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PubMed1985

IgG and IgM rheumatoid factor synthesis in rheumatoid synovial membrane cell cultures.

The detection of rheumatoid factors (RFs) in synovial membranes and fluids of patients with rheumatoid arthritis (RA) has suggested that local production of these antiimmunoglobulin autoantibodies may have a role in the pathogenesis of synovitis. To quantitate RF synthesis in the rheumatoid synovial membrane, 12 synovial specimens were obtained from patients with seropositive RA, 5 from patients with seronegative RA, and 6 from patients with other arthritides. Single cell suspensions were cultured, and supernatants were analyzed for IgG, IgM, IgG-RF, and IgM-RF by solid-phase radioimmunoassays. IgM-RF was detected in all of the 12 seropositive culture supernatants, and IgG-RF was detected in 8 of the 12. Addition of cycloheximide to the cultures resulted in a greater than or equal to 40% decreased in the amount of IgM-RF. A similar decrease in IgG-RF occurred in the 4 cultures in which the largest amounts of IgG-RF were detected. IgM-RF synthesis represented 7.3 +/- 0.7% (mean +/- SEM) of the total IgM produced, and IgG-RF represented 2.6 +/- 1.1% (mean +/- SEM) of the IgG synthesized in those cultures with detectable IgG-RF. Cultures of synovial membrane cells (SMC) from seronegative RA patients or patients with other arthritides did not contain detectable amounts of IgM-RF or IgG-RF. Selective synthesis of RF by seropositive synovium was suggested by the observation that the fractions of synthesized IgM with RF activity were greater in the SMC supernatants than in paired sera in all cases, and the fractions of IgG with RF activity were greater in the SMC supernatants of 3 of the 4 cases in which substantial amounts of IgG-RF were produced. Comparison of the percentages of newly synthesized IgM with RF activity in paired cultures of SMC and peripheral blood mononuclear cells similarly indicated selective synthesis of IgM-RF by the synovium. These results demonstrate active and selective synthesis of both IgG-RF and IgM-RF by seropositive SMC. However, RFs account for only a minor fraction of the total Ig produced.

Arthritis, Rheumatoid↗
PubMed1986

Estimation of the relative avidity of 19S IgM rheumatoid factor secreted by rheumatoid synovial cells for human IgG subclasses.

19S IgM rheumatoid factors (RF) may play an important role in sustaining inflammation in rheumatoid arthritis (RA). As yet, no unique antigenic specificity for RF in RA has been identified. Because the synovium is central to the pathogenic changes in RA, RF produced therein might be pathogenically more important than serum RF. Therefore, we examined the reactivity and relative avidity of 19S IgM-RF in serum and rheumatoid synovial cells (RSC) from 20 patients with seropositive RA. Reactivities were determined by competitive inhibition of serum RF hemolytic activity and RSC RF-plaque-forming cells (PFC) by added soluble antigen, i.e., monomeric human IgG subclasses. Estimation of relative avidities of RSC RF for human IgG subclasses was done by calculation of fractional RF expression in the RSC RF-PFC assay following inhibition by IgG subclasses. RSC RF had greatest reactivity with IgG3 and IgG1, some reactivity with IgG2, and the least reactivity with IgG4. Serum RF reacted most with IgG1 and IgG2, reacted some with IgG4, but reacted poorly with IgG3. The antigenic determinants with which RSC RF reacted were common to many IgG3 molecules. The highest relative avidity of RSC RF was for IgG3. These observations indicate a selective deficiency of serum RF compared with RSC RF and suggest an important pathogenic role for these qualitatively different RSC RF molecules for in situ RF immune complex-mediated inflammation in RA synovial tissue.

Animals↗
PubMed1995

Prognostic value of quantitative measurement of rheumatoid factor in early rheumatoid arthritis.

