 vs 7.5%, p = 0.006) among African American patients compared to Caucasian patients. No clinical or laboratory associations were found with any of the autoantibodies. Patients had a mean followup up 11.8 years. There were no protective or negative effects of the different autoantibodies on the probability of survival of the patients studied. CONCLUSION: Our study failed to demonstrate the impact of the autoantibodies studied in the survival of our patients.

Adult↗
PubMed1993

Effects of nonsteroidal antiinflammatory drugs on bone loss in chronic inflammatory disease.

Several controlled clinical trials have indicated that nonsteroidal antiinflammatory drugs may slow alveolar bone loss in periodontitis. Demonstration of this efficacy is dependent on the development of accurate, sensitive, and specific quantitative methods for the assessment of bony change, such as digital subtraction radiography. Further studies of such methodologies are required to more fully investigate the effect of nonsteroidal antiinflammatory drugs in rheumatoid arthritis.

Alveolar Bone Loss↗
PubMed1993

The use of monozygotic and dizygotic twins to estimate the effects of inheritance on the levels of immunoglobulin isotypes and antibodies to phosphocholine.

In the elderly there is a pronounced increase in susceptibility to infectious disease. Evidence for particular immune deficits that result in susceptibility to specific agents is lacking, however, and there is little information on the degree to which differences in the susceptibility among the elderly are due to genetic versus environmental effects. A strong association has been observed between eventual fatal pneumonia and elevated levels of IgM antibody to phosphocholine (PC) levels at age 70. In this study we evaluated the heritability of IgM and IgG antibody levels to phosphocholine in the elderly using monozygotic and dizygotic male twins. We observed genetic regulation of serum levels of IgM antibody to PC, a finding which suggests that susceptibility of the elderly to fatal pneumonia may be heritable. Levels of total IgM were under separate genetic control and there was no genetic effect on IgG and IgA levels or levels of IgG antibody to phosphocholine.

Aged↗