Expression of the mucosal γδ 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 γδ T cells in the intestinal mucosa of patients with IgAN. The Vγ and Vδ usage of TCR transcripts was determined using a semiquantitative reverse transcriptase-PCR protocol. Primers specific for the four human Vγ and six Vδ subfamilies were used each with a constant (C) γ or Cδ specific primer, and the PCR-amplified TCR transcripts were detected by Southern blotting and oligonucleotide hybridization, γδ TCR V region expression was determined in gut biopsies and peripheral blood of 11 patients with IgAN, and the TCR Vγ and Vδ repertoires were compared to those in gut and peripheral blood of 11 control individuals, γδ T cells in normal blood predominantly expressed Vγ2 (Vγ9 gene) and Vδ2 gene segments whereas those in normal gut mainly expressed Vγ3 and Vδ3. In IgAN patients, Vδ2 was also the predominant Vδ gene utilized by peripheral blood γδ T cells, however, we observed a predominance of Vγ3 and reduced Vγ2 usage by these cells, γδ T cells in the gut of IgAN patients mainly used Vγ3 and Vδ1. 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 Vδ 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 Vδ3 gene expression in IgAN gut compared to control gut (P = 0.043). These findings indicate that a subpopulation of γδ T cells, which represent the majority of γδ T cells in normal gut mucosa, are significantly diminished in the gut of patients with IgAN. This suggests that a “hole” in the mucosal γδ T cell repertoire may play a fundamental role in contributing to the pathogenesis of IgAN.
Hermansky-Pudlak syndrome is an uncommon cause of renal dysfunction. Because of the risk of bleeding in this condition, few patients have undergone a renal biopsy. Renal dysfunction has been ...attributed to the deposition of ceroid pigment in the tubules and interstitial fibrosis. We report a case with renal biopsy findings of ceroid deposition and interstitial fibrosis, but also of mesangial IgA deposition, crescentic glomerulonephritis, and an interstitial lymphocytic infiltrate. Furthermore, perinuclear antineutrophil cytoplasmic antibodies of the IgG subclass were detected in a blood sample. It is well known that ceroid pigment in this syndrome accumulates in monocytes, macrophages and T lymphocytes and it has been suggested that this may affect their function. We suggest that this novel combination of renal changes might be explained on the basis of alterations in immune mechanisms in the Hermansky-Pudlak syndrome.
Renal effects of amlodipine in normotensive renal transplant recipients. The use of cyclosporin A (CsA) has improved the success of renal transplantation, but is associated with hypertension and ...significant renal toxicity. Previous reports suggest that calcium channel blockers may be useful in opposing the adverse effects of CsA. We have evaluated the effects of amlodipine (5 mg, once daily for 8 weeks) on renal function in 27 normotensive renal transplant recipients with stable renal function, in a double-blind, placebo-controlled, multicentre, cross over study. Amlodipine significantly reduced serum creatinine concentration relative to placebo (mean+/-SD: 168+/-65 vs 177+/-66 micromol/l; P=0.002) and there was a strong trend towards an increase in effective renal plasma flow on amlodipine relative to placebo (238+/-92 vs 217+/-87 ml/min; P=0.055). Glomerular filtration rate and lithium clearance were unaffected. Trough CsA blood concentration was unaffected. Amlodipine was well tolerated, with a low incidence of adverse events, and did not affect blood pressure or heart rate. In conclusion, amlodipine reduced serum creatinine in normotensive renal transplant recipients after only 8 weeks treatment, and was well tolerated in concomitant administration with CsA.
Pathogenesis of IgA nephropathy Feehally, J; Allen, A C
Annales de médecine interne,
02/1999, Letnik:
150, Številka:
2
Journal Article
Recenzirano
IgA nephropathy (IgAN) is initiated by glomerular deposition of polymeric IgA1(pIgA1). In IgAN pIgA production is reduced in the mucosal immune system, perhaps mediated by a mucosal gamma delta T ...cell defect, and mucosal IgA responses to immunisation are impaired. But pIgA1 production by the marrow is increased. Human pIgA1 has an O-glycosylated hinge region unique to circulating immunoglobulins and there is reduction of galactosyl residues in the hinge of serum IgA1 in IgAN and Henoch-Schönlein nephritis. This reduced galactosylation may be due to a functional defect in plasma cell beta 1,3-galactosyltransferase. Altered hinge region glycosylation may alter IgA1 structure, modifying interactions with matrix proteins, IgA receptors and complement, and therefore influence mesangial deposition and subsequent injury through mechanisms other than classical antigen-antibody reactions. IgA clearance through the hepatic asialoglycoprotein receptor or Fc alpha receptors on circulating white cells may also be impaired. The unique features of human IgA1 have prevented development of satisfactory animal models for the early stages of IgAN. It is likely that events after pIgA1 deposition which result in glomerular inflammation and scarring are not specific to IgAN but generic to many forms of glomerulonephritis.
Immunosuppressive treatment with cyclosporin A (CsA) improves the survival of renal allografts, but is associated with renal vasoconstriction and hypertension. Previous reports suggest that the ...calcium-channel blockers nifedipine and amlodipine may improve graft function in CsA-treated patients. We have compared the effects of amlodipine (5-10 mg once daily) and nifedipine retard (10-40 mg twice daily) on renal function and blood pressure in renal transplant recipients treated with CsA.
This was a multicentre, two-way, crossover study in 27 evaluable hypertensive patients with renal insufficiency following renal transplantation, who were maintained on a stable dose of CsA. Patients received either amlodipine (5-10 mg once daily) or nifedipine retard (10-40 mg twice daily) for 8 weeks, and were then crossed over to the other treatment for a further 8 weeks.
Trends were seen during amlodipine treatment towards larger improvements, in serum creatinine (by 8% of baseline on amlodipine vs 4% on nifedipine), lithium clearance (13% vs 2%), and glomerular filtration rate 11% vs 7%). Effective renal plasma flow was increased by 11% of baseline on nifedipine vs 9% on amlodipine. There were no significant differences between treatments. Amlodipine and nifedipine lowered systolic blood pressure to a similar extent (21 mmHg vs 15 mmHg respectively, P=0.25), but amlodipine was more effective than nifedipine in lowering diastolic blood pressure (13 mmHg vs 8 mmHg, P=0.006). Both treatments were well tolerated.
Once-daily amlodipine is at least as effective as twice-daily nifedipine retard in controlling blood pressure and does not adversely affect graft function in hypertensive renal allograft recipients.
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