The prognostic value of quantitative measurement of rheumatoid factor (RF) by immunoturbidimetry was evaluated in 78 patients with early rheumatoid arthritis (RA) during a 3-yr follow-up. After starting disease-modifying antirheumatic treatment, a significant improvement in conventional clinical and laboratory variables measuring disease activity was observed, while a steady increase was found in radiological progression. Initial RF levels correlated with radiologically determined joint damage up to 3 yr, whereas no correlation of other initially determined conventional variables of disease activity was found. High levels of RF at entry and persistent RF positivity during the follow-up were markers for destructive disease. Initial RF positivity alone was a sensitive predictor for later joint destruction, but quantitative measurement of the initial RF level and especially repeated measurements of RF seemed to add significantly to the prognostic value of RF in distinguishing between progressive and non-progressive disease in early RA.

Adult↗
PubMed1992

Genetic analysis of self-associating immunoglobulin G rheumatoid factors from two rheumatoid synovia implicates an antigen-driven response.

Although much has been learned about the molecular basis of immunoglobulin M (IgM) rheumatoid factors (RFs) in healthy individuals and in patients with mixed cryoglobulinemia and rheumatoid arthritis, little is known about the genetic origins of the potentially pathogenic IgG RFs in the inflamed rheumatoid synovia of patients. Recently, we generated from unmanipulated synovium B cells several hybridomas that secreted self-associating IgG RFs. To delineate the genetic origins of such potentially pathogenic RFs, we adapted the anchored polymerase chain reaction to rapidly clone and characterize the expressed Ig V genes for the L1 and the D1 IgG RFs. Then, we identified the germline counterparts of the expressed L1 IgG RF V genes. The results showed that the L1 heavy chain was encoded by a Vh gene that is expressed preferentially during early ontogenic development, and that is probably located within 240 kb upstream of the Jh locus. The overlap between this RF Vh gene and the restricted fetal antibody repertoire is reminiscent of the natural antibody-associated Vh genes, and suggests that at least part of the "potential pathogenic" IgG RFs in rheumatoid synovium may derive from the "physiological" natural antibody repertoire in a normal immune system. Indeed, the corresponding germline Vh gene for L1 encodes the heavy chain of an IgM RF found in a 19-wk-old fetal spleen. Furthermore, the comparisons of the expressed RF V genes and their germline counterparts reveal that the L1 heavy and light chain variable regions had, respectively, 16 and 7 somatic mutations, which resulted in eight and four amino acid changes. Strikingly, all eight mutations in the complementarity determining regions of the V gene-encoded regions were replacement changes, while only 6 of 11 mutations in the framework regions caused amino acid changes. Combined with L1's high binding affinity toward the Fc fragment, these results suggest strongly that the L1 IgG RF must have been driven by the Fc antigen.

Amino Acid Sequence↗
PubMed1997

Clinical significance of IgA rheumatoid factor subclasses in rheumatoid arthritis.

OBJECTIVE: IgA rheumatoid factor (RF) is associated with greater disease activity and radiological progression in rheumatoid arthritis (RA). We examined whether measuring IgA RF subclasses gives additional clinically relevant information. METHODS: Total IgA RF plus IgA1 RF and IgA2 RF subclasses were estimated by ELISA using rabbit IgG as antigen in 144 patients with established RA. Disease activity was assessed by Disease Activity Score and Health Assessment Questionnaire; the acute phase response was assessed by C-reactive protein levels and joint damage by the Larsen score. RESULTS: Fifty percent of patients had elevated total IgA RF, 60% elevated IgA1 RF, and 50% elevated IgA2 RF. There were significant correlations between total IgA RF and both IgA RF subclasses (p < 0.0001). Measures of disease activity, the acute phase response, and joint damage were all significantly higher (p < 0.001 in each case) in patients with elevated total IgA RF and both IgA RF subclasses compared with RF negative cases. Disease duration influenced the relationship of IgA RF subclasses to joint damage. The Larsen score was only significantly higher in late disease (duration 5 years or more) in both IgA1 RF and IgA2 RF positive patients. CONCLUSION: We found IgA RF positive patients have more aggressive RA than negative cases. Measuring IgA1 RF and IgA2 RF subclasses did not give more information about clinical status than measuring total IgA RF alone.

