Gamma Globulin Complexes in Rheumatoid Arthritis

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 presumption has been that these represent aggregates formed in the process of chemical fractionation; they were not found in y-globulin isolated by electrophoretic convection (8). Certain myeloma proteins have been found in which either the major component or accessory components have sedimentation rates in this range (9, 10). This has been particularly true of some of the more rapidly migrating mnveloma proteins (11). fiery little work has been carried out on these components particularly fronm the standpoint of association and dissociation, although Pedersen (12) described a myeloma protein with an s-rate of approximately 11S at high protein concentrations and approximately 7S at lower concentrations. Similar abnormal proteins have been encountered in certain ill-defined disorders (13). Particularly pertinent is a recent report of a macroglobulin studied by Rees and Resner (14) that could be dissociated in acid. Certain sera with similar proteins probably have been considered to represent macroglobulins of the Waldenstr6m type and have been reported as such in the literature (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 defined. Evidence for and against the hypothesis that they represent antigen-antibody complexes of the y-globlulin-anti-y-glol)bulin type was sought.