Gamma Globulin Complexes in Rheumatoid Arthritis and Certain Other Conditions

Abstract

Recent studies have demonstrated that the factors responsible for the various serological reactions currently employed for the diagnosis of rheumatoid arthritis represent macroglobulins which, in the isolated state, have a corrected sedimentation coefficient of approximately 19S (1-5). In serum and plasma, these proteins exist as complexes with low molecular weight y-globtulins and show a higher sedimentation rate, approximately 22S (6, 7). It has become clear that the rheumatoid factors have a specific affinity for ordinary y-globulin showing a behavior, particularly in certain of the serological tests, like that of anti-y-globulin antibodies. The possibility has been raised that the rheumatoid factor complex in serum represents an antigen-antibody complex.During the course of investigation of the rheumatoid factors and their complexes through ultracentrifugal analyses of sera showing high titer reactions in the latex fixation test and y-globulin precipitin test, another group of y-globulin complexes was encountered. These had sedimentation rates between 9 and 17S and were dissociated in urea and acid buffers in a manner similar to the previously observed dissociation of the rheumatoid factor complexes. Again the question arises as to whether these are antigen-antibody comlplexes or simple aggregates of y-globulin.Gamma globulin components in the 9 to 12S range have been observed in many preparations of normal Fr II y-globulin. The (15,16), although the sedimentation rate of the main abnormal protein was lower than the 18 to 20S range of the proteins described by Waldenstr6m. Macroglobulins of the latter class are a homogeneous group and are known to be stable proteins which do not dissociate in urea and acid and alkaline buffers (17). They have specific immunological properties and dissociate in the presence of agents breaking disulfide bonds (18).In the present study, sera from 11 different patients, 7 with classical rheumatoid arthritis, were found to contain multiple y-globulin complexes. These were readily detected in whole serum and plasma by direct ultracentrifugal analysis. They did not possess rheumatoid factor activity but were associated in the same sera with large amounts of rheumatoid factor. Investigation of the association and dissociation reactions of these complexes was carried out and certain of their properties de-fined. Evidence for and against the hypothesis that they represent antigen-antibody complexes of the y-globlulin-anti-y-glol)bulin type was sought. MATERIAL AND MIIETHODSSix of the 11 patients whose sera were specifically analyzed in this study were observed in the clinic and outpatient department of the Rockefeller Hospital. Three of the remainder represented patients in various New York 1-17

Enforced Bcl‐2 expression in B lymphocytes induces rheumatoid factor and anti‐DNA production, but the Yaa mutation promotes only anti‐DNA production

“…RF formed in non-autoimmune mice are nearly always restricted to the IgM class, while lupusprone MRL-lpr/lpr mice deficient in the Fas apoptosis receptor spontaneously produce high titers of IgG RF as well as IgM RF [5][6][7]. Circulating intermediate-sized immune complexes (IC) consisting of IgG RF [8,9], similar to those found in sera or synovial fluids from patients with rheumatoid arthritis [10], could contribute to several pathological manifestations, such as necrotizing arteritis and arthritis, uniquely observed in MRL-lpr/lpr mice [11][12][13]. Moreover, studies with mouse monoclonal RF reveal that RF of the IgG3 subclass are highly pathogenic, inducing glomerulonephritis and necrotizing vasculitis [14,15].…”

Studies on Circulating Immune Complexes

“…(Received for publication 21 August 1967) With the observations of immune complexes or antigens in the circulation of patients with rheumatoid arthritis (1,2), systemic lupus erythematosus (3,4), and other diseases, much attention has been drawn to their possible significance in the pathogenesis of the lesions in these disorders. Abundant data derived from experimental models have shown that the presence of complexes in the circulation coincides temporally with the development of the lesions, e.g., acute glomerulonephritis and vasculitis (5,6) and chronic glomerulonephritis (7).…”

Guinea pigs with inherited deficiencies of complement components C2 or C4 have characteristics of immune complex disease.

“…Although these animals have no overt clinical symptoms, we tested the sera ofthese genetically C-deficient guinea pigs for serologic abnormalities in order to determine whether they are predisposed to autoimmunity. In particular, we tested for circulating immune complexes, antibodies against complement proteins, and socalled rheumatoid factors, which is a collective term for immunoglobulins of the IgM or IgG class specific for antigenetic determinants on homologous or heterologous aggregated IgG (6,(8)(9)(10)(11)(12). We also determined levels of serum IgM, IgG, and Receivedfor publication 4 December 1985 and in revisedform 26 March 1986.…”