Spontaneous recovery from early glomerular inflammation is associated with resistance to anti-GBM glomerulonephritis: tolerance and autoimmune tissue injury

Abstract

Different susceptibility to anti-GBM glomerulonephritis (GN) among animal strains has been reported. Using our rat model for T cell-mediated anti-GBM GN, this study initiated an investigation on the mechanism related with GN-susceptibility. Anti-GBM GN was induced either though immunization with the nephritogenic T cell epitope pCol(28-40) from Col4α3NC1 or through the transfer of specific T cells. WKY rats were highly susceptible to GN while immuno-compatible LEW rats were GN-resistant. GN-resistance in LEW rats was not associated immune response to pCol (28-40). First, both strains mounted a Th1 T cell response to pCol(28-40) with identical specificities; transfer of T cells from LEW to WKY rats induced glomerular injury. Second, co-transfer of antibody from WKY to LEW failed to induce GN. Time-course studies revealed that LEW rats did develop T cell-mediated inflammation in glomeruli at early stages similar to WKY rats, as evidenced by histopathology, proteinuria, CD4 + T cell infiltration in glomeruli, and glomerular expression of inflammatory molecules. However, glomerular inflammation in LEW rats was transient followed by a full recovery. Thus, GN-resistance in LEW rats was due to its ability to contain early T cell-mediated autoimmune glomerular damage. Our model may reveal a potential tolerance mechanism after autoimmune tissue damage has been initiated.

Natural Recovery from Antiglomerular Basement Membrane Glomerulonephritis Is Associated with Glomeruli-Infiltrating CD8α+CD11c+MHC Class II+ Cells

“…1a) [19]. Detailed analyses by immunofluorescence and flow cytometry showed that T cells invaded glomeruli as early as day 15 (fig.…”

“…Detailed analyses by immunofluorescence and flow cytometry showed that T cells invaded glomeruli as early as day 15 (fig. 1b) [19,20], followed by an influx of both ED1 + macrophage and CD4 + T cells at days 17–20 (fig. 1b).…”

“…The single cells were first removed by cell strainer (80 µm). The glomeruli were isolated to a purity of approximately 95% through repeated low-speed centrifugation [19]. The isolated glomeruli were used for isolation of glomeruli-infiltrating cells.…”

“…In fact, it is fibrosis rather than inflammation that leads to end-stage renal disease. In spite of sharing identical MHC molecules and mounting a similar T cell response to WKY rats, the Lewis (LEW) strain is GN resistant [19]. The GN resistance in LEW is due to a spontaneous termination of T cell-mediated glomerular inflammation at an early stage [19].…”

“…In spite of sharing identical MHC molecules and mounting a similar T cell response to WKY rats, the Lewis (LEW) strain is GN resistant [19]. The GN resistance in LEW is due to a spontaneous termination of T cell-mediated glomerular inflammation at an early stage [19]. Thus, an unknown mechanism arrests autoimmune GN after pathogenic T cells have initiated tissue inflammation.…”