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PubMed1995

Human IgG rheumatoid factors and RF-like immune complexes induce IgG1 rheumatoid factor production in mice.

The synovial fluid of patients with rheumatoid arthritis (RA) was found to contain IgG and/or IgG-containing immune complexes (ICs) that stimulated an intense antibody formation when injected into mice of certain strains, notably of NZ background. The response was characterized by high and sustained levels of IgG1 antibodies with rheumatoid factor (RF) activity. In the study described, we investigated whether it is the antibodies with RF activity in the synovial fluid, that are responsible for stimulation of mouse RF in vivo. Different mouse strains were injected with synovial fluid from a seropositive RA patient (RA-SF), with human monoclonal antibodies with RF activity, with a human non-RF monoclonal antibody or with different preformed RF-like antibody-antibody (Ab-Ab) ICs. The experimental mice were monitored subsequently for IgG1 RF production. IgG1 RF antibodies were found in all strains (NZB, BALB/c and CBA) injected with Ab-Ab ICs formed at equivalence, but only in NZB using RA-SF or human monoclonal antibodies with RF activity. Optimal production of IgG1 RF by Ab-Ab ICs required the integrity of Fc and F(ab)'2 portions respectively of the antibodies; soluble and truncated ICs were less effective. Further studies demonstrated that the IgG1 RF response was not simply the result of a specific immune response against human IgG, since humoral immunity against human IgG was induced only when combined with an efficient adjuvant. During a typical adjuvant-associated primary response specific antibodies of IgM, IgG1 and IgG2a isotypes were found, i.e. quite different from the selective IgG1 response induced by RF-like containing immune complexes. This conclusion is substantiated further by the clear differences in responses to IgG containing fraction obtained from RA-SF in NZ mice compared to other strains. Our findings argue for a different type of reaction leading to the selective IgG1 response and might aid in elucidating the mechanisms for chronic production of antibodies with RF activity in patients with RA.

Animals↗
PubMed1985

Activity of rheumatoid factors of different molecular sizes: comparison of autologous monomeric and polymeric monoclonal IgA rheumatoid factors.

Differences in rheumatoid factor (RF) activity among the molecular species of IgA were investigated with the use of monomeric and polymeric monoclonal IgA RF paraprotein from the serum of a patient (PS) with idiopathic hyperviscosity syndrome. After fractionation by gel chromatography in acidic buffer, RF activity as determined by latex fixation and solid-phase radioimmunoassay (RIA) specific for IgA RF was confined to the high m.w. (greater than 7S) fractions. However, after adsorption into polystyrene wells, fractions containing monomeric (7S) IgA, as well as those containing polymeric IgA, bound 125I-labeled heat-aggregated human IgG. These observations were confirmed after further purification of the IgA fractions by passage through a protein A-Sepharose CL-4B column followed by precipitation of the IgA proteins with ammonium sulfate at 50% saturation. After "cross-linkage" by a hybridoma anti-human alpha-chain antibody, the activity of the monomeric IgA preparation in the IgA RF RIA approached that of the polymeric IgA preparation. Gel filtration studies verified that this activity was not due to contamination by polymeric IgA RF. Further, classic RF specificity was confirmed for both the monomeric and polymeric IgA RF by reaction with human Fc-coated but not Fab-coated wells. A control monomeric IgA myeloma protein and normal serum IgA did not react in the RF RIA when analyzed in the presence or absence of the hybridoma anti-alpha-chain antibody. Moreover, the activity of the polymeric IgA RF preparation from patient PS in the RIA was minimally influenced by the hybridoma antibody. These results indicate that IgA RF can coexist in both polymeric and monomeric forms, demonstrate that monomeric IgA RF may escape detection by previously described RIA techniques, and suggest an approach for its detection.

Animals↗
PubMed1986

Generation of monoclonal rheumatoid factors after immunization with collagen II-anti-collagen II immune complexes. An anti-idiotypic antibody to anti-collagen II is also a rheumatoid factor.

