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PubMed1988

Antigen induced rheumatoid factors: characteristics of monoclonal rheumatoid factors produced after protein and carbohydrate immunization.

We generated a panel of monoclonal rheumatoid factors (MRF) from BALB/c mice immunized with ovalbumin, dextran or group-A-carbohydrate. Individual MRF were analyzed in terms of their binding to the four isotypes of murine IgG, isotypes of human IgG, and rabbit IgG, the idiotypes they express, and the VH gene families they employ. We found that antigen induced rheumatoid factors could be divided into three different families based on their isotypic specificity for murine IgG: an IgG1 binding family, and IgG3 binding family, and a family of MRF that bound all four murine isotypes. Rheumatoid factors belonging to all three families were isolated from mice immunized with carbohydrate antigens. The rheumatoid factors isolated from protein immunized mice all belonged to the IgG1 binding family. We were able to define two cross-reactive idiotypes among MRF, one expressed by a subgroup of the IgG1 binding family, and a second cross-reactive idiotype expressed by some members of the pan-binding family. We determined VH gene use in five of six MRF belonging to the IgG1 binding family and four of four members of the pan-binding family. Four of the IgG1 binding rheumatoid factors and three of the pan-binding rheumatoid factors utilize the J558 VH gene family. Rheumatoid factors produced after carbohydrate antigen immunization, as compared with those generated by protein immunization, are diverse in their isotypic specificity, and show a greater ability to bind heterologous IgG.

Animals↗
PubMed1988

Environmental and social factors in rheumatoid factor epidemiology.

The effect of social and environmental conditions on the epidemiology of Rheumatoid Factor (RF) in healthy population was studied. For this purpose 2 sample of 828 subject was studied using 5 tests for RF. Our sample included: 419 randomized subjects from a quarter at the outskirts of Bologna (high rate immigration, non homogeneous habits and health background; 409 randomized subjects from one rural small town on the Romagna's hills (no immigration, no change in residence or profession for generations, uniform, habits and health background). These tests included: three on slide with binded human (2) and rabbit (1) IgGs and sheep-cells tests-one on slide (Scat) and the other in tube (W.-Rose by Mizuoka). The most frequent positive test was Scat test, in urban population and one human IgG latex-test in the rural population. No urban subject reacted at the same time to 4 or 5 tests. Associated positive results for 2, 3 or 4 tests are usually observed in rural subjects. These results are the expression of the different and more uniform social and biological background acquired by rural people.

Adult↗
PubMed2004

Differences in the relationship of specificity to titre and functional affinity between circulating Ga- and pan-reactive IgM rheumatoid factors in rheumatoid arthritis.

OBJECTIVE: To determine if there are the differences in titre and functional affinity for immunoglobulin (Ig) G subclasses and glycoforms between the Ga- and pan-specific IgM rheumatoid factors (RFs) present in the sera of patients with rheumatoid arthritis (RA), and to determine whether these two broad specificities have different functional roles in RA. METHODS: We used direct ELISA and modified ELISA to study the binding of IgM RF in the sera of 32 patients with RA with a range of RF titres to a panel of 14 IgG paraproteins of all four subclasses, some allotypes and different glycosylation patterns. RESULTS: Pan-specific RFs were mostly found in RA sera with high RF titres, and these RFs generally had higher avidity. A trend towards higher avidity of RFs with higher titre was observed for pan-specific, but not for Ga-specific RFs. With increasing titre, pan-specific RFs tended to react strongly with fucosylated and bisected variants of hypogalactosylated IgG3 of G3m(b1) allotype and hypergalactosylated IgG4 of 4a allotype. CONCLUSION: Among high-titred pan-specific IgM RFs, there is a subpopulation responsible for strong anti-IgG activity in RA. The possible mechanisms of production of pan- and Ga-specific RFs are discussed.

