Anti-y-Globulin Activity

negative in all test systems. The structures which were recognized by the cryoglobulins were localized to the Fc-fragment. Only primate yG-globulins contained these antigenic determinants and in some cases the cryoglobulin appeared to show specificity for one human heavy chain subclass over the others. Antigenic analysis revealed that four of the five cryoglobulins with definite antibody activity belonged to the yG3-subclass, the fifth belonged to the yGl-subclass. The two cryoglobulins which reacted only weakly or failed to combine with yG-globulins were both of the yGl-subclass. These findings taken together with the localization of the combining site to the Fab-fragment suggests that many of these cryoglobulins may represent antibodies to yG-globulin, and that the cryoprecipitate in these cases represents antigen-antibody complexes of such a nature that they precipitate only in the cold. Address requests for reprints to Dr. Howard M. Grey, Scripps Clinic and Research Foundation, 476 Prospect Street, La Jolla, Calif. 90237. Received for publication 11 March 1968. INTRODUCTION Immunoglobulins are a physically and chemically heterogeneous group of proteins. In some instances, they precipitate or gelify on cooling and such proteins are known as cryoglobulins. While cryoglobulinemia is occasionally seen as a primary or idiopathic disease, it is most often associated with multiple myeloma or Waldenstrom's macroglobulinemia. In these subjects a major or minor fraction of the abnormal homogeneous protein behaves as a cryoglobulin. Recently it has become apparent that small amounts of cryoglobulins can also occur in other diseases, most often in those included in the group of collagen diseases such as systemic lupus erythematosus or related symptom complexes resembling this disorder (1-3). The frequency of these cryoglobulins is born out by a recent study of 29 unselected cases of cryoglobulinemia which indicated that about 40% of the proteins studied possessed rheumatoid factor activity, in which 11 of 12 instances was shown to be a yM-rheumatoid factor (2, 3). In one case the anti-y-globulin activity was associated with a yG-protein. The biochemical basis for the phenomenon of cold precipitation of these proteins is largely unknown. The present study was performed first, to study a group of yG-myeloma proteins which were also cryoglobulins for the purpose of determining whether these yG-cryoglobulins possessed antibody activity to normal y-globulin. Second, since previous studies on the yG-heavy chain subclasses indiThe Journal of Clinical Investigation Volume 47 1968 1875 cated that they differ considerably in certain biological and biochemical properties (4-6 and footnote 1), it was of considerable interest to classify the yG-cryoglobulins with respect to heavy chain