Aged↗
PubMedDate not supplied

ELISA determined IgM and IgA rheumatoid factors in seronegative rheumatoid and psoriatic arthritis.

Previous studies have strongly suggested an association between rheumatoid factors (RF's), particularly IgA-RF, and the presence of erosions in rheumatoid arthritis (RA). The present study was aimed at studying this association in seronegative erosive arthritides. Forty-eight patients with seronegative arthritis were evaluated for the presence of IgM- and IgA-RFs using an enzyme linked immunosorbent assay (ELISA). Twenty-nine had seronegative RA and nineteen had psoriatic arthritis (PA). Twelve (41%) seronegative RA patients were found to be seropositive for IgM- or IgA-RF. Only 1 (7%) patient with PSA was positive for IgA-RF alone. Fifteen (51%) of the RA patients and eight (42%) of the PSA patients had erosive disease. A significant correlation between IgA-RF alone and erosive disease was found only in the seronegative RA patient (p less than 0.02). We conclude that in PSA patients there appears to be no need to define isotype specific RFs. On the other hand, our findings indicate that an early detection of IgA-RF can have clinical importance in seronegative rheumatoid arthritis, as it may constitute an indication for the timely institution of disease-modifying drugs in these patients.

Adult↗
PubMedDate not supplied

Does IgA-alpha1 antitrypsin complex correlate with IgM, IgG and IgA rheumatoid factor in early rheumatoid arthritis?

This study was undertaken to determine whether the rheumatoid factor (RF) isotypes affect the level of IgA-AT complex in early rheumatoid arthritis. IgA-AT complex and IgM, IgG, and IgA RF were evaluated using a double antibody enzyme-linked immunosorbent assay (ELISA) in sera of 83 (61 women and 22 men) patients. The mean level of the complex was higher in RA patients as compared with the control group (0.60 +/- 0.41 U vs 0.19 +/- 0.11 U, p < 0.05). The IgA-AT complex values exceeding the norm were found in 19 of 83 RA cases (23%), mainly in patients non-treated with DMARDs. IgM RF values judged as positive were present in 53 (64%), IgG RF in 55 (66%), and IgA RF in 56 (67%) patients. Higher RF values of IgM and IgG, but not those of IgA class, were found more frequently in patients with elevated IgA-AT levels. A good correlation was established between IgA and IgM RF (r = 0.61, p < 0.01), but not between IgA and IgG, or IgM and IgG RF in the group of patients under study. However, we did not find any significant correlation between isotypes of RF and parameters of the disease activity.

Adult↗
PubMed2004

Diagnostic and clinical value of anti-cyclic citrullinated peptide antibodies compared with rheumatoid factor isotypes in rheumatoid arthritis.

OBJECTIVE: To assess the additional diagnostic and clinical value of the second test generation of anti-cyclic citrullinated peptide antibodies (CCP2) compared with rheumatoid factor isotypes (IgG-RF, IgA-RF, IgM-RF) in patients with rheumatoid arthritis. METHODS: This was a prospective study on 715 patients: rheumatoid arthritis (n = 295), degenerative or other inflammatory joint disease (n = 163), connective tissue disease or vasculitis (n = 103), and healthy controls (n = 154). Sera from each subject were tested for CCP2 and RF isotypes by enzyme linked immunosorbent assay (ELISA). Agreement with clinical indices such as disease activity, joint destruction, disease duration, and other laboratory tests was assessed. Sensitivity and specificity of the tests were evaluated taking the clinical diagnosis as the gold standard. RESULTS: Highest sensitivity was found for IgM-RF (66.4%) and CCP (64.4%). Highest specificity was achieved by CCP (97.1%) and IgG-RF (91.0%). In rheumatoid patients with high disease activity or severe joint damage, CCP was more often present (81.4% and 83.6%) than all RF isotypes. Of special diagnostic value was the detection of positive CCP in 34.5% of all patients with rheumatoid arthritis when all measured RF isotypes (IgG-RF, IgA-RF, and IgM-RF) were negative. CONCLUSIONS: As a screening method for rheumatoid arthritis the IgM-RF and the CCP assays are superior to other RF isotypes. Positivity in the highly specific CCP ELISA supports the diagnosis of rheumatoid arthritis. CCP proved to be a powerful diagnostic tool, especially in ambiguous cases or RF negative patients with rheumatoid arthritis.

