NKG2D ligand overexpression in lupus nephritis correlates with increased NK cell activity and differentiation in kidneys but not in the periphery

Abstract

NK cells are a major component of the immune system, and alterations in their activity are correlated with various autoimmune diseases. In the present work, we observed an increased expression of the NKG2D ligand MICA in SLE patients' kidneys but not healthy subjects. We also show glomerulus-specific expression of the NKG2D ligands Rae-1 and Mult-1 in various murine SLE models, which correlated with a higher number of glomerular-infiltrating NK cells. As the role of NK cells in the immunopathogenesis of SLE is poorly understood, we explored NK cell differentiation and activity in tissues and organs in SLE-prone murine models by use of diseased and prediseased MRL/MpJ and MRL/lpr mice. We report here that phenotypically iNK cells accumulate only in the spleen but not in BM or kidneys of diseased mice. Infiltrating NK cells in kidneys undergoing a lupus nephritic process showed a more mature, activated phenotype compared with kidney, as well as peripheral NK cells from prediseased mice, as determined by IFN-γ and STAT5 analysis. These findings and the presence of glomerulus-specific NKG2D ligands in lupus-prone mice identify a role for NK cells and NKG2D ligands in the lupus nephritic process, which could aid in understanding their role in human SLE.

Recent findings on the role of natural killer cells in the pathogenesis of systemic lupus erythematosus

“…These differences are kidney specific, as neither bone marrow nor spleen NK cells from diseased mice show increased activity [77]. These data support the findings of Huang et al [42], who showed that kidney NK cells in mice with active disease produce more cytotoxic granules (perforin and granzyme B) and IFN-g than controls when stimulated with PMA + ionomycin; this increase in IFN-g production contributed, to some extent, to kidney damage in SLE [42,77]. These activated NK cells could be among the main IFN-g producers, responsible for promoting and sustaining inflammation in nephritic lupus kidney.…”

“…T-bet and Eomes are transcription factors that drive NK cell maturation and development locally and in the periphery and imprint the activated lymphoid program into these cells [89,90]. These differences are kidney specific, as neither bone marrow nor spleen NK cells from diseased mice show increased activity [77]. These data support the findings of Huang et al [42], who showed that kidney NK cells in mice with active disease produce more cytotoxic granules (perforin and granzyme B) and IFN-g than controls when stimulated with PMA + ionomycin; this increase in IFN-g production contributed, to some extent, to kidney damage in SLE [42,77].…”

“…Studies by Jevnikar's groups [87,88] showed that NK cells contribute directly to renal injury by killing tubular epithelial cells during renal ischemia-reperfusion injury and that NK cells are involved in mediating damage in long-term kidney transplants. Our recent research shows that kidney NK cells from diseased SLE-like MRL/MpJ lpr and MRL/MpJ mice are more active than in controls, indicated by increased CD11b and CD43 expression (mature NK cell markers), CD11b High CD27 Low cell percentage (mature NK), STAT5 phosphorylation (a key NK cell-signaling modulator), IFN-g production, and the percentage of T-bet + Eomes 2 NK cells [77]. T-bet and Eomes are transcription factors that drive NK cell maturation and development locally and in the periphery and imprint the activated lymphoid program into these cells [89,90].…”

Quantitative and functional analysis of CD69+ NKG2D+ T regulatory cells in healthy subjects

“…In this regard, an enhanced expression of NKG2D has been detected in CD3 + T cells from patients with SLE [20], which is apparently associated with chronic stimulation of these lymphocytes and an enhanced degradation of the CD3f (CD247) chain [21]. In addition, a significant expression of the NKG2D ligand MICA has been reported in kidneys from patients with SLE that is apparently associated with an enhanced local activation of NK cells [22].…”

The Players: Cells Involved in Glomerular Disease

“…However, for example, NK cells and their ligands are present in the kidney in human lupus nephritis (71). Experimentally, deficiency of invariant natural killer T cells exacerbated GN (72,73), while proinflammatory gd T cells are present in kidneys after passive antibody transfer (74).…”