Regulatory interactions of αβ and γλ T cells in glomerulonephritis

Regulatory interactions of αβ and γλ T cells in glomerulonephritis.BackgroundSeveral lines of evidence suggest that cellular immune mechanisms contribute to glomerulonephritis.MethodsThe roles of αβ and γλ T cells in the pathogenesis of glomerulonephritis were investigated in a model of nephrotoxic nephritis in mice deficient in either T-cell population [T-cell receptor (TCR)β and TCRλ knockout mice]. The model, induced by the injection of rabbit anti-mouse glomerular basement membrane antibody, is characterized by the development of proteinuria and glomerular damage over a 21-day observation period in wild-type mice.ResultsMice deficient in either αβ or γλ T cells developed minimal proteinuria and glomerular lesions and had a significant reduction in macrophage accumulation compared with wild-type mice. In γλ T-cell–deficient mice, circulating levels and glomerular deposition of autologous IgG were comparable to wild-type levels, while αβ T-cell–deficient mice had no autologous IgG production. Autologous antibody production was not required for the development of glomerulonephritis since mice that lack IgG and B cells (μ-chain-/-) developed similar proteinuria to that observed in wild-type mice.ConclusionsThese studies suggest a proinflammatory role for both αβ and γλ T cells in glomerular injury, independent of the humoral response. This is the first demonstration, to our knowledge, that both T-cell subsets contribute to the progression of a disease, and it suggests that complex regulatory interactions between αβ and γλ T cells play a role in glomerular injury

Endogenous TNF alpha orchestrates the trafficking of neutrophils into and within lymphatic vessels during acute inflammation

This work was supported by funds from Arthritis Research UK (19913 to M.-B.V.) and the Wellcome Trust (098291/Z/12/Z to S.N.). S. A. was supported by a QMUL Principal’s Award PhD Studentship

Performance related factors are the main determinants of the von Willebrand factor response to exhaustive physical exercise

Background: Physical stress triggers the endothelium to release von Willebrand Factor (VWF) from the Weibel Palade bodies. Since VWF is a risk factor for arterial thrombosis, it is of great interest to discover determinants of VWF response to physical stress. We aimed to determine the main mediators of the VWF increase by exhaustive physical exercise. Methods: 105 healthy individuals (18-35 years) were included in this study. Each participant performed an incremental exhaustive exercise test on a cycle ergometer. Respiratory gas exchange measurements were obtained while cardiac function was continuously monitored. Blood was collected at baseline and directly after exhaustion. VWF antigen (VWF:Ag) levels, VWF collagen binding (VWF:CB) levels, ADAMTS13 activity and common variations in Syntaxin Binding Protein-5 (STXBP5, rs1039084 and rs9399599), Syntaxin-2 (STX2, rs7978987) and VWF (promoter, rs7965413) were determined. Results: The median VWF:Ag level at baseline was 0.94 IU/mL [IQR 0.8-1.1] and increased with 47% [IQR 25-73] after exhaustive exercise to a median maximum VWF:Ag of 1.38 IU/mL [IQR 1.1-1.8] (p<0.0001). VWF:CB levels and ADAMTS13 activity both also increased after exhaustive exercise (median increase 43% and 12%, both p<0.0001). The strongest determinants of the VWF:Ag level increase are performance related (p<0.0001). We observed a gender difference in VWF:Ag response to exercise (females 1.2 IU/mL; males 1.7 IU/mL, p = 0.001), which was associated by a difference in performance. Genetic variations in STXBP5, STX2 and the VWF promoter were not associated with VWF:Ag levels at baseline nor with the VWF:Ag increase. Conclusions: VWF:Ag levels strongly increase upon exhaustive exercise and this increase is strongly determined by physical fitness level and the intensity of the exercise, while there is no clear effect of genetic variation in STXBP5, STX2 and the VWF promoter

Fcγ Receptors in Solid Organ Transplantation.

In the current era, one of the major factors limiting graft survival is chronic antibody-mediated rejection (ABMR), whilst patient survival is impacted by the effects of immunosuppression on susceptibility to infection, malignancy and atherosclerosis. IgG antibodies play a role in all of these processes, and many of their cellular effects are mediated by Fc gamma receptors (FcγRs). These surface receptors are expressed by most immune cells, including B cells, natural killer cells, dendritic cells and macrophages. Genetic variation in FCGR genes is likely to affect susceptibility to ABMR and to modulate the physiological functions of IgG. In this review, we discuss the potential role played by FcγRs in determining outcomes in solid organ transplantation, and how genetic polymorphisms in these receptors may contribute to variations in transplant outcome.MRC is supported by the NIHR Cambridge BRC, the NIHR Blood and Transplant Research Unit (Cambridge) and by a Medical Research Council New Investigator Grant (MR/N024907/1).This is the final version of the article. It first appeared from Springer via https://doi.org/10.1007/s40472-016-0116-