Correlation between disease phenotype and genetic heterogeneity in rheumatoid arthritis.

Objective. To compare the frequencies and responsiveness of rheumatoid factor (RF)-producing B cells in the peripheral blood of patients with seronegative and seropositive rheumatoid arthritis (RA).Methods. Frequencies of IgM+, IgG+, and RF+ B cells were determined by limiting-dilution analysis of purified peripheral blood B cells from 6 patients with seropositive RA, 8 patients with seronegative RA, and 7 normal controls. B cell help was provided by cloned T helper cells, which were stimulated by either anti-CD3 or the bacterial superantigen staphylococcal enterotoxin D (SED). IgM and IgG antibodies and RF in culture supernatants were detected by enzyme-linked immunosorbent assay.Resuh. In the presence of anti-CD3-stimulated

Section: Methodssupporting

confidence: 70%

“…We have recently reported that these 2 forms of RA exhibit distinct genetic associations (2). RF+ R4 patients preferentially express the RA-associated HLA-DRB1*0401 allele.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Increased responsiveness of rheumatoid factor–producing B cells in seronegative and seropositive rheumatoid arthritis

Zhong

McCarthy

et al. 1996

“…We and others have previously reported that HLA genes, in particular the combination of 2 RA associated HLA-DR alleles, is highly associated with severe disease (25)(26)(27)(28). Detailed correlations of disease phenotype and genotype have revealed a risk hierarchy determined by HLA gene products.…”

Section: Discussionmentioning

confidence: 93%

Expansion of unusual CD4+ T cells in severe rheumatoid arthritis

Martens

Goronzy

Schaid

et al. 1997

267

181

Objective. The repertoire of T cells in patients with rheumatoid arthritis (RA) is characterized by clonal expansion of selected CD4+ T cells, which are autoreactive and lack the expression of the functionally important CD28 molecule. The goal of this study was to determine the contribution of these unusual lymphocytes to the disease process. Methods. RA patients (n = 108) and normal controls (n = 53) were examined for the expression of CD4+CD28‐ T cells by 2‐color fluorescence‐activated cell sorter analysis. Clinical data were ascertained by retrospective chart review. Results. The frequencies of CD4+CD28‐ T cells displayed a bimodal distribution, defining carriers and noncarriers in normal subjects and RA patients. In longitudinal studies, the noncarrier and carrier phenotypes were stable over time. Carriers of CD4+CD28‐ T cells accumulated in the RA population (64% versus 45%; P = 0.02). The expansion of CD4+CD28‐ T cells correlated with extraarticular involvement, but not with disease duration, antirheumatic treatment, or severity of joint destruction. The patient subsets with nodular disease (P = 0.02) and rheumatoid organ disease (P = 0.04) had the highest proportion of CD4+CD28‐ T cell carriers. The size of the CD4+CD28‐ compartment correlated with extraarticular progression of RA (P = 0.001 in nodular RA, P = 0.003 in rheumatoid organ disease). Conclusion. The bimodality of distribution of CD4+CD28‐ T cell frequencies is compatible with genetic control of the generation of these unusual T cells. In RA patients, CD4+CD28‐ T cells are not an epiphenomenon of the disease process, but predispose patients to developing inflammatory lesions in extraarticular tissues.

“…Between these two extremes, there are patients with various combinations of doses and alleles, who have disease of intermediate severity (12).…”

mentioning

confidence: 99%

HLA—DRB1 genes and disease severity in rheumatoid arthritis

Reveille

Alarcón

Fowler

et al. 1996

Objective. To examine the effect of alleles encoding the "shared"/"rheumatoid" epitope on rheumatoid arthritis (RA) disease severity in patients who participated In the minocycline in RA (MIRA) trial.Methods. Of 205 patients with a week-48 visit, blood was available for typing of HLA-DRB1 and HLA-DQB1 in 174 (85%) and successfully completed in 169 (82%). Baseline erosioes were used to assess disease severity and new erosions a t the last visit served as a proxy for progression.Results. At baseline, there was no association between the presence of erosive disease or rheumatoid factor status and the dose of rheumatoid epitope (homozygous, heterozygous, none) or the specific alleles identified. At the final visit, a gradient was observed for the 3 allelic subgroups (and their gene doses) in the occurrence of new erosions among the Caucasian placebo-