Role for Nephritogenic T Cells in Lupus Glomerulonephritis: Progression to Renal Failure Is Accompanied by T Cell Activation and Expansion in Regional Lymph Nodes

Abstract

Autoreactive T cells are critical in the initiation and maintenance of autoantibody responses that are a hallmark of systemic lupus erythematosus. However, the direct contribution of T cells in end-organ disease like lupus glomerulonephritis (GN) is poorly understood. In this study, we investigated the role of T cells in progression of lupus GN in NZM2328 mice, a murine model of spontaneous systemic lupus erythematosus. At 26 wk of age, NZM2328 female mice showed glomerular immune complex deposits and acute proliferative GN. This was associated with up-regulation of MHC class II and the detection of T cells and CD11c+ dendritic cells in the glomeruli. The regional lymph nodes (LN) showed preferential activation of T cells and an oligoclonal T cell response with skewed expansion of certain Vβ families. This suggests an Ag-driven response occurring in the regional LN of nephritic mice during acute GN. In contrast, male NZM2328 mice developed glomerular immune complexes and acute GN, but rarely progressed to fatal chronic GN. Significantly, male kidneys at 40 wk of age did not have detectable dendritic cells and T cells in the glomeruli. Thus, glomerular immune complex deposition initiates an immune response against renal Ags in the regional LN, leading to T cell recruitment into the kidney during acute proliferative GN. This T cell activation and infiltration are influenced by gender-dependent end-organ factors and may determine the progression of acute GN to chronic GN and renal failure.

Oral administration of artemisinin analog SM934 ameliorates lupus syndromes in MRL/lpr mice by inhibiting Th1 and Th17 cell responses

“…Otherwise, blockade of CCR1 could selectively halt interstitial leukocyte recruitment and fibrosis but not glomerular injury in MRL/lpr mice (39). Some published studies demonstrated that CD4ϩ T cells were major infiltrating cells in glomeruli, whereas F4/80ϩ macrophages were predominant in the interstitium of both MRL/lpr mice and lupus-prone NZM2328 mice (40,41). Thus, we reasoned that differential effects of SM934 on autoantibody production and inflammatory leukocyte migration and/or function will result in differential therapeutic effects on glomerular and interstitial inflammation.…”

The Renal Mononuclear Phagocytic System

“…73,74 Whether intraglomerular rMoPh present at the initiation of injury also migrate to renal lymph nodes for antigen presentation is unknown, but glomerular infiltration by rMoPhs with the phenotype of conventional and plasmacytoid DCs has been described in human lupus nephritis. 21,75 In any respect, the degree to which inflammatory monocyte-derived rMoPh perform the repertoire of Mø and DC functions ( Figure 1 and Table 1) within glomerular or tubulointerstitial compartments is not fully understood. In the following sections, we summarize current knowledge of the role of the renal mononuclear phagocytic system in active renal immunity and inflammation and their resolution.…”

Enhanced Activity of Akt in Teff Cells From Children With Lupus Nephritis Is Associated With Reduced Induction of Tumor Necrosis Factor Receptor–Associated Factor 6 and Increased OX40 Expression

“…T cells also play a critical role in renal inflammation and injury in lupus through direct effects (3,4).…”