[Rheumatoid factor--rheumatoid factor as an antibody and its relationship to the disease process].
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We have studied the distribution of rheumatoid factor isotypes amongst patients with loiasis with and without accompanying glomerulonephritis to determine the possible role of rheumatoid factor antiglobulins in this disease. Our findings indicate an increase in both immunoglobulin (Ig) G and IgM rheumatoid factor isotypes in patients with filariasis alone as well as in patients with accompanying glomerulonephritis. No association with IgA rheumatoid factor was found. The raised IgG and IgM rheumatoid factor levels did not correlate with corresponding IgG and IgM levels.
Rheumatoid factors are immunoglobulins with antibody specificity for antigenic sites on the Fc part of the heavy chain of IgG. The heterogeneity of RF in terms of antigenic specificity and class of immunoglobulin is indicative of the complexity of the provoking immune response. There is little doubt that in many patients rheumatoid factors are autoantibodies which form part of immune complexes, and that complexes containing IgG rheumatoid factor appear to be of pathogenetic importance. Although IgM rheumatoid factors are not specific for RA, their detection aids in the diagnosis and categorisation of rheumatoid arthritis. On the other hand, IgG rheumatoid factors occur in a variety of rheumatic diseases and are of little diagnostic value.
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Rheumatoid synovial fluids generated significantly greater amounts of superoxide, lysosomal enzymes, and superoxide dismutase from neutrophils into extracellular fluid than osteoarthritic synovial fluids. Rheumatoid factors isolated from serum suppressed superoxide-generating activity of performed immune complexes, but did not suppress that of intermediate-sized immune complexes isolated from RA serum. Synovial fluid neutrophils has a greater capacity to generate superoxide and lower intracellular superoxide dismutase activity, compared with peripheral neutrophils of the corresponding patients. These results suggest that neutrophil superoxide release may be modulated, both by rheumatoid factor and by intracellular and extracellular superoxide dismutase.
Rheumatoid factor (RF) is a major source of interference in many immunoassays. Most immunoassays use mammalian polyclonal or monoclonal antibodies, and RF can react with IgG from mammalian species, thus causing false-positive results. In this work we have studied RF interference in a sandwich ELISA, where RF in the sample may react with both the capture antibody and the detection antibody to give a false-positive reaction. We show that rheumatoid factors do not react with chicken IgY; if the capture antibody or detection antibody (or both) is of avian origin, the interference of RF or other anti-IgG antibodies in sandwich ELISA can be avoided.
A linkage disequilibrium was searched for between HLA-DR antigens and rheumatoid factor level both measured using latex agglutination and a solid phase immuno-enzymic assay (FR-PAP) among 251 sera from patients suffering from classical rheumatoid arthritis for at least 5 years, recorded in the Cooperative Swiss Study on Rheumatoid Arthritis. An association between the presence of HLA-DR7 and low levels of rheumatoid factor was found. This association was stronger when the DR4, 7 heterozygous subjects were excluded. The comparison of the DR7, not equal to 4 and DR not equal to 4, not equal to 7 subjects demonstrated that the DR7 effect was independent of DR4. Although the association between DR4 and high levels of rheumatoid factor was not statistically significant in this study, these data suggested an opposite influence of DR4 and DR7 on rheumatoid factor level among rheumatoid arthritis suffering patients. The influence of DR4 appeared to be dominant among heterozygous DR4, 7 patients.
Rheumatoid factor (RF) was found in titers greater than 1:8 in 72.2% of cases of classical or definite canine rheumatoid arthritis (RA) and in 5.9% or normal sera. Serum fractionation and immunoabsorbant studies that much of the RF present was IgG, although activity was demonstrated in all 3 major immunoglobulin classes. Evidence of involvement of both IgG and IgM to form complexes of varying sizes was obtained.
Rheumatoid factors (RF) constitute the major autoantibodies in rheumatoid arthritis (RA). RF are directed against IgG Fc, are polyclonal, and are predominantly of the IgG and IgM classes. RF may participate in both synovial and extraarticular inflammation in RA, although the precise roles of serum IgG and IgM RF are unclear. The purpose of our study was to correlate serum IgG RF with serum IgM RF levels measured by radioimmunoassay and with clinical disease activity in 42 prospectively evaluated seropositive RA patients. IgM RF correlated with IgG RF levels and articular disease activity. IgG RF correlated with IgM RF but not with articular disease activity when adjusted for IgM RF.
