Antibody-mediated injury to proximal tubules in Heymann nephritis

Abstract

To evaluate the hypothesis that antibody-mediated damage to proximal tubules (PT) could be a feature of Heymann nephritis (HN), we studied the kidneys of rats in different stages of the disease by light, immunoflourescence (IF), transmission, and scanning electron microscopy. The observations of morphology were correlated with titers of circulating antibodies directed against the brush border (BB) and with proteinuria. Antibody titers reached a maximum 5 to 7 weeks after immunization with Fx1A, coincident with the onset of proteinuria. IgG and C3 were deposited along the BB of PT in all animals within the first week of proteinuria. BB antibodies were present in the urine of those rats. As antibody titers declined, a decrease in the extent of in vivo IgG deposition along the BB was also noted. The results of indirect IF tests, by using BB antibodies on kidneys of rats with HN of 3 to 4 months' duration, suggested extensive loss of the BB antigen(s) from the PT. Numerous granular deposits of IgG were present along the basement membrane of PT at that time. Study of kidney histology revealed that deposition of IgG and C3 along the BB of PT was associated with extensive loss of microvilli, as well as degeneration and proliferation of PT cells. Subepithelial electron-dense deposits were present along the basement membrane of PT. In rats with HN of more than 4 months' duration, with little or no circulating BB antibodies and persistent proteinuria, IgG and C3 were found in minimal amounts along BB. Examination by light and electron microscopy provided evidence of partial recovery of PT lesions in those kidneys. Rats with similar proteinuria resulting from chronic serum sickness did not have similar abnormalities of PT. These observations are consistent with the interpretation that, in rats with HN, BB antibodies induce cytotoxic injury to PT.

Immune Complex Tubulointerstitial Nephritis Due to Autoantibodies to the Proximal Tubule Brush Border

“…Sera from these rats react with megalin in the brush border of proximal tubules and podocytes. 13 Passive transfer of antibodies causes deposition of antibodies in vivo along the GBM in an epimembranous pattern, the proximal tubule brush border and deposit in the TBM, 14 with associated disruption of the normal architecture of the proximal tubules. 14,15 In humans, megalin is expressed in the brush border but not in podocytes.…”

Modified self-antigen Caused Autoimmune Disease and its Reversal by a new Vaccination Technique

“…We have shown that only modified nephritogenic ags, injected into rats in adjuvants [6,7] or in a chemically modified state [3], can induce the production of pathogenic IgG aabs which are responsible for the autoimmune kidney disease after coming into contact with and damaging the BB region of the renal proximal convoluted tubules [27,45] where the nephritogenic ag resides (primary insult to the kidney causing the autoimmune kidney disease. )…”

“…HN and its variant SPHN were extensively studied by us over the years [1,5,7,44] and allowed us: to decipher those immunopathological processes which were responsible for the autoimmune kidney disease [26,27] and the glomerular lesion [26]; and to find ways for preventing/terminating the disease processes [1,38,39,44];…”

“…The injected nephritogenic ag in a modified state is able to evoke the production of pathogenic IgG aabs [5]. These aabs are primarily directed against the injected modified nephritogenic ag but they are also able to cross react with the native BB associated nephritogenic ag in the renal proximal convoluted tubules and cause damage that results in an autoimmune kidney disease [5,26,27]. Liberated nephritogenic ag -as a result of rat anti-rat kidney fraction 3 (rarKF3) pathogenic IgG aab reacting with the BB associated ag -will get into the urine and the circulation [28,29].…”

“…damage to the nephritogenic ag, localized in the BB region of the renal proximal convoluted tubules (primary insult to the kidney causing the autoimmune disease) will occur [27]; and released nephritogenic ags contribute with circulating pathogenic IgG aabs , in the presence of complement, to layered depositions of ICs in the glomeruli (secondary insult to the kidney resulting in immune complex glomerulonephritis [ICGN]) will commence [18].…”