Adult↗
PubMed1993

Molecular analysis of rheumatoid factors derived from rheumatoid synovium suggests an antigen-driven response in inflamed joints.

OBJECTIVE: Understanding the molecular genetic basis for rheumatoid factor (RF) production is necessary to a better understanding of the etiology and pathogenesis of rheumatoid arthritis (RA). We sought to define the genetic basis of RF in RA. METHODS: The heavy and light chain variable region genes encoding 4 human monoclonal RF were cloned and sequenced using the polymerase chain reaction and the dideoxynucleotide chain-termination method. RESULTS: The heavy and light chains of the C6 RF and the light chain of the G9 RF were encoded by 3 new RF-related Ig V-region genes. The heavy and light chains of D5 and G4 RFs were identical; most of their mutations caused amino acid substitutions. CONCLUSIONS: The RF-related Ig V-region gene repertoire is large and is still expanding. The data from D5 and G4 strongly suggest that these 2 RFs arise in an antigen-driven response in rheumatoid synovium. The presumed germline V genes for C6 may represent disease-specific RF-related V genes.

Adult↗
PubMed1988

B lymphocytes, B cell clones and rheumatoid factor antibodies in rheumatoid inflammation.

This report focuses on the B lymphocytes and plasma cells in rheumatoid inflammation, and discusses the major autoantibodies in the pathogenetic mechanisms, i.e. the rheumatoid factor (RF) antibodies. We describe ways of raising human hybridomas that produce RF antibodies in rheumatoid arthritis (RA) in order to elucidate how these antibodies differ from the RF antibodies that are part of the normal immune response in man and animals, and from those in diseases other than RA, e.g. in M-components seen in mixed cryoglobulinaemia and in Waldenström's macroglobulinaemia. The preliminary results of these studies are presented and discussed.

Animals↗
PubMed1987

Decreased T-cell-mediated suppression of IgM--rheumatoid factor synthesis in rheumatoid arthritis.

Circulating B-cell precursors specific for rheumatoid factor (RF) are present in normal subjects but spontaneous in vitro synthesis of RF occurs only in rheumatoid arthritis (RA). The regulatory role of RF-specific suppressor T cells in this process was studied in pokeweed mitogen-stimulated in vitro cultures of peripheral blood mononuclear cells. Addition of graded numbers of suppressor T8(+) cells from RA patients to normal B cells resulted in consistently less suppression of IgM and RF synthesis than that achieved by normal suppressor T cells. A preculture system was then used to probe for RF-specific suppressor precursor lymphocytes. RA T-cell populations failed to generate normal levels of RF-specific suppression during in vitro culture for 4 days. Incubation with human-aggregated IgG (HaIgG) resulted in an increase in RF-specific suppression to normal levels. The data indicate that induction and full expression of RF-specific suppressor T-cell function is blocked in vivo in RA but can be overcome in vitro by incubation with HaIgG.

Arthritis, Rheumatoid↗
PubMed1995

IgM, IgA, and IgG rheumatoid factors in early rheumatoid arthritis predictive of radiological progression?