Two monoclonal IgG rheumatoid factors were obtained after hybridization of spleen cells from DBA/1 mice immunized with immune complexes containing native collagen type II and a monoclonal anti-collagen II antibody. One of these rheumatoid factors reacted not only with purified murine Fc fragments, but also with Fab fragments of the anti-collagen II antibody used for immunization, whereas no reactivity was seen with Fab fragments from normal mouse IgG. The findings demonstrate the ability of immune complexes encompassing native collagen type II to induce production of IgG rheumatoid factors, and suggest that an idiotypic relationship may exist between certain rheumatoid factors and anti-collagen II antibodies.

Animals↗
PubMed1980

Rheumatoid factors in mice: plaque assay for homophile and heterophile rheumatoid factors.

It was found that a high proportion of IgM-producing cells secrete homophile or heterophile rheumatoid factors (RF). Injection of lipopolysaccharide (LPS) into CBA mice resulted in a sharp increase in total IgM and in RF-producing cells and in some cases resulted in an increase in RF-producing cells as a proportion of total IgM. RF plaques are indirect IgM in the sense that they require development by IgG2 (anti-IgM) antibody for visualization in a standard haemolytic plaque assay. The RF response to LPS is both dose- and time-dependent.

Animals↗
PubMed1982

A reappraisal of the monoclonal rheumatoid factor test for circulating immune complexes: a comparison of two monoclonal rheumatoid factor reagents.

Assays involving monoclonal rheumatoid factor (mRF) reagents are frequently used for the detection of circulating immune complexes, particularly in the rheumatic diseases. A study has been performed to investigate the interaction of two purified mRF reagents with normal sera, sera and synovial fluid from patients with rheumatic diseases and with heat-aggregated human IgG used as a model of immune complexes. Interaction has been measured by a simple laser nephelometric technique and a sensitive radiolabelled mRF precipitation assay. Both mRF reagents showed little reactivity with normal sera but reacted strongly with many of the pathological specimens. Similarly both mRFs reacted with large molecular sized heat aggregates of IgG while a variable reactivity was found with uncomplexed or monomeric IgG. However in pathological sera, both mRFs reacted predominantly with monomeric IgG and a significant correlation was found between the two reagents. This reactivity with monomeric IgG remained after separation of pathological sera in low pH sucrose gradients suggesting it was not due to the presence of small immune complexes of the classical type. In addition no reactivity was found with either reagent with IgG-RF intermediate complexes. It is concluded that mRF reagents are not specific for IgG containing immune complexes. They also react with monomeric IgG and this reactivity is particularly prominent in certain pathological sera. The possible nature of this reactive monomeric IgG is discussed.

Antibodies, Monoclonal↗
PubMed1991

Production of IgM rheumatoid factor by normal lymphocytes after stimulation with preparations containing IgM rheumatoid factor from patients with juvenile arthritis.

Preparations containing IgM rheumatoid factor (RF) and hidden IgM RF were isolated from the serum samples of nine patients with juvenile rheumatoid arthritis. Six of these preparations stimulated lymphocytes from normal donors to produce IgG and IgM, of which up to 11% had IgM RF activity. In contrast, the polyclonal activator pokeweed mitogen also stimulated IgM production, but only 1% had IgM RF activity. A relation between the activator and IgM RF or hidden IgM RF is suggested. This is based on the positive correlation between IgM RF concentration in these preparations and their ability to stimulate lymphocytes to produce IgG, IgM, and IgM RF. These data indicate that preparations from patients with juvenile rheumatoid arthritis containing IgM RF and hidden IgM RF are potent stimulants of lymphocytes from normal donors, with specific production of IgM RF.

Adolescent↗
PubMed1980

Rheumatoid factors in mice: non-specific activators of heterophile rheumatoid factor production.

Although possibly the best, LPS is by no means the only non-specific activator of immune responsiveness (AIr). Plant lectins such as PHA and PWM have some ability to stimulate both total IgM production (reverse IgM PFC) and more particularly heterophile and homophile IgM rheumatoid factor (RF) responses, together with IgM 'antibody' responses to target antigens such as xenogeneic red blood cells or haptens such as TNP. Some parasitic infections and/or parasite antigens were shown to be powerful non-specific AIr, while the injection of dextran sulphate was shown to lead to a great increase in spleen cellularity and total IgM (reverse) PFC but failed to stimulate a heterophile (BIG) RF PFC response.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1985

IgA rheumatoid factor synthesis by dissociated synovial cells. Characterization and relationship to IgM rheumatoid factor synthesis.

