A mechanism for the induction of immunological tolerance by antigen feeding: antigen-antibody complexes.
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We have previously reported on the induction, in mice, of a systemic (splenic) immune response with IgA as the dominant antibody, as a result of a short (4 day) intragastric immunization course with foreign erythrocytes. This response was followed by a prolonged period of hyporesponsiveness to similarly administered antigen. Here it is shown that this hyporesponsiveness is also manifested towards antigen given intraperitoneally, and that one is therefore dealing with tolerance, not with failure to absorb antigen from the gut. In contrast, mice primed parenterally and then challenged intragastrically behaved as if never having any previous contact with the antigen, i.e., with a primary-type splenic response of predominant IgA character. This agrees with our former conclusion that splenic responses to enterically absorbed antigen reflect colonization of the spleen by cells sensitized locally in the gut wall, a site not readily primed by the parenteral route. Serum from intragastrically immunized mice contained a very active tolerogen. In vivo, it was capable of conferring tolerance to nonimmune recipient mice. In vitro, it paralyzed the activity of antibody-producing cells. Inhibitory sera has weak antibody activity, restricted to the IgA class, and contained immune complexes reacting with rheumatoid factor but not with C1q. Elimination of these complexes by means by insolubilized rheumatoid factor abolished the tolerogenic effect. In conclusion, the enterically induced tolerogen seems to consist of immune complexes with IgA as the antibody. (+info)
Rheumatoid arthritis associated autoantibodies in patients with synovitis of recent onset.
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STATEMENT OF FINDINGS: An inception cohort of 238 patients having peripheral joint synovitis of less than 12 months duration was evaluated clinically and followed prospectively for 1 year to determine the clinical significance of a number of rheumatoid arthritis (RA) associated autoantibodies. Serum samples collected at the time of the initial evaluation were tested for rheumatoid factor (RF) and antibodies to Sa (anti-Sa), RA-33, (pro)filaggrin [antifilaggrin antibody (AFA)], cyclic citrullinated peptide (anti-CCP), calpastatin, and keratin [antikeratin antibody (AKA)]. RF had a sensitivity of 66% and a specificity of 87% for RA. Anti-Sa, AFA, and anti-CCP all had a specificity of more than 90%, but a sensitivity of less than 50% for this diagnosis. Overall, there was a high degree of correlation between AFA, AKA, anti-Sa or anti-CCP, this being highest between anti-Sa and anti-CCP (odds ratio, 13.3; P < 0.001). Of the 101 patients who were positive for at least one of these four autoantibodies, 57% were positive for only one. Finally, anti-SA identified a subset of predominantly male RA patients with severe, erosive disease. Anti-SA, AFA and anti-CCP are all specific for early RA but, overall, have little additional diagnostic value over RF alone. Although these antibodies may preferentially recognize citrullinated antigens, the modest degree of concordance between them in individual patient sera suggests that it is unlikely a single antigen is involved in generating these responses. (+info)
Sequence analysis of the immunoglobulin antigen receptor of hepatitis C virus-associated non-Hodgkin lymphomas suggests that the malignant cells are derived from the rheumatoid factor-producing cells that occur mainly in type II cryoglobulinemia.
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Analysis of the immunoglobulin receptor (IGR) variable heavy- and light-chain sequences on 17 hepatitis C virus (HCV)-associated non-Hodgkin lymphomas (NHLs) (9 patients also had type II mixed cryoglobulinemia [MC] syndrome and 8 had NHL unrelated to MC) and analysis of intraclonal diversity on 8 of them suggest that such malignant lymphoproliferations derive from an antigen-driven pathologic process, with a selective pressure for the maintenance of a functional IgR and a negative pressure for additional amino acid mutations in the framework regions (FRs). For almost all NHLs, both heavy- and light-chain complementarity-determining regions (CDR3) showed the highest similarity to antibodies with rheumatoid factor (RF) activity that have been found in the MC syndrome, thus suggesting that a common antigenic stimulus is involved in MC syndrome and in HCV-associated lymphomagenesis. Moreover, because HCV is the recognized pathologic agent of MC and the CDR3 amino acid sequences of some HCV-associated NHLs also present a high homology for antibody specific for the E2 protein of HCV, it may be reasonable to speculate that HCV E2 protein is one of the chronic antigenic stimuli involved in the lymphomagenetic process. Finally, the use of specific segments, in particular the D segment, in assembling the IgH chain of IgR seems to confer B-cell disorders with the property to produce antibody with RF activity, which may contribute to the manifestation of an overt MC syndrome. (+info)
Arthritis in myasthenia gravis.
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Seven patients with myasthenia gravis developed clinical signs of arthropathy. In two patients, the symptoms were due to a deforming rheumatoid arthritis and the myasthenic symptoms appeared as a transitory phase during the course of the disease. Muscle antibodies of IgG class were demonstrated with sera from both patients. Autoreactivity between muscle antibodies and rheumatoid factor was detected in one patient. Both patients died from sudden cardiac failure. Necropsy was performed in one and revealed a spotty myocardial necrosis. One patient had juvenile rheumatoid arthritis. Two patients had mild articular symptoms with indices of multivisceral disease and serological findings indicating a systemic lupus erythematous. One patient had classical ankylosing spondylitis, and one, unspecified arthropathy. (+info)
Assessment of antibodies to double-stranded DNA induced in rheumatoid arthritis patients following treatment with infliximab, a monoclonal antibody to tumor necrosis factor alpha: findings in open-label and randomized placebo-controlled trials.