Antibody Affinity↗
PubMedDate not supplied

ELISA determined IgM, IgG and IgA rheumatoid factors in rheumatoid arthritis and in other connective tissue diseases.

We used an adaptation of an enzyme-linked immunoadsorbent assay (ELISA) to determine serum levels of IgM, IgG and IgA rheumatoid factors (RF) in 50 patients with classic or definite rheumatoid arthritis (RA) according to the ARA criteria, balanced for positive or negative-routine Latex-RF reaction. A control group of 50 young normal subjects and a reference group of 44 patients with other connective tissue diseases (OCTD) were also studied. We confirmed the high sensibility of the method, together with its good specificity and reproducibility. For the IgM RF a very significant correlation was found between ELISA results and Latex-RF titration (p less than 0.001). Many Latex-RF negative RA patients had high ELISA levels of IgM RF, suggesting that this assay reveals, at least in part, hidden or non-agglutinating IgM RF. Among the OCTD group only some SLE cases, mainly Latex-RF positive, had enhanced IgM RF on ELISA. Considered quantitatively, IgG RF did not play a significant diagnostic role for RA (p greater than 0.05), because they were also found, with widely dispersed values, in normal subjects, and because the mean increase in RA patients was relatively small. Interestingly, IgA RF were above the normal range in many RA patients, both Latex-RF positive or negative. The mean values differed significantly from those of controls (p less than 0.005), and a correlation was observed between IgA RF levels and IgA containing immune-complexes. Normal IgA RF values were observed in SLE patients, even if Latex-RF positive, suggesting that their increase in RA patients is not the mere expression of a polyclonal B cell activation.

Arthritis, Rheumatoid↗
PubMed2006

Synovial fluid levels of anti-cyclic citrullinated peptide antibodies and IgA rheumatoid factor in rheumatoid arthritis, psoriatic arthritis, and osteoarthritis.

OBJECTIVE: To assess the levels of anti-cyclic citrullinated peptide (anti-CCP) and IgA rheumatoid factor (IgA-RF) in synovial fluids of patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), and osteoarthritis (OA). METHODS: Knee effusions of 29 patients with RA (23 women, 6 men; mean +/- SD age 60 +/- 15 years), 20 with PsA (6 women, 14 men; mean age 51 +/- 12 years), and 19 with OA (9 women, 10 men; mean age 73 +/- 11.8 years) were aspirated, tested for white blood cell (WBC) counts, centrifuged, and stored at -20 degrees . Sera of 22, 11, and 12 of these patients with RA, PsA, and OA, respectively, were similarly stored. IgG anti-CCP and IgA-RF were detected by enzyme-linked immunosorbent assay. Erythrocyte sedimentation rate and C-reactive protein levels were used as measures of disease activity. RESULTS: Mean levels of synovial fluid anti-CCP and IgA-RF were significantly increased in RA joint effusions compared with PsA and OA (anti-CCP: 150 +/- 134, 34 +/- 29, and 24 +/- 26 units, respectively [P < 0.003]; IgA-RF: 76 +/- 77, 15.7 +/- 10, and 18 +/- 20 units, respectively). No significant difference was noted between OA and PsA. A significant correlation was found between synovial fluid anti-CCP and serum anti-CCP and IgA-RF. In patients with RA, a significant correlation was found between synovial fluid WBC counts and IgA-RF (P = 0.03) and serum IgA-RF (P = 0.008), but not between synovial fluid and serum anti-CCP levels. In RA patients, C-reactive protein correlated with serum IgA-RF. CONCLUSION: Anti-CCP and IgA-RF were significantly increased in synovial fluid of RA in comparison with PsA and OA patients.

Aged↗
PubMed1986

Rheumatoid factor in rheumatoid arthritis associated renal disease and in lupus nephritis.

