Immunopathologic responses to urinary Tamm-Horsfall protein in the development of chronic pyelonephritis were examined by four different approaches. First, in a rabbit model, tubulointerstitial nephritis developed in 64 of 102 rabbits injected intravenously with urine or rabbit Tamm-Horsfall protein as compared with only one of 17 rabbits in two control groups. Circulating cytotoxic lymphocytes plus immunoglobulin G (IgG) antibodies against Tamm-Horsfall protein were found in 51 percent of challenged (urine or Tamm-Horsfall protein) rabbits with tubulointerstitial nephritis as compared with only 8 percent of those without it (p < 0.001). Second, in a porcine model of reflux nephropathy, 16 of 21 pigs with pyelographic findings indicative of reflux had elevated serum liters of antiTamm-Horsfall protein antibody as compared with 0 of 13 with normal pyelograms. Five of 10 refluxing pigs tested also had circulating lymphocytes that were cytotoxic in the presence of Tamm-Horsfall protein as compared with 0 of 13 with normal pyelograms. Third, in human studies, 12 of 49 patients with recurrent nephrolithiasis demonstrated abnormal elevations in anti-Tamm-Horsfall protein antibody; 13 of 49 had an abnormality in one of two assays of cell-mediated immunity to Tamm-Horsfall protein as compared with 0 of the normal control subjects. These abnormalities were not associated with overt obstruction or bacteriuria, but appeared to be more common in patients with recent onset and active recurrent nephrolithiasis. Lastly, an inhibitor of the binding reaction between human Tamm-Horsfall protein and its IgG antibody was detected in extracts of three uropathic coliforms. The inhibitors were partially purified by chromatographic means. Preliminary immunoautoradiographic studies revealed three or less protein-containing subunits of Escherichia coli that cross-reacted with anti-Tamm-Horsfall protein antibody. These studies suggest that autoimmune responses to Tamm-Horsfall protein may occur after exposure to Tamm-Horsfall protein by intravenous challenge, urinary reflux, or recurrent nephrolithiasis. This autoimmune response to Tamm-Horsfall protein may be the pathogenetic mechanism by which these factors, including bacteriuria, contribute to chronic pyelonephritis.
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