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.

Abstract

Recent efforts in our laboratory have concentrated on autoimmune mechanisms producing an experimental interstitial nephritis called anti-tubular basement membrane (anti-TBM)' disease (1) . Anti-TBM disease is induced in rodents after an immunization with renal tubular antigen (RTA) in adjuvant . Susceptible animals expressing the endogenous antigen (2) develop antibodies to the tubular basement membrane (anti-TBM-Ab) (3), a complex nephritogenic T cell repertoire (4), active fibrogenesis (5), interstitial cell infiltrates, and progressive renal failure . Such renal lesions can also spontaneously develop in patients, resulting in progressive renal insufficiency (6-8) . Both the nephritogenic antigen (3M-1) in the experimental model and the target antigen of human disease are crossreactive moieties of similar size (48,000 Mr) (9) . This association is seemingly unique among immune-mediated renal lesions, and supports the notion that experimental anti-TBM disease may be analogous to the human condition .With the ability to now isolate the active nephritogenic moiety of anti-TBM disease, we have extended our previous observations to provide a detailed anal-

Molecular characterization of a major nephritogenic domain in the autoantigen of anti-tubular basement membrane disease.

“…The nephritogenic epitopes on 3M-1, as well as their paratypic recognition, seem to be highly conserved among mammalian species. By competitive inhibition radioimmunoassay, for example, using 3M-1 as the target antigen, we observed that 21 of 22 Ma3M-1-Abs from five separate fusions inhibited each other (10). Such serologic findings would seem to indicate that our Ma3M-1-Abs recognize similar or nearly identical epitopes on 3M-1.…”

“…3A) and subsequently employed in a series of immunologic studies to determine whether they could be recognized by 3M-1-reactive antibodies and T cells derived from animals with aTBM disease. Monoclonal aTBM-Ab (56R-6), which binds an immunodominant epitope of 3M-1 (10), recognizes P1 in a dose-dependent fashion but does not recognize the P2 peptide (Fig. 4A).…”

“…The nephritogenic autoimmune response has also been characterized in mice, rats, and humans with polyclonal antisera (2,(8)(9)(10)(11), by constructing monoclonal aTBM-Abs reactive to 3M-1 (Ma3M-1-Abs; refs 4, 10), and by establishing tubular antigen (3M-1)-specific CD4' helper (12,13) and CD8' effector T clones (14) that recognize 3M-1 on the surface of MCT cells (5,15) or as a soluble moiety processed by traditional splenic antigen-presenting cells (12). The nephritogenic epitopes on 3M-1, as well as their paratypic recognition, seem to be highly conserved among mammalian species.…”

“…Peptide recognition by 3M-1-reactive MaTBM-Ab was evaluated by solid-phase radioimmunoassay where serial dilutions of 56R-6 antibody (10) (15,16). After 7 days the kidneys were harvested, fixed in 10%o buffered formalin, and stained with hematoxylin/eosin (2).…”

Tubular antigen-binding proteins repress transcription of type IV collagen in the autoimmune target epithelium of experimental interstitial nephritis.

“…MCT cells in culture secrete measurable amounts of basement membrane type IV collagen, as well as lesser amounts of interstitial types I and III collagens (7). Since much of the cortical tubular architecture of the kidney undergoes destructive remodelling during autoimmune interstitial inflammation (13,14), and since our ThF recognizes an autoantigen distributed only along cortical tubules (3,4), we attempted in this report to determine what biologic effect ThF might have on the transcription and secretion oftypes I and IV collagens by MCT epithelium in culture.…”