Human monoclonal γG-cryoglobulins with anti—γ-globulin activity

Abstract

A B S T R A C T Seven human yG-myeloma proteins which were also cryoglobulins were studied with respect to their reactivity with yG-globulins as well as with regard to their antigenic classification within the yG-heavy chain subclasses. Five of the seven cryoglobulins studied were positive in at least two of the three tests used to assay for anti-y-globulin activity. One protein was only weakly positive in one test system and another was 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.

IgM rheumatoid factor and low molecular weight IgM. An association with vasculitis

“…Similar techniques have been used by Schrohenloher (7) with rheumatoid sera, by Munthe and Natvig (18) with eluates from synovial and other granulation tissues of rheumatoid patients, and by Grey et a1 (45) and Cerottini and Grey (46) with monoclonal IgG cryoglobulins with anti-IgG activity. This method is based on the fact that pepsin digestion of the serum destroys the IgM molecules (47,48) as well as the Fc portion of the IgG molecules, leaving behind F(ab').…”

The Molecular Basis of Self-Association of Antibodies to IgG (Rheumatoid Factors) in Rheumatoid Arthritis

“…The results of several investigators indicate that this may be the case, even though the basis of this phenomenon has not been explained previously. Grey et al (21) noted that all F(ab')2 fragments of some cryoglobulins with monoclonal IgG-rheumatoid factors bound to normal IgG. The work of Winchester et al (22) suggested that IgGrheumatoid factors may be the primary constituent in synovial fluid complexes from patients with rheumatoid arthritis, since these materials failed to adsorb to solidified normal IgG, even after acid dissociation.…”

Sialylation Determines the Nephritogenicity of IgG3 Cryoglobulins

“…2 Antibodies of the IgG3 subclass in humans and mice have the unique physicochemical property that allows them to self-associate via Fc-Fc interactions and to display cryoglobulin activity, independently of their specificities. [3][4][5][6][7][8] Nucleotide sequence analysis of the variable regions of cryogenic and noncryogenic IgG3 mAbs, in combination with the assessment of mutant antibodies, showed that cryoglobulin activity of IgG3 was associated with the presence of more positively charged amino-acid residues at positions 6 and 23 of the heavy-chain variable domain. 9,10 Moreover, structural analysis of asparagine-linked biantennary complex-type oligosaccharide chains (N-glycans) attached to the CH2 domain of different IgG3 mAbs revealed an inverse correlation between the extent of terminal sialylation and cryogenic activity.…”