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PubMed1995

Human recombinant IL-2 augments immunoglobulin and induces rheumatoid factor production by rheumatoid arthritis lymphocytes engrafted into severe combined immunodeficient mice.

Recombinant (r) human IL-2 was administered in vivo to improve homing and engraftment of rheumatoid arthritis (RA) patients' peripheral blood mononuclear cells (PBMC) into severe combined immunodeficient (SCID) mice. Human rIL-2 treatment resulted in augmented human Ig production and induced IgM rheumatoid factor (RF) of human origin in SCID-RA chimeras. The increment of human serum IgG in SCID-RA chimeras after IL-2 treatment ranged between 15 and 43% and for IgM between 50 and 98% during 2-8 weeks postengraftment. Human IgM-RF was detectable after 1 to 2 weeks after engraftment and persisted over a period of 10-13 weeks. No RF was produced in SCID mice engrafted with PBMC from healthy individuals with or without exogenous rIL-2 administration. Thus, human rIL-2 expanded autoreactive clones involved in the production of RF in the SCID-RA chimeras. The present study provides a novel approach to establish an in vivo SCID-RA model to study the cellular and molecular mechanisms involved in the production of RF and development of a RA-like lesion.

Adult↗
PubMed1984

Human IgG aggregates induce selective stimulation of IgM rheumatoid factor synthesis by rheumatoid blood mononuclear cells.

Peripheral blood mononuclear cells (PBM) from patients with active rheumatoid arthritis (RA) contain precursor B lymphocytes specific for IgM rheumatoid factor (IgM-RF) synthesis. In this study, human IgG aggregates (HaIgG) were used to stimulate monocyte-depleted PBM from 46 patients with RA and 21 normal controls. The cells were incubated with HaIgG and pokeweed mitogen for 72 hours, washed, and then cultured in microwells for an additional 11 days. HaIgG induced an increase in IgM-RF synthesis by RA cells with optimum response at 0.1 microgram/ml (P less than 0.001). Total IgM synthesis remained unchanged. In contrast, HaIgG did not stimulate IgM-RF production by normal cells. Specificity of the IgM-RF response was shown by the concomitantly increased IgM-RF/IgM ratios, while IgM anti-trinitrophenyl antibodies did not increase. Aggregation of the IgG was required for it to be an effective stimulus. The findings suggest that circulating immune complexes in RA patients may provide the stimulus for sustained production of IgM-RF in vivo.

Arthritis, Rheumatoid↗
PubMedDate not supplied

Complement-fixing hidden rheumatoid factor in juvenile rheumatoid arthritis.

Fifteen to twenty percent of patients with juvenile rheumatoid arthritis (JRA) have positive latex fixation tests (LFT), whereas approximately 46% have previously been demonstrated to have hidden rheumatoid factors (RF), i.e., 19S IgM RF which can be detected by the LFT after acid separation of the IgM-containing fraction from serum. In this study, hidden RF were found in 59% of patients with seronegative JRA by use of a complement-dependent hemolytic assay. The median titer of JRA patients was 1:42, and in healthy and disease controls it was 1:7. The difference was significant at P less than 0.001. When data from patients with active disease were analyzed separately, the median titer for polyarticular JRA was 1:97 and for pauciarticular JRA, 1:91. The differences due to active disease were significant at P less than 0.001 and P less than 0.005, respectively. The results demonstrate that the hemolytic assay is more sensitive than the LFT in determining the presence of hidden RF, and activity of disease correlates well with high hemolytic RF titers.

Adolescent↗
PubMed1980

Hidden 19S IgM rheumatoid factor in juvenile rheumatoid arthritis.

One-hundred twenty-five serum samples from 82 patients with juvenile rheumatoid arthritis (JRA) were studied for the presence of hidden rheumatoid factor (RF) in an effort to find a better serologic marker to define JRA. Hidden 19S IgM RF was detected by means of a hemolytic assay utilizing the IgM-containing fraction of serum. The IgM fraction was obtained after acid separation of serum on a Sephadex G-200 column. Hidden 19S IgM RF was present in 68% of patients with seronegative JRA with a mean titer of 1:63. The mean titer for the polyarticular JRA group was 1:83, for the pauciarticular JRA group, it was 1:32, and for the systemic type-onset JRA patients, it was 1:32. When disease was active, the mean titer for all JRA patients was 1:108, for the active polyarticular JRA group it was 1:119, for the active pauciarticular JRA, it was 1:97, and for the active systemic JRA patients, it was 1:64. All values were significant at the P less than or equal to 0.001 when compared to disease and normal controls. The hemolytic assay for RF on the IgM-containing fraction of serum thus enhances the serologic capabilities of defining JRA.

