The proximal tubular brush border (BB) membrane fraction isolated from rat kidneys contains antigens which induce anti-BB autoantibodies and autoimmune Heymann nephritis in immunized rats. Rabbits immunized with the BB membrane fraction form anti-BB antibodies which, after injection into rats, induce passive Heymann nephritis in rats. Various rat epithelia share antigens with renal tubular BB. However, it is still a controversial issue whether these nonrenal tissues can induce either autoimmune Heymann nephritis in rats or nephritogenic anti-BB antibodies by immunization of rabbits. To test this we have immunized rats and rabbits with different amounts of kidney BB membrane fraction and with tissue fractions known to contain antigens cross-reacting with kidney BB. Using immunohistologic, histologic, and electron microscopic techniques, we studied the development of kidney lesions typical of Heymann nephritis after active or passive immunization of rats. Rat and rabbit anti-BB antibodies were characterized by immunoprecipitation techniques. Both serum anti-BB antibodies and antibodies eluted from the kidneys of the nephritic rats bound to several nonrenal rat epithelia, suggesting that these tissues contain nephritogenic antigens. However, although immunization with 5 micrograms of BB membrane protein could induce glomerular lesions typical of autoimmune Heymann nephritis in a rat, none of the rats immunized with 50 to 600 times greater amounts of nonrenal tissue proteins developed these lesions. Similarly, antibodies from rabbits immunized with rat kidney BB membranes, but not from rabbits immunized with nonrenal epithelia, induced passive Heymann nephritis in rats. The results suggest that the nephritogenic activity is confined to kidney tissue.