NUDT2 Disruption Elevates Diadenosine Tetraphosphate (Ap(4)A) and Down-Regulates Immune Response and Cancer Promotion Genes

Marriott, Andrew S.; Vasieva, Olga; Fang, Yongxiang; Copeland, Nikki A.; McLennan, Alexander G.; Jones, Nigel J.

It is known that Type I IFNs and TNF can mutually suppress each other's expression, and it has been suggested that changes in the cross-regulation of these pathways might affect the balance between the potential destructive and protective roles of these cytokines in the pathogenesis of autoimmune inflammatory diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) [61] . IPA 1 identifies signaling in RA as a top-ranked affected canonical pathway (Table 4 ) and the list of DEGs associated with RA and SLE are shown in S6 Table. Although the modest changes in expression in some other cytokine receptors could potentially be pro-inflammatory (e.g. IL10RA and IL23R), the overall picture is one of the Up-regulated canonical pathways and MHC class II antigens. KBM-7 cells can be regarded as immature precursors to professional antigen-presenting cells such as macrophages and dendritic cells and almost all of the top 20 up-regulated canonical pathways flagged by IPA 1 involve functions associated with the adaptive immune response, including antigen presentation, OX40 signaling, allograft rejection and B cell development (Table 4 and S4 Table) . However, it should be emphasized that this is largely because these pathways all involve one of the most prominent up-regulated gene sets, the inducible MHC class II antigens (MHC-II). MHC-II molecules are mainly concerned with the presentation of antigens derived from extracellular pathogens resulting in CD4+ T helper cell priming and the production of antibodies by B cells [62] . Almost all class II subtype genes show a significant increase in expression, with some showing a large increase, e.g. HLA-DOA 47-fold and HLA-DPA1 12-fold. Thus, the extent to which these canonical pathways can be regarded as up-regulated as a whole is open to question.