Heavy and light chain primary structures control IgG3 nephritogenicity in an experimental model for cryocrystalglobulinemia

Crystal formation by monoclonal immunoglobulins is a well-known but rare co mplication of B-cell neoplasia, We have designed an in vivo model of cryocr ystalglobulinemia by grafting to mice hybridoma clones producing a pathogen ic monoclonal immunogloblulin (Ig) G3 kappa, One clone, 8A4, secreted a sin gular IgG3 that formed crystals both in the proliferating plasma cells and as mesangial and subendothelial deposits in the kidney glomeruli, Morpholog ic analysis of kidneys revealed neutrophil infiltration and endocapillary h yperplasia, while the morphology of deposits was reminiscent of those in cr yocrystalglobulinemia patients, A variant clone that only differed from 8A4 by a 3-amino acid deletion in the V-kappa CDR1 increased its secretion lev el by 7-fold and produced an abundant bona fide serum monoclonal cryoglobul in in mice, without crystal formation within tumoral cells; it yielded no s ubendothelial deposits but only amorphous precipitates in capillary lumens of kidney glomeruli, reminiscent of those seen in the human hyperviscosity syndrome, without other glomerular lesions. A limited variation in the V-ka ppa domain thus proved able to increase secretion, to abrogate crystallizat ion, and to modify patterns of glomerular lesions and deposits. Both the cr ystallizing and noncrystallizing IgG3 kappa sequences were related to previ ously reported murine cryoglobulins, all including a gamma 3 chain and cano nical VH sequences, Two additional Variants of 8A4 with identical VH and VL domains but having switched to IgG1 also lost crystal formation, further s howing this feature of 8A4 to result from a unique 3-dimensional conformati on of the complete immunoglobulin, relying on V and C domain primary struct ures of both chains. (C) 2000 by The American Society of Hematology.