The IFN-STAT1 axis could possibly be a competent inducer of M1 macrophages polarization, using a possible reciprocal cross-regulation of TNF and IFN production (73). Oddly enough, IFN and TNF- have already been described as perhaps implicated in the pathophysiology of aplastic anemia (85) and abnormal STAT1 activation was confirmed in BM examples of few aplastic anemia patients (86). up that adaptive immunity is profoundly altered in DADA2 patients, encompassing both T and B branches, with a disrupted homeostasis in T-cell?subsets and a B-cell skewing defect. Type I/type II IFN pathway upregulation has been proposed as a possible core signature in DADA2 T cells and monocytes but also an increased IFN- secretion directly from endothelial cells has been described. So far, a unifying clear pathophysiological explanation for the coexistence of systemic inflammation, immunedysregulation and hematological defects is lacking. In this review, we 6-Thio-dG will explore thoroughly the latest understanding regarding DADA2 pathophysiological process, with a particular focus on dysregulation of both innate and adaptive immunity and their interacting role in the development of the disease. monocyte differentiation, with increased proinflammatory M1 macrophages and relatively decreased anti-inflammatory M2 macrophages subset in DADA2 patients. This monocyte/macrophage polarization is supposed to induce a release of proinflammatory cytokines, leading to downstream endothelial disruption (1, 37). Notably, the lentiviral correction of defective ADA2 enzymatic activity with ADA2 reconstitution in patients Rabbit Polyclonal to SHC3 macrophages is able to restrain inflammation (36, 38). Despite initial 6-Thio-dG reports not being univocal, a preferential binding of ADA2 to CD16+ monocytes instead to the classical CD16- monocytes is reported (24). An in-depth immune-phenotyping analysis of prevalently untreated DADA2 patients showed significantly reduced proportions of classical monocytes (CD14+ CD16-) with an increased proportions of intermediated (CD14+ CD16+) and non-classical (CD14- CD16+) monocytes (12). This finding has been confirmed by Watanabe et al (39), who analyzed CD14+ monocytes subpopulations through single cell RNA sequencing, identifying a higher frequency of nonclassical monocytes and an up-regulation of M1 macrophage markers compared with healthy donors. Indeed, nonclassical monocytes are a prominent source of TNF- compared with classical monocytes (40C42), and these findings are in line with the pathogenic role of TNF-. Interestingly, no differences were found comparing monocyte 6-Thio-dG transcriptomes of patients with a hematologic phenotype versus a nonhematologic phenotype, suggesting that the explanation for the BM failure observed in DADA2 is to be sought elsewhere (39, 42). A possible pivotal role in DADA2 pathogenesis has been recently attributed to a dysregulation of the IFN type I and II axis. An upregulation of several 6-Thio-dG pathways involved in the immune response, including IFN/ and IFN signaling, was evident in all monocyte subsets (39). This observation was in line with the identification of elevated plasma levels of IFN. Similar findings were reported in other studies profiling transcriptome and proteome analysis on whole blood samples or gene expression on DADA2 PBMCs (37, 43). The authors suggested that elevated IFN may activate cell signaling, leading to monocytes differentiation into M1 macrophages and release of TNF (39). Interestingly, Yap and colleagues (12) identified a twofold higher level of expression of CD169/SIGLEC1 on all subsets of ADA2-deficient monocytes compared to controls. CD169/SIGLEC1 is a cell adhesion protein induced by type I IFN-signaling and a potential myeloid cell-specific biomarker for an overt type I IFN response on monocytes (44). This finding is in line with reported evidence of upregulated type I IFN signaling in DADA2 with elevation of IFN score (12, 37, 43C48). Finally, an upregulation of STAT1 phosphorylation in DADA2 monocytes after stimulation with IFN and IFN was recently shown (37) confirming similar findings regarding STAT1 central role in altered DADA2 immune response (43, 49). Together with IFN type I, the latter study also identified a clear NFKB signature in the whole blood of untreated patients, with normalization of both findings after anti-TNF treatment (37). Natural Killer (NK) Cells and Dendritic Cells (DCs): The Producers of Interferons in DADA2? NK cells are mainly involved in antiviral and antitumor response (50C52). ADA2 can bind NK cells, so NK is a target cell to ADA2 (23). After the initial reports showing a reduction in NK numbers (24) in DADA2 patients a consensual reduction of mature CD56 dim CD57- NK cells, displaying high cytotoxicity and low cytokine production, was found (3, 12). An increased proportion of immature CD56 bright NK cells, known as NK regulatory (53), was also identified (12). These later cells are characterized by low cytotoxicity and high cytokine production, including TNF-. It would be fascinating to investigate the functional role of this subset, particularly to understand the possible involvement.
