Thymic Deletion and Regulatory T Cells Prevent Antimyeloperoxidase GN

Abstract

Loss of tolerance to neutrophil myeloperoxidase (MPO) underlies the development of ANCA-associated vasculitis and GN, but the mechanisms underlying this loss of tolerance are poorly understood. Here, we assessed the role of the thymus in deletion of autoreactive anti-MPO T cells and the importance of peripheral regulatory T cells in maintaining tolerance to MPO and protecting from GN. Thymic expression of MPO mRNA predominantly localized to medullary thymic epithelial cells. To assess the role of MPO in forming the T cell repertoire and the role of the autoimmune regulator Aire in thymic MPO expression, we compared the effects of immunizing Mpo 2/2 mice, Aire 2/2 mice, and control littermates with MPO.Immunized Mpo 2/2 and Aire 2/2 mice developed significantly more proinflammatory cytokine-producing anti-MPO T cells and higher ANCA titers than control mice. When we triggered GN with a subnephritogenic dose of anti-glomerular basement membrane antibody, Aire 2/2 mice had more severe renal disease than Aire +/+ mice, consistent with a role for Aire-dependent central deletion in establishing tolerance to MPO. Furthermore, depleting peripheral regulatory T cells in wild-type mice also led to more anti-MPO T cells, higher ANCA titers, and more severe GN after immunization with MPO. Taken together, these results suggest that Aire-dependent central deletion and regulatory T cell-mediated peripheral tolerance both play major roles in establishing and maintaining tolerance to MPO, thereby protecting against the development of anti-MPO GN.

T cell infiltration is associated with kidney injury in patients with anti-glomerular basement membrane disease

“…These features may account for the uncommon recurrences of anti-GBM disease compared with other autoimmune glomerulonephritis (Wolf et al, 2005;Ooi et al, 2011;Tan et al, 2013). In this study, few Tregs were observed in the kidney.…”

“…A few unique features of the T cell response to GBM include the appearance of long-living Tregs and the inversion of T cell effector/regulatory cell ratios in later stages of the disease in animal models (Wolf et al, 2005;Ooi et al, 2011;Tan et al, 2013). These features may account for the uncommon recurrences of anti-GBM disease compared with other autoimmune glomerulonephritis (Wolf et al, 2005;Ooi et al, 2011;Tan et al, 2013).…”

The Changing Landscape of Renal Inflammation

“…Tregs have an important protective role in kidney inflammatory diseases. In mouse models, Treg impairment has been associated with exacerbated disease in cisplatin-induced nephrotoxicity, [66] nephrotoxic nephritis (NTN), [67-72] anti-myeloperoxidase GN, [73] and ischemic acute kidney injury. [74-76] Furthermore, adoptive transfer of Tregs prior to induction of nephrotoxic nephritis significantly decreased kidney damage.…”

Overview of the Pathogenesis of ANCA-Associated Vasculitis

“…The research group of Kitchen and Holdsworth [64,65,66,67] have used a mouse model to study potential pathogenic roles for T cells in AAV. They induced glomerulonephritis by immunizing mice with human MPO, which induced B- and T-cell autoimmunity to mouse MPO.…”

“…The same research group also showed the importance of T cells in the pathogenesis of their model of AAV by blocking the induction of MPO autoimmunity by impairing central thymic T cells or peripheral regulatory T cells [66], or by inducing tolerance to the nephritogenic MPO peptide by nasal insufflation of the peptide [67]. …”