The significance of IgM, IgA and IgG rheumatoid factors (RF) for the prediction of radiological progression, and as process variables during follow-up, was evaluated in a three-year prospective study of 149 patients with early rheumatoid arthritis (symptoms < 1 year at study entry). The occurrence of IgA-RF and IgG-RF at study entry without simultaneous occurrence of IgM-RF, and the seroconversion from RF-negative at entry to RF-positive during follow-up appeared to be unusual. A significant correlation was found between each of the RF-isotype levels at entry and radiological progression after three years. However, no significant prognostic value of IgA-RF and IgG-RF could be demonstrated if analysed in combination with IgM-RF, initial disease activity (as measured by C-reactive protein level), initial radiologic score, HLA-DR4 and HLA-DR2. Although IgM-RF levels generally reflected the course of disease activity and did so better than IgA-RF and IgG-RF levels, their clinical significance as process variables appeared to be limited compared to C-reactive protein.

Adolescent↗
PubMed1983

Effect of pregnancy on immune complexes and rheumatoid factors in patients with rheumatoid arthritis.

Rheumatoid arthritis is associated with circulating and intra-articular immune complexes and rheumatoid factors. The clinical activity of rheumatoid arthritis improves during pregnancy in the majority of women, with exacerbation following delivery. Concentrations of immune complexes, as detected by the Clq-binding assay, the Clq-solid phase assay, and the monoclonal rheumatoid factor-solid phase assay, decreased during gestation, with elevations following delivery. Concentrations of IgM-rheumatoid factor and IgG-rheumatoid factor, analyzed by radioimmunoassay, changed variably during pregnancy, increasing in some patients and decreasing in others. When examined serially before, during, and following pregnancy, changes in the concentration of circulating immune complexes and/or rheumatoid factors corresponded with the clinical changes in three patients. These observations document the significant effect of gestation on the concentration of circulating immune complexes in patients with rheumatoid arthritis. They also support the role of these laboratory tests in monitoring the clinical course of rheumatoid arthritis.

Antigen-Antibody Complex↗
PubMedDate not supplied

Longitudinal study of the presence of hidden 19S IgM rheumatoid factor in juvenile rheumatoid arthritis.

Complement-fixing hidden 19S IgM rheumatoid factor (RF), i.e., 19S IgM RF that can be detected in the IgM-containing fraction by the hemolytic assay after separation of the serum by acid gel filtration, was evaluated serially (3 or more evaluations) over a 4-year period in 26 children with juvenile rheumatoid arthritis (JRA) correlating its presence with disease activity. Six children with continually active disease had consistently elevated hidden RF titers (26 evaluations), and the titers of 4 children with inactive disease remained insignificant (12 evaluations). Sixteen children had disease with variable activity over this period. Of these, 11 (43 evaluations) demonstrated positive correlation between disease activity and hidden RF titers. Five patients (8/20 evaluations) did not show correlation of disease activity with hidden RF titers. Thus, the presence of hidden RF correlated with disease activity in 93 of 101 evaluations. When hidden RF titers and the erythrocyte sedimentation rate were determined simultaneously on 40 occasions, the presence of hidden 19S IgM RF correlated significantly better (p less than 0.001) with disease activity.

Arthritis, Juvenile↗
PubMed1990

Occurrence of two germline-related rheumatoid factor idiotypes in rheumatoid arthritis and in non-rheumatoid seropositive individuals.

