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

Abstract

Systemic lupus erythematosus (SLE) is a severe autoimmune disease of unknown etiology. The major histocompatibility complex (MHC) class I-related chain A (MICA) and B (MICB) are stress-inducible cell surface molecules. MICA and MICB label malfunctioning cells for their recognition by cytotoxic lymphocytes such as natural killer (NK) cells. Alterations in this recognition have been found in SLE. MICA/MICB can be shed from the cell surface, subsequently acting either as a soluble decoy receptor (sMICA/sMICB) or in CD4+ T-cell expansion. Conversely, NK cells are frequently defective in SLE and lower NK cell numbers have been reported in patients with active SLE. However, these cells are also thought to exert regulatory functions and to prevent autoimmunity. We therefore investigated whether, and how, plasma membrane and soluble MICA/B are modulated in SLE and whether they influence NK cell activity, in order to better understand how MICA/B may participate in disease development. We report significantly elevated concentrations of circulating sMICA/B in SLE patients compared with healthy individuals or a control patient group. In SLE patients, sMICA concentrations were significantly higher in patients positive for anti-SSB and anti-RNP autoantibodies. In order to study the mechanism and the potential source of sMICA, we analyzed circulating sMICA concentration in Behcet patients before and after interferon (IFN)-α therapy: no modulation was observed, suggesting that IFN-α is not intrinsically crucial for sMICA release in vivo. We also show that monocytes and neutrophils stimulated in vitro with cytokines or extracellular chromatin up-regulate plasma membrane MICA expression, without releasing sMICA. Importantly, in peripheral blood mononuclear cells from healthy individuals stimulated in vitro by cell-free chromatin, NK cells up-regulate CD69 and CD107 in a monocyte-dependent manner and at least partly via MICA-NKG2D interaction, whereas NK cells were exhausted in SLE patients. In conclusion, sMICA concentrations are elevated in SLE patients, whereas plasma membrane MICA is up-regulated in response to some lupus stimuli and triggers NK cell activation. Those results suggest the requirement for a tight control in vivo and highlight the complex role of the MICA/sMICA system in SLE.

MICA-specific nanobodies for diagnosis and immunotherapy of MICA+ tumors

“…We observed no reduction in cytotoxicity of VHH A1 -DM1 on MICA + cells upon addition of sMICA to the medium ( Figure 3E ). Publications report concentrations of sMICA in the serum of MICA + patients in the range of 0.1-15 ng/mL ( 51 – 53 ) which is at least 10-fold lower than the sMICA concentration in our competition assay. We thus expect little to no impact of sMICA in patients’ serum on the ability of these nanobodies to target membrane-bound MICA in vivo .…”

The Significance of Major Histocompatibility Complex Class I Chain-related Molecule A in Solid Organ and Hematopoietic Stem Cell Transplantation: A Comprehensive Overview

“…13 The generation of soluble MICA can be affected by polymorphisms that alter cell-surface expression, varied cleavage efficacy, or MICA recruitment into exosome-like vesicles. 17,18 Preliminary studies suggest that soluble MICA is of importance in solid organ transplantation, 19 graft versus host disease (GVHD), autoimmune disease, 20 and malignancy. 14 The MICA-129 Dimorphism and Other Relevant Polymorphisms…”

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 ].…”

“…MICA enhances the capacity of the immune system to recognize and eliminate infections through the activation of NK and CD8+ T cells [ 6 , 8 , 9 ]. The emergence of graft-versus-host disease and systemic lupus erythematosus (SLE) is attributed to the processes of NK cell-mediated cytotoxicity and the production of immunosuppressive soluble MICA (sMICA) particles [ 10 , 11 , 12 ]. Autoimmune inflammatory illnesses emerge as a result of an imbalance in the regulation of immunological activation and tolerance.…”