Increased intestinal intra-epithelial T lymphocytes in primary glomerulonephritis - A role of oral tolerance breakdown in the pathophysiology of human primary glomerulonephritides?

Background. There is increasing evidence that some organ-specific and gener alized autoimmune diseases in humans might be related to a breakdown of ora l tolerance. We explored this hypothesis in human primary glomerulonephriti des. We prospectively counted intraepithelial T lymphocytes in the duodenal mucosa las a marker of rupture of oral tolerance), together with IgA1 and IgA2 mucosal plasma cells, in patients with primary glomerulonephritides. Methods. We investigated eight adults with immune-complex glomerulopathy (m embranous nephropathy + membranoproliferative glomerulonephritis), 16 adult s with an idiopathic nephrotic syndrome, and 25 adults with IgA nephropathy . Patients with glomerulonephritides were compared to two control groups: g roup I consisted of nine healthy adults; group 2 comprised five adults with coeliac disease before dietary gluten withdrawal or during a clinical rela pse related to gluten ingestion. (The latter disease is associated with inc reased numbers of intraepithelial T lymphocytes, and a breakdown of oral to lerance to gliadins is involved in the pathogenesis of coeliac disease). Du odenal fibroscopy was performed under neuroleptanalgesia. Four to six endos copic biopsy specimens were taken from the second duodenum. Intraepithelial T lymphocytes were blindly counted on paraffin sections stained with haema tein-eosin-saffron (HES), within the epithelium of a villus in a zone with at least 100 cells. Mucosal IgA1 and IgA2 plasma cells were blindly counted in a mucosal tissue unit by using specific mouse monoclonal antibodies dir ected against IgA1 and IgA2, with alkaline phosphatase anti-alkaline phosph atase (APAAP) revelation. As values were not normally distributed, we used nonparametric analysis of variance with the Kruskal-Wallis test, and compar ed median values by using the non-parametric Mann-Whitney test. Results. Intraepithelial T lymphocytes were significantly more abundant in patients with primary glomerulonephritides and coeliac disease than in heal thy controls (P < 0.0001 in the Kruskal-Wallis test): healthy controls, med ian 11 (range 4.65-16); immune complex glomerulopathy, 27.45*** (15-93); id iopathic nephrotic syndrome, 16.5** (9-26.5); IgA nephropathy, 26.10*** (11 .3-47.5); coeliac disease, 55*** (20-80) (*P<0.05; **P<0.01; ***P<0.005, Ma nn-Whitney test). No difference was found in the number of duodenal IgA1 an d IgA2 plasma cells between controls and patients with primary glomerulonep hritides. IgA1 and IgA2 plasma cells were increased in patients with coelia c disease. Conclusion. The significant increase in intestinal intraepithelial T lympho cytes in primary glomerulonephritides suggests a pathophysiological role of oral tolerance breakdown.