To test the hypothesis that rheumatoid factor (RF) protects against (immune complex mediated) renal disease, patients with rheumatoid arthritis (RA; 48 with nephropathy of various types, 35 without renal disease) and systemic lupus erythematosus (SLE; 35 with and 17 without nephritis) were evaluated for the presence and titre of RF. There was no correlation between RF and nephropathy in RA, whereas in SLE RFs were almost exclusively seen in patients without nephropathy. This result supports the above hypothesis for lupus nephropathy but not for RA associated renal disease, and it may be explained by a more pronounced role for immune complexes in SLE and interference of RFs with the complexes.

Arthritis, Rheumatoid↗
PubMed1985

Class specific rheumatoid factors in rheumatoid arthritis: response to chrysotherapy and relationship to disease activity.

IgG rheumatoid factors (RF) may play an important role in the pathogenesis of rheumatoid arthritis (RA). Our study investigates the relationship between class specific RF levels measured by radioimmunoassay and disease activity in patients with RA undergoing chrysotherapy. Nineteen patients were treated with 20 mg disodium aurothiomalate weekly for 6 months. Rheumatoid disease activity was assessed before and after 6 months' treatment and the level of IgG, IgA and IgM RF measured. There were significant falls in disease activity (p less than 0.005), IgA RF (p less than 0.005) IgG RF (p less than 0.005) and SCAT (p less than 0.025), but not IgM RF, over the 6 month treatment period. No correlation was found between absolute levels of IgA, IgG or IgM RF and disease activity before or after 6 months' therapy but there was a highly significant linear correlation between reduction in IgG RF levels and fall in disease activity (r = 0.642, p less than 0.005) with treatment.

Adult↗
PubMed1983

Local synthesis of IgM and IgM rheumatoid factor in rheumatoid pleuritis.

Pleura from 3 patients with rheumatoid pleuritis and from 5 patients with other diseases was examined for its capacity to synthesize IgM and IgM rheumatoid factor (RF). IgM was synthesized by pleura from all 3 patients with rheumatoid pleuritis and IgM RF by 2. Pleura from each of the control patients synthesized less than or equal to 1 ng/mg of IgM and IgM RF. Moreover, pleura from a 4th patient with rheumatoid pleuritis incorporated 3H-leucine into newly synthesized IgM. Simultaneously obtained pleural fluid mononuclear cells (MNL) and pleural tissue from a patient with rheumatoid pleuritis synthesized identical proportions of IgM and IgM RF whereas IgM RF production was not observed with peripheral blood MNL from the same patient. The results support the view that local production of IgM and IgM RF occurs in rheumatoid pleuritis and suggest that local immune events contribute to the pathogenesis of this disorder.

Arthritis, Rheumatoid↗
PubMed1989

[IgM, IgG and IgA rheumatoid factors in rheumatoid arthritis].

The IgM, IgG and IgA rheumatoid factors (RF) were studied by ELISA in the serum of 122 patients with rheumatoid arthritis (RA) associating the Waaler-Rose test results, with the clinical and radiological aspects of the disease. 75 patients (61%) had RF IgM positive according to the Waaler-Rose test while the ELISA showed positive in 104 (85%). The RF (IgG was positive in 64 cases (52%) and RF IgA in 82 (67%). The levels of RF IgA were correlated to RF IgM levels, determined by the Waaler-Rose test (p < 0.01) and ELISA (p < 0.001), while RF IgG levels were not correlated to RF IgM or IgA. There was a significant correlation between RF IgA titles and Lansbury's index (p < 0.01), and between RF IgG and sedimentation rate (p < 0.01). In patients with extraarticular disease high levels of RF have been observed, especially RF IgM and IgA. We concluded that the ELISA technique is the preferred method to measure the RF.

Adult↗
PubMed1990

Lymphocyte infiltration and the synthesis of IgM and IgA rheumatoid factors by rheumatoid synovial membrane.

