Molecular structure of a cross-reactive idiotype on autoantibodies recognizing parenchymal self.
The autoimmune B cell repertoire in anti-tubular basement membrane (alpha TBM) disease is focused on the nephritogenic P1 domain of the 3M-1 target Ag in kidney and normally expresses a disease-modifying cross-reactive Id (IdX). The molecular structure of this Id was determined from a library of rat mAb alpha TBM/alpha 3M-1 by using anchor polymerase chain reactions. Our findings provide the first alignment of V region sequences for rat IgG and reveal that specificity for the P1 domain among alpha 3M-1 antibodies is derived from several recurring germ-line VH genes which have not undergone somatic mutation. The IdX in this repertoire localizes to the H chain on Western blot, and to the CDR3 region as deduced from the cDNA encoding several informative clones. Computer modeling of the Id reveals a conformational structure largely dependent on hydroxyl groups in or near turn position 4 of the H chain CDR3 region. These findings demonstrate that regulatory elements protective of autoimmunity are not encoded in the germ line as IdX, but rather emerge from a recombinatorial diversity engaged by the recognition of parenchymal self.
Karp
S L
SL
Renal-Electrolyte Divisions, University of Pennsylvania, Philadelphia 19104.
Kieber-Emmons
T
T
Sun
M J
MJ
Wolf
G
G
Neilson
E G
EG
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics; D001323:Autoantibodies / Q000737:chemistry / Q000235:genetics*; D001483:Base Sequence; D001485:Basement Membrane / Q000276:immunology; D002874:Chromosome Mapping; D003198:Computer Simulation; D003429:Cross Reactions; D004247:DNA / Q000302:isolation & purification; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007130:Immunoglobulin Idiotypes / Q000737:chemistry / Q000235:genetics*; D007135:Immunoglobulin Variable Region / Q000235:genetics; D007684:Kidney Tubules / Q000276:immunology*; D008969:Molecular Sequence Data; D009395:Nephritis, Interstitial / Q000276:immunology*; D011487:Protein Conformation; D051381:Rats
D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D007143:Immunoglobulin Heavy Chains; D007130:Immunoglobulin Idiotypes; D007135:Immunoglobulin Variable Region; D004247:DNA