Clonotypic heterogeneity in experimental interstitial nephritis. Restricted specificity of the anti-tubular basement membrane B cell repertoire is associated with a disease-modifying crossreactive idiotype.
Experimental anti-tubular basement membrane (anti-TBM) disease is an autoimmune interstitial nephritis elicited in susceptible rodents after immunization with renal tubular antigen. The nephritogenic antigen in the immunizing preparation is 3M-1, a 48,000 Mr noncollagenous glycoprotein. The hallmarks of the renal lesion are the presence of anti-TBM antibodies (anti-TBM-Ab) and a dense mononuclear cell infiltrate. The anti-TBM B cell repertoire in this disease was analyzed using a library of 22 anti-TBM mAbs generated in a prototypically susceptible Brown Norway rat. These anti-TBM mAbs were all demonstrated to be 3M-1 specific and their characterization formed the basis for the following observations: (a) The size of the anti-TBM B cell population is estimated at 58 distinct clones; (b) by competitive inhibition criteria, all anti-TBM mAbs recognize the same (or spatially close) epitope(s) on 3M-1. This focused recognition was maintained in spite of considerable variability in affinity. Epitopic dominance could also be demonstrated in human polyclonal anti-TBM antisera from a patient with anti-TBM disease; and (c) a crossreactive idiotype was documented, and antisera directed toward this set of variable region determinants was shown to be effective as a prophylactic regimen to abrogate disease, and as a therapeutic modality to arrest the progression of disease; (d) analysis of VH gene families suggested biased usage of Q52- and 7183-like families, although at least three gene families are used in the anti-TBM-Ab response. Thus, the anti-TBM B cell compartment in BN rats is moderately large, but is primarily focused to a single epitope on the nephritogenic antigen and is associated with a disease-modifying crossreactive idiotype.
D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000276:immunology*; D000941:Antigens / Q000276:immunology*; D001323:Autoantibodies / Q000235:genetics / Q000276:immunology*; D001327:Autoimmune Diseases / Q000276:immunology / Q000473:pathology* / Q000628:therapy; D001402:B-Lymphocytes / Q000473:pathology*; D001485:Basement Membrane / Q000276:immunology; D002999:Clone Cells / Q000473:pathology; D007074:Immunoglobulin G / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007130:Immunoglobulin Idiotypes / Q000276:immunology*; D007135:Immunoglobulin Variable Region / Q000235:genetics; D007684:Kidney Tubules / Q000276:immunology*; D009395:Nephritis, Interstitial / Q000276:immunology / Q000473:pathology* / Q000628:therapy; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew
D000888:Antibodies, Anti-Idiotypic; D000911:Antibodies, Monoclonal; D000941:Antigens; D001323:Autoantibodies; D007074:Immunoglobulin G; D007143:Immunoglobulin Heavy Chains; D007130:Immunoglobulin Idiotypes; D007135:Immunoglobulin Variable Region; C048844:anti-IgG; C035812:renal tubular antigen