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OBJECTIVE: To compare the incidence of anti-double-stranded DNA (anti-dsDNA) antibodies in rheumatoid arthritis (RA) patients receiving either single or multiple doses of a chimeric anti-tumor necrosis factor alpha (anti-TNFalpha) antibody or placebo infusions, with or without methotrexate, in open-label, randomized, placebo-controlled trials. METHODS: Multiple sera obtained from 156 patients before and after treatment with infliximab and from 37 patients treated with placebo infusions were tested for anti-dsDNA antibodies by 3 methods: Crithidia luciliae indirect immunofluorescence test (CLIFT), a commercial Farr assay (Ortho Diagnostics radioimmunoassay [RIA]) in which the antigen source is mammalian DNA, and a Farr assay employing 125I-labeled circular plasmid DNA (Central Laboratory of The Netherlands Red Cross Blood Transfusion Service [CLB] RIA). Patients with positive findings on the CLIFT were also tested for antibodies to histones (H1-H5) and chromatin and for IgM rheumatoid factors (IgM-RFs). RESULTS: None of the RA patients had a serum sample that was positive for anti-dsDNA antibodies by the CLIFT prior to infliximab therapy. Of the 22 patients who developed a positive CLIFT result, 11 (7% of 156 exposed to infliximab) also had positive findings on the Ortho RIA at a concentration of >10 units/ml and another 8 (5%) were positive at a concentration of >25 units/ml. In all but 1 patient, the anti-dsDNA antibodies were solely of the IgM isotype. Only 1 patient had detectable anti-dsDNA antibodies by the CLB RIA. All sera containing anti-dsDNA by the CLIFT contained antibodies to chromatin, and sera from 2 patients also contained antibodies to histones. IgM-RF titers showed a significant reduction following infliximab therapy in these 22 patients. One patient developed anti-dsDNA antibodies of IgG, IgA, and IgM isotype and had positive results on both Farr assays (peaking at 22 weeks and resolving by 54 weeks); this was associated with a reversible lupus syndrome. CONCLUSION: Anti-dsDNA antibodies of IgM class are induced by infliximab therapy; the frequency is dependent on the assay method used. Only 1 of the 156 patients who were treated with infliximab developed a self-limiting clinical lupus syndrome; that patient developed high titers of anti-dsDNA antibodies of IgG, IgM, and IgA class, as detected by the CLIFT and by 2 different Farr assays. (+info)
Smoking, rheumatoid factor isotypes and severity of rheumatoid arthritis.
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OBJECTIVES: Smokers have an increased incidence of rheumatoid factor (RF) and rheumatoid arthritis (RA) and one report has also indicated that smoking may also adversely influence the severity of RA. METHODS: Sixty-three women with advanced RA answered a structured questionnaire that included detailed information about their smoking history. The women were also evaluated clinically and radiologically. RESULTS: Heavy smoking (>/= 20 pack-yr) was associated with rheumatoid nodules (P: = 0.01), a higher HAQ score (P: = 0.002) and a lower grip strength (P: = 0.01). Smoking was also associated with more radiological joint damage (P: = 0.02). A positive correlation was observed between smoking and RF levels, in particular IgA RF and a combined elevation of IgM and IgA RF. CONCLUSIONS: Smoking has an adverse effect on disease progression in patients with RA. An association was also observed between smoking and those RF types that predispose to RA and have the highest diagnostic specificity for this disease. (+info)
Psoriatic arthritis in severe psoriasis.
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SUMMARY: Of 100 patients admitted to hospital for treatment of psoriasis, 32 had clinical or radiologic evidence of psoriatic arthritis and 17 had both types of evidence. Eight had radiologic evidence of spinal or sarroiliac involvement without symptoms and seven had clinical evidence of peripheral arthritis without radiologic evidence. Patients with psoriatic sacroilitis and spondylitis were most likely to have typical radiograpic changes. It was concluded that psoriatic arthritis is common in patients with severe psoriasis and that is associated with more extensive skin disease than is found in patients without arthritis. (+info)
Kinetic analysis of interaction of different types of rheumatoid factors with immobilized IgG using surface plasmon resonance.
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Rheumatoid factors (RFs) are autoantibodies, which recognize antigens on a constant region of immunoglobulin G (IgG). Among various RF classes, RF of the IgG class (IgGRF) forms immune complexes in rheumatoid joints and is implicated in the pathogenesis of rheumatoid arthritis (RA). To characterize the formation of IgGRF immune complexes, in the present study, IgGRF was isolated from sera of RA patients, and its interaction with immobilized IgG was analyzed and compared to that of IgMRF or IgARF by means of surface plasmon resonance. On gel filtration, the IgGRF was eluted as a single peak corresponding to IgG, excluding the possible formation of self-associating IgGRF complexes in solution. Sensorgrams of the interaction of IgGRF with immobilized IgG revealed that it clearly bound to the IgG at 6 degrees C, but not at 30 degrees C. The degree of interaction decreased inversely with an increase in temperature, suggesting that IgGRF is much more reactive at lower temperatures. In contrast, the interaction of IgARF and IgMRF with IgG at 6 degrees C was similar to that at 30 degrees C. The association rate constant (k(a)) of IgGRF decreased with an increase in temperature, while those of IgARF and IgMRF were similar under various thermal conditions. The dissociation rate constant (k(d)) of IgGRF was greatly reduced at 25 degrees C, but those of IgARF and IgMRF slightly increased with an increase in temperature. These results suggested that the mode of interaction of IgGRF with IgG differed from in the cases of IgMRF and IgARF. The kinetic properties of the IgGRF-IgG interaction may facilitate elucidation of the IgGRF immune complex formation in rheumatoid joints. (+info)