Adolescent↗
PubMed2005

Elevated levels of IgM and IgA antibodies to Proteus mirabilis and IgM antibodies to Escherichia coli are associated with early rheumatoid factor (RF)-positive rheumatoid arthritis.

OBJECTIVE: Antibodies to Proteus mirabilis were previously detected in patients with established rheumatoid arthritis (RA). We examined the prevalence of antibodies to P. mirabilis and their associations with RA in early synovitis patients. METHODS: Two hundred and forty-six patients with inflammatory arthritis for less than 1 yr were prospectively evaluated for 1 yr. Of these patients, 30% had rheumatoid factor (RF)-positive RA, 16% RF-negative RA, 17% a spondyloarthropathy and 37% undifferentiated arthritis. Serum antibodies to P. mirabilis, Escherichia coli and other potentially arthritogenic organisms (Chlamydia, Salmonella, Shigella, Campylobacter, Yersinia and parvovirus B19) and for antibodies specific for immunoglobulin (Ig) G damaged with advanced glycation end-products (anti-IgG-AGE) were measured. RESULTS: IgM and IgA anti-Proteus antibodies were significantly higher in patients with RF-positive RA compared with all other patient groups (P < 0.0005 and P < 0.005). Anti-P. mirabilis IgG, and IgG, IgA, and IgM antibodies to other potentially arthritogenic pathogens did not differ in the patient groups. IgM antibodies to E. coli were elevated in RF-positive RA patients. Anti-P. mirabilis IgM and IgA results were not explained by false-positive reactions, because after absorption of RF there was no decrease in antibodies to Proteus in 10 of 12 patients. Proteus and E. coli antibodies were highest in patients positive for both RF and anti-IgG-AGE antibodies (P<0.001). Patients with erosions tended to have higher IgA anti-Proteus titres, but no association with the shared HLA epitope or treatment was detected. CONCLUSION: Anti-P. mirabilis IgM and IgA and anti-E. coli IgM antibody elevations are associated with early seropositive RA and the presence of anti-IgG-AGE antibodies. The role that P. mirabilis or E. coli plays in early RF-positive RA requires further investigation.

Adult↗
PubMed1979

IgG rheumatoid factor. Relationship to seropositive rheumatoid arthritis and absence in seronegative disorders.

IgG rheumatoid factor was detected in the sera of the majority of patients with seropositive rheumatoid arthritis. Values suggestive of IgG rheumatoid factor were noted in one-quarter of patients with seronegative inflammatory arthropathies. These determinations were always low and correlated with elevated IgG concentrations, suggesting nonspecific adherence of IgG rather than a true antigen-antibody reaction. In support of this conclusion, nonrheumatoid factor IgG was capable of concentration-dependent nonspecific adsorption to the solid phase. IgG, but not IgM, rheumatoid factor corresponded with disease activity in patients with seropositive rheumatoid arthritis, suggesting that IgG rheumatoid factor may be important in the pathogenesis.

Arthritis, Juvenile↗
PubMed1990

Human rheumatoid factor cross-idiotypes. III. Bla monoclonal rheumatoid factor, prototype of the BLA cross-idiotype group, has distinct kappa chains related to the V kappa III subgroup and VH4 heavy chains.

The BLA cross-idiotype (XId) is present on a unique subset of rheumatoid factors (RF) that cross-react with DNA-histone. In this study, prototype Bla monoclonal RF was shown from serologic investigations and N-terminal amino acid sequence analysis to have distinct kappa chains related to the V kappa III subgroup and VH4 heavy chains. The amino terminus of the heavy chain was cyclized, rendering the protein resistant to Edman degradation and providing a possible investigator bias to the published Ig sequence data to date. This appears to be the first definitive report of a serum IgM that expresses the VH4 gene. RF with DNA cross-reactivity have been reported to be produced by human and mouse cloned cells that have the VH4 or homologous mouse Vh36-60 gene.

Amino Acid Sequence↗
PubMed1991

IgE rheumatoid factor. Occurrence and diagnostic importance in comparison with IgM rheumatoid factor and circulating immune complexes.