IgM and IgA rheumatoid factor (RF) synthesis by synovial membrane mononuclear cells was measured in 14 patients with rheumatoid arthritis (RA). The results were compared with blood mononuclear cell cultures and correlated with the intensity of lymphocyte infiltration of the synovium. IgM RF was produced by all synovial cultures compared with 56% of blood cultures; IgA RF was produced by 86% of synovial cultures and by 21% of blood cultures. A correlation was observed between synovial IgM RF synthesis, but not IgA RF synthesis, and the intensity of T cell and B cell infiltration of the synovial membrane.

Adult↗
PubMed1985

Comparative specificities of serum and synovial cell 19S IgM rheumatoid factors in rheumatoid arthritis.

Rheumatoid factor (RF) may play a role in sustaining the inflammatory events and tissue damage in rheumatoid arthritis (RA). However, many serum RF have greater specificity for rabbit IgG than for human IgG, thus raising questions about RF pathogenicity in RA. Serum RF also has specificity for human IgG subclasses 1, 2 and 4, but not for IgG3. The synovium is central to the pathology of RA; thus, RF made there may have greater pathogenicity than serum RF. We examined the specificity of 19S IgM RF in an RF plaque forming cell assay (RF-PFC) using RA synovial cells (RSC). We found that: (1) RSC produced greater numbers of RF-PFC/10(6) cells than did RA peripheral blood mononuclear cells (PBM); (2) RSC RF-PFC had greater specificity for human than for rabbit IgG compared to autologous serum RF; (3) RSC RF had significantly greater specificity for human IgG3 relative to autologous serum RF. In contrast, RSC RF and autologous serum RF had the same relative specificities for polyclonal human IgG, IgG1, IgG2, and IgG4. Thus, the specificity of much of the RF synthesized by RSC differed from serum RF. The potential pathogenic significance of these observations is discussed.

Animals↗
PubMed1996

Comparison of rheumatoid factors of rheumatoid arthritis patients, of individuals with mycobacterial infections and of normal controls: evidence for maturation in the absence of an autoimmune response.

We analyzed the rheumatoid factors (RF) produced by Epstein-Barr virus-transformed monoclonal B cells established from four patients with rheumatoid arthritis (RA), three individuals with a history of Mycobacterium tuberculosis (TB) and four normal controls (NI). Fifty-eight RF were analyzed for specific activity (international units-RF/microgram) for the Fc part of IgG and their interaction with tetanus toxoid (TT) and DNA (polyspecificity). Furthermore, we sequenced the V-D-J heavy chain region of 16 (9TB-/7RA-) RF. Significant differences were observed between the NI-RF and the TB- and RA-RF. While the RF repertoire of normal individuals comprised of low-avidity RF of which the majority (15/17) were polyspecific, more than half of the TB- and RA-RF were monoreactive. Furthermore, the monospecific TB- and RA-RF were of significantly higher avidity than the NI-RF (RA > TB > > NI). With respect to polyspecificity specificity, the RF in the three groups were comparable: the interaction with DNA, TT as well as with Fc was inhibited either by an increase of the ionic strength to 0.3-0.5 M NaCl or by addition of the polyanion dextran sulfate, indicating that the antibodies interacted with similar anionic epitopes shared by the three antigens. Analysis of the V-D-J heavy chain regions showed significant differences between the respective RF. The salt-sensitive binding was highly correlated with the presence of arginine in the complementarity-determining region 3 (CDR3). Furthermore, whereas the polyspecific RF consisted predominantly of germ-line encoded antibodies, the genes of the monospecific RA/TB-RF were somatically mutated (RA > TB). It is therefore likely that maturation of RF can be initiated by chronic infections and that monospecific, somatically mutated RF are not a unique characteristic of autoimmune diseases.

Adolescent↗
PubMed1994

IgG3 reactive rheumatoid factor in rheumatoid arthritis: etiologic and pathogenic considerations.

