A subgroup of lupus patients with nephritis, innate T cell activation and low vitamin D is identified by the enhancement of circulating MHC class I-related chain A

Abstract

The major histocompatibility complex (MHC) class I-related chain A (MICA) is induced upon stress, and labels malfunctioning cells for their recognition by cytotoxic lymphocytes. Alterations in this recognition and also abnormal natural killer (NK) functions have been found in systemic lupus erythematosus (SLE). MICA can be shed from cells, subsequently acting as a soluble decoy receptor (sMICA). Our purpose was to study circulating sMICA levels in relationship with the activation of innate pathways in PBMC in a cohort of lupus patients. NK cells were characterized by flow cytometry. Gene expression of Toll-like receptors (TLR), interferon (IFN)-I sensitive genes and MICA were separately analyzed in monocytes, T cells and B cells. Serum sMICA was measured with enzyme-linked immunosorbent assay (ELISA). In our cohort, NK cell counts dropped in relationship with disease activity. sMICA showed an inverse trend with NK cell counts, as well as a significant association with activity indices, but not with complement decrease. Levels of sMICA associated to proteinuria and active nephritis. A multivariate regression model revealed anti-nuclear antibody (ANA) titres, the up-regulation of TLR-4 in T cellsand lower vitamin D as predictors of sMICA enhancement. Interestingly, vitamin D showed an inverse association with proteinuria and a strong correlation with T cell MICA mRNA levels. According to our data, circulating sMICA identifies a subgroup of lupus patients with low vitamin D, innate activation of T cells and nephritis. We propose that lymphocyte shedding could account for the enhancement of sMICA and reflect an immune evasion mechanism driving disease activation in lupus.

Functional MICA Variants Are Differentially Associated with Immune-Mediated Inflammatory Diseases

“…However, sMICA promotes the proliferation of immunosuppressive NKG2D+CD4+ T cells, which correlates inversely with SLE disease activity [ 41 ]. A particular category of lupus individuals who had low levels of vitamin D, innate T-cell activation, and nephropathy had elevated levels of circulating sMICA [ 42 ], which were also substantially elevated among those with anti-SSB and anti-RNP autoantibodies [ 12 ]. Contact across MICA and NKG2D initiates NK cell activation and upregulation of CD69 and CD107 on NK cells, which contributes to NK cell exhaustion in SLE patients [ 12 ].…”

Increased Concentrations of Circulating Soluble MHC Class I-Related Chain A (sMICA) and sMICB and Modulation of Plasma Membrane MICA Expression: Potential Mechanisms and Correlation With Natural Killer Cell Activity in Systemic Lupus Erythematosus

“…MICA expression is increased in the kidneys of SLE patients, and in lupus mice NKG2D ligand expression in the kidney correlates with infiltrating NK cells displaying high IFN-γ production ( 45 ). However, although concentrations of circulating sMICA were not higher in SLE patients in comparison to healthy individuals, sMICA concentrations were shown to be increased in SLE patients with active nephritis versus patients without nephritis and an inverse trend, although not significant, with blood NK cell concentrations was observed ( 46 ). Those two studies suggest a pathogenic role for MICA or sMICA, associated with increased tissue NK cells or decreased blood NK cells.…”

The Multiple Effects of Vitamin D against Chronic Diseases: From Reduction of Lipid Peroxidation to Updated Evidence from Clinical Studies

“…This stimulates adjacent macrophages, which often appear in the bloodstream, reaching serum concentrations of 30 ng/mL, causing hypercalcemia (hypercalcemia is also a marker of infectious status) [ 125 ]. Moreover, 1,25(OH) 2 D is able to maintain immune tolerance in APC cells and finely manage the surface expression of MHC class II, immunogenic cytokines, and co-stimulation molecules ( Figure 5 ) [ 126 ]. The modulation of the immunogenic cytokine profile is a key orchestrator of immune homeostasis; for example, Vit D increases IL-10 expression, which is characterized by anti-inflammatory activity [ 126 ].…”

“…Moreover, 1,25(OH) 2 D is able to maintain immune tolerance in APC cells and finely manage the surface expression of MHC class II, immunogenic cytokines, and co-stimulation molecules ( Figure 5 ) [ 126 ]. The modulation of the immunogenic cytokine profile is a key orchestrator of immune homeostasis; for example, Vit D increases IL-10 expression, which is characterized by anti-inflammatory activity [ 126 ]. Conversely, 1,25(OH) 2 D reduces the expression of the pro-inflammatory and atherogenic cytokines involved in immune hyperactivation, such as IL-6 and IL-17 [ 127 ].…”