We examined patterns of IgA rheumatoid factor (RF) and IgM-RF synthesis by dissociated synovial cells obtained from 27 patients with seropositive rheumatoid arthritis. Synthesis of IgA-RF was observed in 19 of 34 synovial cell preparations from these patients and constituted a mean of 16% of the total IgA produced. IgA-RF expression correlated only weakly with IgM-RF production (r = 0.385) and could be dissociated from production of IgA-RF (and IgM-RF) exhibited by simultaneously obtained peripheral blood plasma cells. While wide variations were observed in the ratio of IgA-RF:IgM-RF produced by synovial B cells in the patient sample studied, remarkable consistency in the relationship of IgA-RF to IgM-RF synthesis was observed over time in different joints of the same patient. IgA-RF synthesized by dissociated synovial cells was predominantly of the IgA1 subclass and existed in both monomeric and polymeric forms. Our results are compatible with the view that local production of IgA-RF and IgM-RF are regulated independently of each other.

Adult↗
PubMed1995

VH3-21 B cells escape from a state of tolerance in rheumatoid arthritis and secrete rheumatoid factor.

BACKGROUND: Rheumatoid factor (RF) is a characteristic but not pathognomic feature in patients with rheumatoid arthritis (RA). It is unknown whether the repertoire of immunoglobulin genes utilized by RF+ B cells of RA patients is unique and whether RF+ B cells in normal individuals are silenced or deleted. MATERIALS AND METHODS: Clonal B cell populations were established from the peripheral blood of normal donors (127 B cell clones), RA patients (113 RF- and 60 RF+ B cell clones) and patients with primary Sjögren's syndrome (82 RF- and 47 RF+ B cell clones) by coculturing with anti-CD3-stimulated T helper cell clones. The cross-reactivity pattern of antibodies secreted by the B cell clones was determined by ELISA on a panel of antigens. The molecular structure of the IgM heavy chains was characterized by VH family-specific RT-PCR and sequencing. VH elements which correlated with RF specificity were identified. The responsiveness of B cells expressing these VH elements to T helper cell signals was compared in normal individuals and RA patients. RESULTS: The majority of RF+ B cells were monospecific when specificity was tested on five antigens. RF+ B cells expressed a significantly different repertoire of VH gene segments than RF- B cells. In particular, the VH3 gene segment V3-21 was not detected in B cell clones from normals but was the most frequent VH element in RF+ B cell clones from RA patients. Most of the V3-21 sequences were in germline configuration. The correlation between RF specificity and V3-21 gene segment usage was maintained in patients with Sjögren's syndrome. V3-21 transcripts were present in peripheral blood B cells from normal individuals. VH3-21+ B cells from RA patients but not from normal donors were responsive to preactivated T helper cells. Stimulation with a bacterial superantigen could overcome the nonresponsiveness of V3-21+ B cells in normal donors and induce the secretion of RF. CONCLUSIONS: RF production is correlated with the usage of the V3-21 gene segment in two distinct RF+ diseases. In patients with these diseases, V3-21+ B cells secrete antibodies with RF activity in response to activated T helper cells. V3-21+ B cells remain in a state of nonresponsiveness in normal individuals that can be broken by superantigen stimulation. The germline configuration of VH3-21+ RF+ immunoglobulins in RA patients suggests that the loss of tolerance is not an antigen-driven process.

Antibody Specificity↗
PubMedDate not supplied

Raising rheumatoid factor cutoff helps distinguish rheumatoid arthritis.

