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Blood, Vol. 95 No. 11 (June 1), 2000:
pp. 3467-3472
Heavy and light chain primary structures control IgG3
nephritogenicity in an experimental model for cryocrystalglobulinemia
Jens-Uwe Rengers,
Guy Touchard,
Catherine Decourt,
Sophie Deret,
Hartmut Michel, and
Michel Cogné
From the Max-Planck-Institute for Biophysics, Frankfurt, Germany;
the Laboratory of Immunology, CNRS EP118, University Hospital, Limoges,
France; the Nephrology Department, University Hospital, Poitiers,
France; and the Clinical Immunology Department, INSERM U25, Paris,
France.
Crystal formation by monoclonal immunoglobulins is a well-known but
rare complication of B-cell neoplasia. We have designed an in vivo
model of cryocrystalglobulinemia by grafting to mice hybridoma clones
producing a pathogenic monoclonal immunogloblulin (Ig) G3 . One
clone, 8A4, secreted a singular IgG3 that formed crystals both in the
proliferating plasma cells and as mesangial and subendothelial deposits
in the kidney glomeruli. Morphologic analysis of kidneys revealed
neutrophil infiltration and endocapillary hyperplasia, while the
morphology of deposits was reminiscent of those in
cryocrystalglobulinemia patients. A variant clone that only differed
from 8A4 by a 3-amino acid deletion in the V CDR1
increased its secretion level by 7-fold and produced an abundant bona
fide serum monoclonal cryoglobulin in mice, without crystal formation
within tumoral cells; it yielded no subendothelial 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
domain thus proved able to increase secretion, to abrogate
crystallization, and to modify patterns of glomerular lesions and
deposits. Both the crystallizing and noncrystallizing IgG3 sequences
were related to previously reported murine cryoglobulins, all including
a  3 chain and canonical VH sequences. Two additional variants of 8A4
with identical VH and VL domains but having switched to IgG1 also lost
crystal formation, further showing this feature of 8A4 to result from a
unique 3-dimensional conformation of the complete immunoglobulin,
relying on V and C domain primary structures of both chains.
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