The sera of 80 patients suffering from rheumatoid arthritis (RA)--30 of them with extraarticular manifestations (EAM) and 50 patients with articular disease only--of 25 patients with other joint diseases and of 30 normal healthy subjects, were analyzed for the presence of 1) IgE rheumatoid factors (IgE RF) by means of a solid phase radioimmunoassay and an ELISA, 2) IgM rheumatoid factors by using solid phase radioimmune techniques, and 3) circulating immune complexes (CIC) with the C1q binding test (C1q BT) and the solid phase conglutinin binding test (SPCBT). The best technique to discriminate RA patients with EAM from RA patients without EAM and patients with other articular diseases was the determination of IgE RF (73.3%, 38.0%, 0%, resp.) compared to IgM RF (86.7%, 78.0%, and 56.0%) and CIC (C1q BT: 80.0%, 66.0% and 45.0%; SPCBT: 46.7%, 22.0%, and 20.0%). The results suggest a certain role of IgE RF for diagnosis and a possible development of extraarticular manifestations in rheumatoid arthritis.

Antigen-Antibody Complex↗
PubMed1980

Lack of hidden complement fixing IgM rheumatoid factor in adult seronegative rheumatoid arthritis.

IgM rheumatoid factors capable of complement fixation and activation are commonly present in the sera of adults with rheumatoid arthritis. Hidden complement fixing IgM rheumatoid factor has been demonstrated in the majority of patients with juvenile RA and hidden agglutinating IgM rheumatoid factors have been demonstrated in the serum of adults with seronegative rheumatoid arthritis. We studied 27 adults with seronegative rheumatoid arthritis and were unable to demonstrate hidden complement fixing IgM rheumatoid factor in their sera.

Adult↗
PubMed1990

Smoking, lung function, and rheumatoid factors.

Positive rheumatoid factor (RF) reactions commonly precede the onset of clinically manifest rheumatoid arthritis (RA). Thus if items associated with RF reactions were traced at the community level this might provide clues to the cause of RA. The relations between smoking and lung functions and the occurrence of RA and RFs in a population sample representative of the adult Finnish population were studied. Rheumatoid factor testing was performed for 7124 subjects (89% of the sample) by the sensitised sheep cell agglutination test. Forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) were measured with spirometry. 'False positive' RF reactions occurred twice as often in current smokers and ex-smokers than in those who had never smoked. The prevalence of high titres was fourfold greater among current smokers than among those who had never smoked. These associations were statistically significant and independent of age, FVC, and FEV1 in both sexes. The women with airflow limitation (FEV1/FVC less than 70%) had a significantly increased occurrence of RFs which was independent of their smoking history, but no such relationship was found in men. The results suggest an impact of smoking on RF production; a follow up study may show whether the raised RF titers in smokers will be reflected as an increased incidence of RA.

Adult↗
PubMed1984

Influence of serum complement and rheumatoid factor on detection of immune complexes by the C1q and monoclonal rheumatoid factor solid-phase assay.

Soluble purified monoclonal and polyclonal rheumatoid factor, total serum complement, and soluble C1q all inhibit the detection of model tetanus toxoid/anti-toxoid immune complexes in the solid-phase C1q assay. The binding of these immune complexes to solid-phase monoclonal rheumatoid factor is less inhibited by soluble C1q and by total serum complement, but clearly decreased by soluble monoclonal or polyclonal rheumatoid factor. Serum complement does not reduce the size of these model complexes. We recommend the use of low ionic strength EDTA (10 mM) to partly neutralize the complement-mediated inhibition. This procedure is shown to be superior to currently used higher EDTA concentrations and to the use of IgG-Sepharose.

Antibodies, Monoclonal↗
PubMed1994

Erosive rheumatoid factor negative and positive rheumatoid arthritis are immunogenetically similar.

OBJECTIVE: The relationship between rheumatoid factor positive (RF+) and rheumatoid factor negative (RF-) rheumatoid arthritis (RA) is controversial. We sought to determine whether the HLA genes conferring susceptibility for erosive RF+RA are also prevalent in patients with erosive RF-RA. METHODS: DNA-based HLA typing for DRB1, DQB1, and DPB1 was performed on 16 consistently RF--patients with erosive RA. RESULTS: Thirteen of 16 (81%) RF-RA patients had the HLA susceptibility genes DRB1 *0401, *0404, or *0101, which are associated with RF+RA, as compared to 46% of normal controls (p = 0.017). By contrast, no associations with HLA-DQB1 and HLA-DPB1 alleles were apparent. CONCLUSION: Specific HLA susceptibility alleles are prevalent in patients with erosive RA, regardless of RF status, suggesting a similar immunogenetic basis for RA in these patients.

Adult↗
PubMed1989

[Comparison of the immunoenzyme test (ELISA) with other methods in the detection of rheumatoid factor].