Human rheumatoid factor (RF) paraproteins express two distinct light chain cross-reactive idiotypes defined by the monoclonal antibodies 17.109 and 6B6.6. These germline gene-related cross-reactive idiotypes are both carried on VK3 light chains and are each present on about one-third of IgM RF paraproteins. We assessed the degree to which these idiotypes are represented in polyclonal RFs. We used rheumatoid arthritis (RA) and non-RA RF-positive sera selected from a large cross-sectional population study (the Mini-Finland Health Survey), and sera from a community-based follow-up study of recent-onset RA patients from Heinola, Finland. In the Mini-Finland Health Survey, elevated levels of the 17.109 RF idiotype were seen in sera of 13% of the RA and 19% of the non-RA group; 6B6.6 RF was seen in 26% of the RA and 28% of the non-RA group. In sera of the Heinola follow-up study, 17.109 RF was seen in 12% initially, but in only 3% at 8 years. Similarly, 6B6.6 RF was detected in 25% initially, but in only 7% at 8 years. Ten sera positive for RF prior to the onset of clinical RA were identified from individuals of a second large population study from Finland (North Karelia project); two of these sera exhibited the 6B6.6 idiotype; none exhibited the 17.109 idiotype. The data are consistent with the concept that these germline gene-related cross-reactive RF idiotypes occur frequently in the polyclonal RF of non-RA as well as RA sera, and that in RA the idiotypes may sometimes be reduced or lost as a consequence of somatic diversification of the RF through somatic mutation, usage of new germline genes, or both.

Arthritis, Rheumatoid↗
PubMed2005

Additional diagnostic and clinical value of anti-cyclic citrullinated peptide antibodies compared with rheumatoid factor isotypes in rheumatoid arthritis.

In the past decade significant advantages have been made in the treatment of rheumatoid arthritis (RA) and therapeutic strategies have changed a lot. These days, highly effective disease modifying anti-rheumatic drugs enable intervention early in the disease process, in order to prevent major joint damage. For years, serological support in the diagnosis of RA has been limited to the presence of rheumatoid factors, although not very specific for RA. During the last years a variety of circulating non-RF antibodies have been discovered and reported to be of potential diagnostic value. CCP2 proved to be a very disease-specific and even sensitive marker for RA. In addition to the diagnostic properties, CCP showed to be a good prognostic marker, CCP helps to predict the erosive or nonerosive progression of the disease, and CCP is already present early in the disease. This diagnostic tool enables the clinician to choose the optimal therapeutic management for each single RA patient.

Antibodies↗
PubMed1984

Decreased pokeweed mitogen-induced IgM and IgM rheumatoid factor synthesis in rheumatoid arthritis patients treated with gold sodium thiomalate or penicillamine.

Prospective and retrospective analysis of data obtained on 119 patients with rheumatoid arthritis suggested a relationship between clinical response induced by gold salts or D-penicillamine and decreased in vitro antibody synthesis by peripheral blood mononuclear cells. A subgroup of 21 patients with inactive disease receiving these drugs was found to have decreased pokeweed mitogen-induced in vitro synthesis of IgM and IgM rheumatoid factor. Detailed analysis of the cellular mechanisms responsible for this decreased responsiveness demonstrated markedly decreased B cell function. Patients treated with D-penicillamine also had altered T cell helper function manifested by incomplete reconstitution of the normal IgM response, while patients treated with gold salts had normal T cell function. Monocytes appeared not to have a major role in the decreased in vitro responsiveness. The results suggest that, in patients who respond to gold salts or D-penicillamine, antibody synthesis by circulating B cells is profoundly decreased, probably due to an indirect effect of these disease-modifying agents.

Arthritis, Rheumatoid↗
PubMedDate not supplied

Prevalence of IgM, IgA and IgG rheumatoid factors in juvenile rheumatoid arthritis.

Using an enzyme immunoassay, sera from 50 children with juvenile rheumatoid arthritis (JRA) and 39 controls were tested for IgM, IgA and IgG rheumatoid factors (RF). RF of the IgM and IgA isotypes were present in 11 (22%) patients, but in only one control (p = 0.008). IgG RF was present in the sera of 2 (4%) patients and in none of the controls (p = 0.21). Of the 22 patients with IgM RF or IgA RF, only 3 sera (14%) contained RF of both isotypes. IgM RF was more common in patients with polyarticular disease, while IgA RF was more common in patients with pauciarticular disease. These results indicate that IgM and IgA RF are present in a significant minority of JRA patients and suggest that there is independent expression of the respective RF isotypes.

Adolescent↗