Expression of the mucosal γδ T cell receptor V region repertoire in patients with IgA nephropathy

Expression of the mucosal γ δ T cell receptor V region repertoire in patients with IgA nephropathy. IgA nephropathy (IgAN) is characterized by the deposition of IgA in the glomerular mesangium and often leads to progressive renal dysfunction and kidney failure. We have previously shown that the mesangial IgA is likely to derive from the bone marrow plasma cells, and suggested that a primary abnormality within the mucosal immune system may underly the pathogenesis of IgAN. This study has analyzed the T cell receptor (TCR) variable (V) region expression by γ δ T cells in the intestinal mucosa of patients with IgAN. The Vγ and V δ usage of TCR transcripts was determined using a semiquantitative reverse transcriptase-PCR protocol. Primers specific for the four human Vγ and six V δ subfamilies were used each with a constant (C) γ or C δ specific primer, and the PCR-amplified TCR transcripts were detected by Southern blotting and oligonucleotide hybridization, γ δ TCR V region expression was determined in gut biopsies and peripheral blood of 11 patients with IgAN, and the TCR Vγ and V δ repertoires were compared to those in gut and peripheral blood of 11 control individuals, γ δ T cells in normal blood predominantly expressed Vγ2 (Vγ9 gene) and V δ 2 gene segments whereas those in normal gut mainly expressed Vγ3 and V δ 3. In IgAN patients, V δ 2 was also the predominant V δ gene utilized by peripheral blood γ δ T cells, however, we observed a predominance of Vγ3 and reduced Vγ2 usage by these cells, γ δ T cells in the gut of IgAN patients mainly used Vγ3 and V δ 1. While the γ and δ TCR V region repertoires did not differ significantly between the peripheral blood of patients and controls, there were significant differences in Vγ and V δ repertoire expression between IgAN and control gut biopsies. Vγ3 gene expression was significantly decreased in IgAN gut compared to control gut ( P = 0.023). In addition, there was a significant decrease in V δ 3 gene expression in IgAN gut compared to control gut ( P = 0.043). These findings indicate that a subpopulation of γ δ T cells, which represent the majority of γ δ T cells in normal gut mucosa, are significantly diminished in the gut of patients with IgAN. This suggests that a “hole” in the mucosal γ δ T cell repertoire may play a fundamental role in contributing to the pathogenesis of IgAN.