The presence of rheumatoid factor (RF) is one of the clinical criteria for the diagnosis of rheumatoid arthritis (RA). The cutoff point of RF assays is usually based on a reference level obtained from normal subjects in the same population as the patients. We evaluated 63 rheumatoid arthritis (RA), 25 other arthritis patients and 110 blood donors. Their rheumatoid factors (RF) ranged from < 9.9 to 2,264, < 9.9 to 262, and < 9.9 to 66 mIU/ml, respectively. The sensitivity at different cutoff points of 15, 20, and 25 mIU/ml was 92.1%, 90.5%, and 88.9%, respectively. The specificity at the same cutoff points was 81.5%, 84.4%, and 85.2%, respectively. Having minimally sacrificed the sensitivity, we recommend using a higher RF cutoff to increase specificity.

Adult↗
PubMed1992

Heteroclitic polyclonal and monoclonal anti-Gm(a) and anti-Gm(g) human rheumatoid factors react with epitopes induced in Gm(a-), Gm(g-) IgG by interaction with antigen or by nonspecific aggregation. A possible mechanism for the in vivo generation of rheumatoid factors.

Heteroclitic rheumatoid factors (RF) are specific for allotypic determinants, e.g., Gm(a) or Gm(g) on allogeneic, but not autologous IgG. All polyclonal RF we isolated from nine rheumatoid arthritis patients with circulating Gm(a-), (b+), (g-), (f+) IgG displayed dual heteroclitic activity for the Gm(a) and Gm(g) allotypes, as shown by using appropriate RBC agglutination assays and affinity columns bearing Gm(a+) or Gm(g+) IgG. To investigate possible mechanisms underlying the in vivo generation of heteroclitic RF, we tested the ability of nonspecifically and immune-specifically aggregated Gm(a-), (g-) IgG to function as targets for RF from Gm(a-), (g-) patients with rheumatoid arthritis. Heat aggregation (63 degrees C for 20 min) or binding to Ag (as in tetanus toxoid-antitetanus toxoid complexes) induced a "functional" Gm(a+) and/or (g+) phenotype in Gm(a-), (g-) IgG from five healthy subjects and five rheumatoid patients, as suggested by the ability of these altered IgG to function as efficient targets for six heteroclitic RF in direct binding and competitive inhibition experiments. That heterocliticity and dual Gm(a), Gm(g) specificity can be features of a single antibody molecule was formally demonstrated by analysis of a monoclonal RF (IgM mAb 61) generated from a Gm(a-), (g-) rheumatoid patient. RF mAb 61 displayed a high affinity (Kd, 10(-7) M) for IgG Fc fragment of Gm(a+) and (g+) IgG or aggregated autologous Gm(a-), (g-) IgG but did not bind to native autologous IgG. To investigate the molecular basis of the acquired Gm(a) phenotype, PBMC from five Gm(a-) patients with rheumatoid arthritis and two Gm(a-) normal subjects arthritis and two Gm(a-) normal subjects were cultured in vitro after activation with PWM. In most instances, these PBMC produced IgG that behaved as Gm(a+) in sensitive ELISA. Application of the polymerase chain reaction (PCR), using probes specific for the nucleotide sequence coding for the Gm(a) tetrapeptide, to the amplification of DNA from the in vitro-stimulated Gm(a-) normals or rheumatoid patients' PBMC provided no evidence for Gm(a) nucleotide sequences. The present data suggest that acquisition of the Gm(a) determinant by Gm(a-) IgG may result from subtle changes in the CH2-CH3 RF-binding region. Such changes would occur when Gm(a) IgG are complexed with Ag or nonspecifically altered, thereby providing a possible explanation for the induction of heteroclitic RF in Gm(a-) rheumatoid arthritis patients.

Antibodies, Monoclonal↗
PubMed1985

A new assay for IgG rheumatoid factor activity and its use to analyse rheumatoid factor reactivity with human IgG isotypes.

