Decreased A20 expression on circulating CD56bright NK cells contributes to a worse disease status in patients with ankylosing spondylitis

Abstract

A20, a pivotal anti-inflammatory protein, preserves immune homeostasis and regulates prolonged inflammation. A previous study has shown that A20 expression levels are down-regulated in peripheral blood mononuclear cells (PBMCs) from patients with ankylosing spondylitis (AS). However, the precise role of A20 in reducing autoimmune disorders needs to be further elucidated. In this study, A20 expression was found to be preferentially reduced on circulating CD56 bright natural killer (NK) cells in patients with AS, and its level was negatively correlated with that of proinflammatory cytokines. Further investigation demonstrated that A20 reduces interferon (IFN)-γ and tumour necrosis factor (TNF)-α production in CD56 bright NK cells after stimulation with monokines or phorbol myristate acetate (PMA)/ionomycin(P/I). Furthermore, CD56 bright NK cells isolated from AS patients promote TNF-α secretion by autologous monocytes, and increasing the A20 expression level partially attenuates this process. More importantly, decreased A20 expression on circulating CD-56 bright NK cells is associated with worse disease status in patients with AS. Our findings reveal that A20 participates in the pathogenesis of AS by negatively regulating CD56 bright NK cells and that its reduced expression contributes to a worsened disease status in patients with AS. Fig. 5. A20 on the circulating CD56 bright subset is negatively associated with disease activity. (a) Negative correlations between A20 expression on the CD56 bright subset and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) in ankylosing spondylitis (AS) patients. (b) Significant negative correlations between A20 expression on the CD56 bright subset and AS Disease Activity Score (ASDAS) in patients with AS. A P-value <0·05 was considered statistically significant for the test.

The Role of Natural Killer Cells in Autoimmune Diseases

“…The functional subsets of NK cells were further investigated in AS and the cytotoxic CD16 + CD56 dim subset of NK cells were increased in comparison with healthy individuals ( 293 ). A20 functions as an inhibitor of inflammatory cytokines in several cell types and A20 expression was decreased in the CD56 bright NK cell subset of AS patients compared to healthy individuals ( 294 ). Patients with AS have a higher expression of T-bet compared to healthy individuals especially in NK and CD8 + T cells.…”

A Predictive Disease Risk Model for Ankylosing Spondylitis: Based on Integrated Bioinformatic Analysis and Identification of Potential Biomarkers Most Related to Immunity

“…Kucuksezer et al summarized a substantial number of studies [ 35 ], reporting that HLA-B27, ERAP-1, KIRS, and other AS-related genes can potentially affect the function of NK cells and that some changes in NK cell function can be used to anticipate the response to therapy in patients with AS. According to a study, TNF- α secretion by autologous monocytes was enhanced by circulating CD56bright NK cells in AS patients, and this could contribute to the persistent invasive immunological process in AS, which led to aberrant inflammation [ 36 ]. Jiao et al studied the gene polymorphisms in NK cell receptors and found that due to genetic factors related to HLA-B27, the variation in KIRS and its corresponding specific HLA-C ligand might hinder the role of NK cells in recognizing and eliminating targets in the immune response, thus promoting the development of AS [ 37 ].…”

Innate Lymphocytes in Inflammatory Arthritis

“…A previous study demonstrated a tissue-protective role of NKp44 + IL-22-producing cells in the gut tissue of AS patients (122). However, another study showed that circulating CD56 bright NK cells in AS patients promoted TNF-α secretion by autologous monocytes, which contributed to a worsened disease status (128). NK cells were thought to play a regulatory role in sJIA, and the dysfunction of these cells in sJIA was strongly associated with macrophage activation syndrome (MAS) (129).…”