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Blood, 15 April 2002, Vol. 99, No. 8, pp. 2922-2928
IMMUNOBIOLOGY
Level of galactosylation determines cryoglobulin activity of
murine IgG3 monoclonal rheumatoid factor
Aki Kuroki,
Yasuhiro Kuroda,
Shuichi Kikuchi,
Frédéric Lajaunias,
Thierry Fulpius,
Yves Pastore,
Liliane Fossati-Jimack,
Luc Reininger,
Toho Toda,
Munehiro Nakata,
Naoya Kojima,
Tsuguo Mizuochi, and
Shozo Izui
From the Department of Pathology, Faculty of Medicine,
University of Geneva, Switzerland; Institute of Glycotechnology and
Department of Applied Biochemistry, Tokai University, Hiratsuka,
Kanagawa, Japan; and Institut National de la Santé et de la
Recherche Médicale U 399, Marseille, France.
Autoantibodies of the cryoprecipitating IgG3 isotype have
been shown to play a significant role in the development of murine lupus-like autoimmune syndrome. At present, the structural basis of
IgG3 cryoprecipitation and its role in autoantibody pathogenicity remain to be defined. Using molecular variants of an IgG3 monoclonal rheumatoid factor, 6-19, derived from an autoimmune
MRL-Faslpr mouse, we have investigated the
implication of charged residues in the heavy-chain variable (VH)
region, potential CH3-linked oligosaccharides, and galactosylation of
CH2-linked oligosaccharides in its cryoglobulin activity. The
cryoglobulin activity of the IgG3 6-19 mutant bearing more negatively
charged residues at VH 6 and 23 was found to be reduced but still
highly significant, whereas that of the mutant lacking a potential CH3
glycosylation site remained unchanged. In marked contrast, IgG3 6-19 variants obtained from 6-19 heavy-chain transgenic mice displayed
barely detectable cryoglobulin activity associated with an increased level of galactosylation in the CH2 oligosaccharide side chains. Thus,
our data strongly suggest that the cryoglobulin activity of IgG3 6-19 autoantibody is critically determined by levels of galactosylation in
the CH2 oligosaccharide side chains, whereas VH residues play a
secondary role in 6-19 IgG3 cryoglobulin activity.
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