Rheumatoid factors (RF), which are auto-antibodies recognising the Fc fragment of IgGs, are the commonest auto-antibodies in man. They are present in polyclonal form in a large number of auto-immune disorders as well as in certain inflammatory states. In monoclonal form, they are frequently the product of "mature" malignant (chiefly Waldenström's macroglobulinemia and chronic lymphoid leukemia) and allegedly benign (such as cryoglobulinemias) lymphoid proliferations. In addition, RF account for a significant part of the normal antibody repertory, notably during the fetal and neonatal periods, suggesting that they may play an important role in the development and regulation of the immune system. As a result, RF are an excellent model for the analysis of auto-immunity in man. Thus many indirect (analysis of antigens recognised and of idiotopes carried) and, more recently, direct (protein or nucleotide sequencing of their various regions) studies have now provided the following conclusions. RF are coded by a very limited repertory of V genes. These genes are present in the normal genome and appear to be highly preserved in the human species. They are used with very few somatic mutations by monoclonal B proliferations (which opens up valuable therapeutic possibilities) as well as probably by RF producing B lymphocytes in normal individuals. In contrast, in the context of auto-immune disorders, these same genes have many somatic mutations suggesting maturation governed by the antigen and/or escape from idiotype control.
We report the first molecular characterization of V kappa regions of the main human autoantibodies occurring during rheumatoid arthritis, the polyclonal rheumatoid factors. Using two sets of polymerase chain reactions in order to amplify the cDNA derived from both peripheral blood and synovial fluid rheumatoid factor-secreting cells, nucleotide analysis of the V kappa III family usage shows the following: (a) at least three different V kappa III genes are used to encode polyclonal rheumatoid factors in a single patient, (b) each one of these genes seems more or less somatically mutated (from 1 to 14 mutations), (c) the mutation process preferentially affects the complementarity determining regions suggesting a selective pressure of antigen and (d) there is no clear difference between the mutation rates affecting the synovial fluid and peripheral blood rheumatoid factor-secreting cells. These results are able to explain some of the known idiotypic differences between monoclonal and polyclonal rheumatoid factors in humans. They also provide evidence that polyclonal autoantibodies arising during an autoimmune disease can be the products of multiple somatically mutated genes and suggest that this process is antigen driven, whether this antigen is the Fc piece of IgG or another unknown antigen.
To study the occurrence of rheumatoid factors (RF) in relation to the activity of rheumatoid arthritis and the occurrence of vasculitis, RF of IgM, IgA, and IgG classes were measured in sera from 35 patients with definite or classic rheumatoid arthritis (RA) using ELISA. For 26 patients, the RF levels were studied longitudinally and compared with changes in the articular index. Although IgM RF was occasionally found in patients without RA, IgA and/or IgG RF were almost exclusively associated with RA. The titers of IgM, IgA, and IgG RF were significantly higher in sera from patients with clinically diagnosed rheumatoid vasculitis than in sera from patients without vasculitis. No significant correlation between changes in the articular index and changes in titer of any class-specific RF could be found for the group of RA patients as a whole. However, in individual patients, increases or decreases in IgM and IgG RF titer were significantly correlated with an increase or decrease in the articular index.
Fc gamma-receptor-(CD16-)positive natural killer (NK) cells are activated by rheumatoid factor in the synovial fluid of patients with rheumatoid arthritis. This activation induces modulation of the CD16 molecule and release of IFN gamma and TNF alpha by NK cells.
Complement (C) activating rheumatoid factors (RF) were measured in 16 patients with rheumatoid arthritis (RA) by a simple haemolysis in gel (HIG) assay. IgM-RF, but not IgG-RF or IgA-RF, measured by an enzyme linked immuno-sorbent assay, were closely correlated with C activating RF (r = 0.86). In neither assay did the concentrations of RF appear to be directly related to C1 activation as expressed by serum concentrations of C1r-C1s-C1 inactivator complexes or of C4. In the sera, C1q binding substances, measured by C1q binding assay, were markedly correlated with C activating RF (r = 0.88), whereas C1q binding substances detected by the C1q deviation test were not. Treatment with podophyllotoxin derivatives for 6 months clearly reduced patients' RF concentrations. The decrease of IgG-RF, IgA-RF and IgM-RF was significantly more pronounced than that of the IgG, IgA and IgM concentrations, respectively.
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.