IgM rheumatoid factor was detected, beside ELISA test, by Waaler-Rose, Latex agglutination and indirect immunofluorescent test. 107 patients hospitalized in the Clinic for heart diseases and rheumatism, as well as 50 healthy subjects were examined. In the first group were 50 patients with RA, 30 patients with other rheumatic diseases and 27 with nonrheumatic diseases. According to our results there was no significant difference between sensitivity of ELISA test and other laboratory tests used. ELISA test was positive in 94% of cases of RA, 20% in other rheumatic diseases and only in one case (3,7%) of a nonrheumatic disease. Compared with the control group in which there was no specific reaction, Waaler-Rose and immunofluorescent testing showed a nonspecific reaction in 2% and Latex test in 4% of all cases. Although ELISA test was not significantly sensitive as compared with other laboratory methods, according to our results, it has high reproducibility, specificity and precision (it is measured in international units/mL serum), and it allows following of the concentration of rheumatoid factor. Besides, ELISA test can be done on 100 specimen of blood within 6 hours and the results are known the same day.

Arthritis, Rheumatoid↗
PubMed1961

Rheumatoid factor and the pathogenesis of rheumatoid arthritis.

In analogy with the two categories of reactants which are used in the serological tests for the unusual category of macroglobulins called rheumatoid factor, two fluorescent reactants have been prepared for the detection of rheumatoid factor in situ in tissue sections: fluorescent antigen-rabbit antibody (immune) complex, in the present study, and fluorescent aggregated human gamma-globulin, in previous work. Plasma cells in the synovial membrane and germinal center cells and internodular plasma cells in lymph nodes are the sites of origin of rheumatoid factor in active rheumatoid arthritis, whether occurring in adults or children. Plasma cells and germinal center cells which form rheumatoid factor detectable with fluorescent immune complex are less numerous than those which contain factor demonstrable with fluorescent aggregate. In the same tissues, plasma cells and germinal center cells which contain macroglobulin (19S human gamma-globulin) detectable with fluorescent antibody-but not showing the reactivity of rheumatoid factor-are more abundant than those containing rheumatoid factor. While macroglobulin and rheumatoid factor are almost exclusively formed in the cytoplasm, these proteins are also detectable in the nucleus of an occasional plasma cell. Normal and pathological synovial and capsular tissues, lymph nodes, and connective tissues obtained from individuals without rheumatoid arthritis are not stained with fluorescent immune complex or, except for an unusual example of Waldenstrom's macroglobulinemia, with fluorescent aggregate. The cellular origin, as well as certain chemical and immunological attributes, of rheumatoid factor suggests an antibody-like nature and function. The observations cited are consistent with the behavior anticipated for cellular rheumatoid factor, were it primarily an antibody direct to an altered human gamma-globulin and cross-reacting with rabbit gamma-globulin. However, it is also possible that there are two or more cellular rheumatoid factors. Lesion-associated protein precipitates having the composition anticipated for rheumatoid factor-antigen complex are localized in the amyloid depositions in kidney and spleen of an individual who died with amyloidosis secondary to rheumatoid arthritis.

Adult↗
PubMed1999

False-positive troponin I in the MEIA due to the presence of rheumatoid factors in serum. Elimination of this interference by using a polyclonal antisera against rheumatoid factors.

We report false-positive cardiac troponin (cTn) I results in the microparticle enzyme immunoassay (MEIA) using the AxSYM analyzer. We studied serum samples from 12 patients with positive rheumatoid factor but with no indication of myocardial infarction (MI); 2 also had positive antinuclear antibody (ANA) titers. Serum samples from 7 patients with positive ANA titers and negative rheumatoid factors also were studied. Total creatine kinase (CK) was run using a Hitachi 747 analyzer, cTnT using an Elecsys 2010 analyzer, and cTnI and CK-MB using an AxSYM analyzer. We observed no measurable cTnI and cTnT concentrations in 12 control samples or in specimens with positive ANA titers and negative rheumatoid factors. In contrast, samples from 7 of 12 patients containing rheumatoid factors had measurable cTnI concentrations. Four specimens showed cTnI concentrations more than 2.0 micrograms/L, the suggested diagnostic cutoff for MI. None of the specimens showed detectable cTnT. The concentrations of total CK and CK-MB were within normal ranges in all specimens. False-positive results were observed only with the MEIA for cTnI. This interference can be eliminated by using a polyclonal antisera against rheumatoid factor. The chemiluminescent assay for cTnI showed no detectable cTnI concentration in any specimen.

Antibodies, Antinuclear↗
PubMed2006

High IgA rheumatoid factor levels are associated with poor clinical response to tumour necrosis factor alpha inhibitors in rheumatoid arthritis.