Rheumatoid factor (RF) is a polyclonal autoantibody directed against the Fc portion of IgG. Although the role of RF in patients with rheumatoid arthritis (RA) is unclear, immune complexes that form between RF and IgG can activate the classical complement (C) pathway, leading to pathogenic outcomes involving inflammatory events and tissue damage. The specificity of serum RF and RF produced by rheumatoid synovial cells (RSC) is different. Serum RF has specificity for rabbit IgG and human IgG subclasses IgG1, 2, and 4, but binds poorly to IgG3. The affinity of serum RF for IgG Fc is low, having an association constant of 10(4)-10(5) M-1. RSC RF, however, has specificity for human IgG and high avidity for IgG3. Because of this greater specificity and avidity for IgG3, and because RSC RF may be pathogenically more important than serum RF, an important role for IgG3-reactive RF in RA may exist. Binding of RF to IgG may be dependent on the allotype and glycosylation of IgG. Infectious agents present in RA patients may directly or indirectly induce the production of certain RF. In this communication, we review and expand on several observations examining the role of IgG3-reactive RF in RA including: 1) binding differences between RF derived from RSC and serum; 2) glycosylation characteristics of IgG and its interaction with RF; 3) apparent allotype dependent binding of IgG3-reactive RF; and 4) possible relationship between infectious agents and the production of IgG3-reactive RF. Taken together, these observations suggest an important role for IgG3-reactive RF in better understanding the etiology and pathogenesis of RA.

Amino Acid Sequence↗
PubMed2004

Raised granzyme B levels are associated with erosions in patients with early rheumatoid factor positive rheumatoid arthritis.

BACKGROUND: Raised granzyme B in serum and synovium of patients with rheumatoid arthritis suggests a role for cytotoxic T cells and natural killer cells in the pathogenesis of this disease. OBJECTIVE: To evaluate serum granzyme B in patients with early arthritis and correlate it with specific diagnosis and clinical indices of disease severity. METHODS: 257 patients with inflammatory arthritis for less than one year (46% rheumatoid arthritis, 17% spondyloarthropathy, 37% undifferentiated arthritis) had a prospective clinical, serological, and radiographic evaluation. Granzyme B was measured in initial sera by ELISA. Patients were HLA typed for DR alleles using sequence specific primers. A logistic regression model was used to evaluate the potential prognostic value of serum granzyme B in predicting radiographic erosions after one year of follow up. RESULTS: Granzyme B values were similar in rheumatoid arthritis, spondyloarthropathy, and undifferentiated arthritis. Concentrations were higher in rheumatoid factor (RF) positive patients than in RF negative patients (mean (SD): 3.15 (0.92) v 2.89 (0.71) pg/ml; p<0.05). After one year, erosions were present in 30% of patients in the overall cohort, and in 44% of patients with rheumatoid arthritis. In the entire cohort, serum granzyme B did not predict erosions independently. However, high granzyme B was an independent predictor of early erosions in patients with RF positive rheumatoid arthritis (odds ratio = 4.83 (95% confidence interval, 1.13 to 20.59)) (p<0.05). CONCLUSIONS: Granzyme B may be a useful prognostic marker in early rheumatoid arthritis and may provide important clues to the pathogenesis of this disease.

Adult↗
PubMed1990

Cross-reactive rheumatoid factors in rheumatoid arthritis with extra-articular disease.

Rheumatoid factors (RF) have been shown to have considerable heterogeneity and bind with IgG as well as with a variety of substances such as nuclear histone, non-histone nuclear protein, nitrophenyl groups or ssDNA. We describe evidence that polyclonal RF cross-reactive with ssDNA (CRRF) are widely distributed in a variety of rheumatic diseases, and that their serum level is significantly higher in rheumatoid arthritis (RA) with extra-articular disease. Although the mechanism of the cross-reactivity is not clear, the presence of CRRF could be a serological feature of a clinical subset of RA. The high prevalence rate of CRRF in RA with extra-articular disease also suggests its pathogenetic role in the extra-articular manifestation of this disease.