A new assay for IgGRF activity is described which employs human IgGFc as the antigen and a radiolabelled monoclonal antibody directed against human IgG (CHI domain) as the developing antibody. Using this assay IgGRF activity against human IgG isotypes was measured and most sera from RA patients were shown to react predominantly with IgG1 and IgG2 but few reacted with IgG3 and IgG4. The same sera were tested for IgMRF to the IgG isotypes. IgG2 was the best antigen, IgG1 and IgG4 were less so and reactivity with IgG3 was the lowest. IgGRF without associated IgMRF was obtained, its specificity compared to that of IgMRF, and found to be broadly similar. With the new assay high levels of serum IgGRF were found in those RA patients with extraarticular disease but not in RA patients with synovitis alone.

Antibodies, Monoclonal↗
PubMed1987

Prospective comparison of laser nephelometry with standard agglutination techniques for detection of rheumatoid factor.

IgM rheumatoid factor was assayed by three routine methods: latex fixation; haemagglutination; and end point laser nephelometry in 69 patients with definite or classical rheumatoid arthritis and 58 patients with other non-rheumatoid arthropathies, selected prospectively according to the American Rheumatism Association clinical criteria. The operators of the assays were unaware of the clinical diagnoses. In the group with rheumatoid arthritis 75.4% were positive by latex fixation, 73.9% by haemagglutination, and 55.1% by nephelometry. In the group with non-rheumatoid arthropathies 10.4% were positive by latex fixation, 8.6% by haemagglutination, and 10.4% by nephelometry. Thus the simple and inexpensive latex fixation test was as good as the haemagglutination test, and both were significantly better than nephelometry in the laboratory confirmation of the clinical diagnosis of definite or classic rheumatoid arthritis (chi 2 = 5.40 and 4.56, and p less than 0.025 and less than 0.05, respectively). None of these tests was significantly better or worse than the others in producing positive results in the group with non-rheumatoid arthropathies.

Adolescent↗
PubMed1985

An assessment of the diagnostic value of quantitative measurements of IgA rheumatoid factor.

IgA rheumatoid factor (RF) was found in a significant number of the normal population. As a consequence, the presence of IgA RF was not more specific for a diagnosis of rheumatoid arthritis than IgM RF. However, further investigation of IgA RF as a prognostic indicator is important. Our results, which show an association between the presence of IgA RF and higher levels of IgM RF, suggest that careful differentiation between the predictive values of the presence of IgA RF and a high level of IgM RF will be necessary.

Arthritis, Rheumatoid↗
PubMed1976

Detection of IgG rheumatoid factor by concanavalin A treatment and complement fixation with IgG rheumatoid factor.

Concanavalin A (Con A) froms precipitates with carbohydrate-rich protein such as IgM, IgD, IgE, and IgA. Since IgG contains little carbohydrate and does not react with Con A, the activity of IgG-rheumatoid factor (RF) can be measured in the supernate of the Con A-treated serum. When the latex fixation test (LFT) and the sensitized sheep cell agglutination test (SSCA) were perfromed in the supernate for the detection of IgG-RF, LFT was positive in 32-1% of sera, out of 137 sera originally positive for LFT, and SSCA was positive in 18-5% of sera, out of 119 sera originally positive for SSCA. IgG-RF exhibited lower complement fixing ability than IgM-RF and correlated with agglutination titres of IgG-RF, while the CH50 of the original serum did not correlate with haemolytic activities of either IgM-RF or IgG-RF.

Arthritis, Rheumatoid↗
PubMedDate not supplied

[The experimental induction of rheumatoid factors of low affinity and cross reactivity with nonhistone nucleoproteins by means of anti-idiotypes directed at rheumatoid factors of high affinity and cross reactivity with histones H1 and H2b].

The study of the anti-nuclear cross reactivity of rheumatoid factors has shown differences between patients with rheumatoid arthritis and healthy seropositive subjects. This paper describes the finding, of a subpopulation of rheumatoid factor molecules which show a cross reactive idiotype and show high affinity for IgG and cross reactivity against histones in rheumatoid arthritis patients but not in healthy subjects. These molecules, in turn, were able to induce, experimentally, heterogeneous rheumatoid factor molecules that show a low affinity for IgG and cross-reactivity against nucleoproteins other than histones, most likely through idiotypic networks. The mechanism could be responsible for the diversification of serum autoantibodies found in rheumatoid arthritis.

Animals↗