OBJECTIVE: To investigate whether rheumatoid factor isotypes and anti-cyclic citrullinated peptide (anti-CCP) antibodies are related to clinical response in patients with rheumatoid arthritis treated with tumour necrosis factor alpha (TNFalpha) inhibitors. METHODS: The study was carried out on 132 patients with advanced rheumatoid arthritis refractory to disease-modifying antirheumatic drugs. Patients were treated with infliximab (n = 63), etanercept (n = 35) or adalimumab (n = 34). All patients completed 1 year of follow-up, and 126 were evaluable for clinical response according to the disease activity score (DAS) criteria. IgM, IgA and IgG rheumatoid factors and anti-CCP antibodies were assessed by ELISA both before anti-TNFalpha treatment and 1 year later. RESULTS: The DAS response was reached in 66% of evaluable patients (61% infliximab, 65% etanercept and 76% adalimumab; p = 0.354). A significant reduction in the rheumatoid factor level was reported by all treatment groups after 1 year. The frequency of positive tests for the different antibodies did not differ between responders and non-responders at baseline; however, significantly higher IgA rheumatoid factor levels were reported by the non-responder group (130.4 U/ml (interquartile range 13.8-276.7) v 24.8 U/ml (10.2-90.8); p = 0.003). A significant decrease (p<0.001) in the levels of all rheumatoid factor isotypes in the responder group was reported after 1 year of treatment, whereas anti-CCP antibody levels were not significantly affected. CONCLUSIONS: According to the clinical response, anti-TNFalpha agents seem to reduce IgM, IgG and IgA rheumatoid factor levels. More interestingly, high pretreatment levels of IgA rheumatoid factor are associated with a poor clinical response to TNFalpha inhibitors.

Adalimumab↗
PubMed1988

Immunogenic and antigenic epitopes of immunoglobulins. XXIII. Idiotypy and molecular specificity of human rheumatoid factors: analysis of cross-reactive idiotype of rheumatoid factor paraproteins from the Wa idiotype group in relation to their IgG subclass specificity.

The expression of idiotypic and variable region-associated isotypic determinants on a panel of human monoclonal rheumatoid factors (RF) was studied by means of murine hybridoma antibodies produced to two IgM-RF paraproteins. Fourteen RF paraproteins from patients with cryoglobulinaemia and one (RF-AN) from an Epstein-Barr virus (EBV)-established B-cell line from a patient with rheumatoid arthritis (RA) were studied. Nine RF paraproteins expressed a VkIIIb light chain sub-subgroup-associated cross-reactive idiotype and seven of these nine also expressed a heavy chain-associated cross-reactive idiotype. The reactivity of the monoclonal RF with human IgG subclass paraproteins revealed four patterns of molecular specificities: (1) RF reactive with an epitope common to all IgG subclasses; (2) RF reactive with an epitope expressed on IgG1, 2, 4 and G3m(s,t) which has histidine at 435, but not G3m(b) or G3m(g) which have arginine at 435; (3) RF reactive with an epitope expressed on IgG1, 2, and 4, but not IgG3 irrespective of allotypic markers; (4) RF reactive with epitopes expressed on some, but not all paraproteins within the subclasses. Four of five RF paraproteins that expressed both the heavy and light chain-associated idiotopes showed a similar pattern of reactivity with IgG subclass proteins.

Cross Reactions↗
PubMed1995

[Clinical significance of IgG rheumatoid factor in patients with rheumatoid arthritis].

We studied 135 patients with rheumatoid arthritis (RA) from February 1991 through June 1992 (mean period: 9 months) to measure serum IgG rheumatoid factor (IgG-RF) by the method of enzyme linked immunosorbent assay. In order to evaluate clinical significance of serum IgG-RF we compared the level of IgG-RF with some of the clinical and laboratory markers including disease activity index of RA and titers of IgM rheumatoid factor (IgM-RF) and IgA rheumatoid factor (IgA-RF). Positive IgG-RF (more than 2.0 on IgG-RF index) was observed only in 22.2% (30 patients) with the examination of the first collected serum samples but was increased to 41.5% (56 patients) by the case of total test samples. The number of patients with positive IgM-RF or positive IgA-RF test was significantly smaller in seronegative patient group than in seropositive patient group, whereas IgG-RF test showed no significant differences between these two groups. These indicate usefulness of consecutive test of IgG-RF for diagnosis of RA especially in seronegative patients. The mean of total score indicating radiographic bone destruction by Sharp's modified method was significantly higher in positive patients than in negative patients of IgG-RF. Multivariate analysis showed positive correlations between serum IgG-RF levels and erythrocyte sedimentation rates as well as between serum IgG-RF levels and Lansbury's indexes. These results suggest that the test of serum IgG-RF level is beneficial for daily management of patients with RA.

Arthritis, Rheumatoid↗