Antibodies, Antinuclear↗
PubMed1992

Molecular analysis of the V kappa III-J kappa junctional diversity of polyclonal rheumatoid factors during rheumatoid arthritis frequently reveals N addition.

Much interest was stirred in recent years by the evidence that rheumatoid factors (RF) variable regions are encoded by a restricted set of V genes, with little or no somatic mutations, that are often overexpressed in the fetal repertoire. This is reminiscent of what has been observed for natural autoantibodies. However, these data come from studies of monoclonal RF (mRF) isolated from patients with lymphoproliferative disorders who usually do not present autoimmune symptoms. The molecular characterization of RF during autoimmune diseases such as rheumatoid arthritis (RA) has been hampered for some time because of their polyclonality; recently using the polymerase chain reaction method, we have demonstrated that RF kappa variable regions from a patient with RA were encoded by V kappa III genes known to code for mRF but that these genes had undergone somatic mutations with a pattern suggesting an antigen-driven maturation. Because an important role of the light chain third complementarity-determining region (CDR3) in anti-IgG reactivity and idiotype expression has already been suspected for RF, we now report the molecular characterization of the junction regions of these rearranged V kappa gens. Surprisingly, our data show that in 55% of the cases there is addition of a proline and/or glycine amino acid residue at the recombination site between V kappa and J kappa. The sequence analysis of our patients' germ-line Vg and J kappa 4 genes segments and their flanking regions demonstrates that the additional codons are not readily explicable by recombination between germ-line sequences and probably result from an N addition process. Since we could not find such an additional codon in 15 previously published mRF kappa chains we suggest that "pathogenic" RF during RA and mRF derive from different, although overlapping, B cell subsets. Moreover, since additional codons at the recombination site of V kappa and J kappa seem exceptional in expressed human kappa chains and because the resulting amino acid residue is a proline in most cases, we think that RF kappa chain CDR3 is under a very strong selective pressure during RA.

Amino Acid Sequence↗
PubMed1974

The molecular basis of self-association of antibodies to IgG (rheumatoid factors) in rheumatoid arthritis.

The serum and synovial fluid of many patients with rheumatoid arthritis contain immune complexes composed of immunoglobulin G (IgG). In this study such complexes from one patient are shown to be formed by self-association of IgG-antibodies to IgG (IgG-rheumatoid factors), so that each molecule serves as an antibody as well as an antigen. All F(ab')(2) and Fab' fragments derived from these complexes have antibody binding sites for normal IgG. Due to a high association constant in the formation of a cyclic complex by these antibodies, normal IgG is excluded as an antigen. These studies serve as a model for further elucidation of presence of similar immune complexes in the serum and synovial fluid of patients with rheumatoid arthritis.

Antibodies, Anti-Idiotypic↗
PubMed1989

Mesangial glomerulopathy and IgM rheumatoid factor in rheumatoid arthritis.

Hematuria and proteinuria in rheumatoid arthritis (RA) are commonly associated with drug therapy but occur independently of drugs, amyloid or urologic disorders. The latter occurrences suggest a primary renal lesion associated with RA. Review of reported renal biopsies identifies mesangial glomerulopathy as a common finding in RA patients without associated drug therapy and that it is frequently associated with hematuria in nonrheumatoid patients. Moreover, immunoglobulins have been shown to concentrate in the mesangium in experimental animals, suggesting that a functional response by the kidney mesangium to remove IgM rheumatoid factor (RF)-IgG complexes could lead to this mesangial lesion. We describe 3 patients with RA who had a mesangiopathy characterized by increased quantities of mesangial matrix and deposition of IgM without other lesions. Together, these observations suggest that: (1) mesangial glomerulopathy is common in RA; (2) removal of circulating RF-IgG complexes is a function of the mesangium and might produce this renal lesion; (3) mesangial glomerulopathy may be responsible for much of the hematuria observed in RA patients and, in many cases, may not be drug related and thus may not require discontinuing beneficial therapy.

Adult↗