NK cells in autoimmune diseases: Linking innate and adaptive immune responses

The growing field of immunometabolism has taught us how metabolic cellular reactions and processes not only provide a means to generate ATP and biosynthetic precursors, but are also a way of controlling immunity and inflammation. Metabolic reprogramming of immune cells is essential for both inflammatory as well as anti-inflammatory responses. Four anti-inflammatory therapies, DMF, Metformin, Methotrexate and Rapamycin all work by affecting metabolism and/or regulating or mimicking endogenous metabolites with anti-inflammatory effects. Evidence is emerging for the targeting of specific metabolic events as a strategy to limit inflammation in different contexts. Here we discuss these recent developments and speculate on the prospect of targeting immunometabolism in the effort to develop novel anti-inflammatory therapeutics. As accumulating evidence for roles of an intricate and elaborate network of metabolic processes, including lipid, amino acid and nucleotide metabolism provides key focal points for developing new therapies, we here turn our attention to glycolysis and the TCA cycle to provide examples of how metabolic intermediates and enzymes can provide potential novel therapeutic targets.

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“…95 A correlation between NK cell counts and autoimmune disorders has been reported for RA, SLE, MS and others (reviewed in ref. 96 ).…”

Section: Metforminmentioning

confidence: 99%

Targeting immunometabolism as an anti-inflammatory strategy

2020

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“…However, NK cells are a unique subset that play different roles in different autoimmune disease models. For instance, NK cells play a protective role in certain autoimmune diseases, whereas they play a pathogenic role in the onset of other autoimmune diseases [13]. Furthermore, the proportion of CD56 bright or CD56 dim NK cells in the peripheral blood of patients with certain autoimmune diseases is similar to that in healthy subjects [24][25][26].…”

Section: Discussionmentioning

confidence: 96%

“…Interestingly, both TNF-α and IFN-γ can significantly activate the promoter of human leucocyte antigen (HLA)-B27, indicating that they might contribute to the onset of AS [12]. Recently, natural killer (NK) cells have been shown to play a key role in the pathogenesis of autoimmune diseases [13]. Human NK cells…”

Section: Introductionmentioning

confidence: 99%

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

Yang

Zhou

Liu

et al. 2019

Clinical &Amp; Experimental Immunology

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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.

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“…(Liu et al 2005) NK cells are regarded as a bridge between innate and adaptive immunity, serving as a key regulator in the pathogenesis and development of autoimmune diseases. (Gianchecchi et al 2018) It have been reported that high percentages of NK cells and their activity were found in the synovial fluid of active RA patients at advanced stage (Yamin et al 2019), and dysfunction of NK cell was also observed in patients with systemic-onset JIA and its complication. (Grom et al 2003) NO2-dependent IL12 pathway plays a unique role in the activation of NK cells by macrophage.…”

Section: Discussionmentioning

confidence: 99%

Peer Review #2 of "Genetic architecture study of rheumatoid arthritis and juvenile idiopathic arthritis (v0.2)"

2020

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Background. Rheumatoid arthritis and juvenile idiopathic arthritis are two types of autoimmune diseases with inflammation at the joints, occurring to adults and children respectively. There are phenotypic overlaps between these two types of diseases, despite the age difference in patient groups. Methods. To systematically compare the genetic architecture of them, we conducted analyses at the gene and pathway levels and constructed protein-protein-interaction network based on summary statistics of genome-wide association studies of these two diseases. We examined their difference and similarity at each level. Results. We observed extensive overlap in significant SNPs and genes at the human leukocyte antigen region. In addition, several SNPs in other regions of the human genome are also significantly associated with both diseases. We found significantly associated genes are enriched in 32 pathways shared by both diseases. After genes in human leukocyte antigen region being removed, significant enrichment is present for pathways like interleukin-27 pathway and NO2-dependent interleukin-12 pathway in natural killer cells. Discussion. The identification of commonly associated genes and pathways may help in finding population at risk for both diseases, as well as shed light on repositioning and designing drugs for both diseases.

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NK cells in autoimmune diseases: Linking innate and adaptive immune responses

Cited by 111 publications

References 233 publications

Targeting immunometabolism as an anti-inflammatory strategy

Targeting immunometabolism as an anti-inflammatory strategy

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

Peer Review #2 of "Genetic architecture study of rheumatoid arthritis and juvenile idiopathic arthritis (v0.2)"

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