Investigations into the pathogenesis of lupus have largely focused on abnormalities

Investigations into the pathogenesis of lupus have largely focused on abnormalities in components of the adaptive immune system. I interferons. These priming events are responsible for initiating the adaptive responses that ultimately mediate the pathogenic process. Batimastat (BB-94) Introduction Discoveries underpinning current understanding of the basic pathophysiology of systemic lupus erythematosus (SLE) have begun to dissect fundamental pathways and branches and provide an explanation for the common presence of antinuclear antibodies (ANAs). This has focused attention on two major innate immune system factors the type I interferons (IFN-I) and the nucleic acid-sensing Toll-like receptors (NA-TLRs). Here we will review this area focusing on recent publications. Type I interferons in SLE It is now widely accepted that IFN-I are a driving pathogenic pressure in the majority of SLE patients based on substantial clinical epidemiologic and genetic data (examined in [1? 2 3 4 as well as direct evidence from animal models using IFN-I receptor-deficient lupus mice or anti-IFN-α/βR antibody treatment [5 6 Additional studies in these models have also documented: (a) the presence of IFN-I-independent lupus in MRL-mice due to background genes and not Fas deficiency [7 8 (b) a requirement for IFN-I in mouse lupus models despite the absence of elevated IFN-α or interferon-stimulated genes (ISGs so called ‘IFN-I signature’) [5] consistent with the recent finding that IFN-I expression even at very low concentrations modulates immune homeostasis by affecting tonic signaling [9]; (c) IFN-α induction of clinically-significant lupus required genetic susceptibility [10] which could explain the infrequent occurrence of lupus in patients treated with high dose IFN-I; and (d) inhibition of lupus was most effective when IFN-I signaling was blocked in early disease stages implying IFN-I is mainly important at this innate stage but not after the pathogenic adaptive autoimmune response has been established [6?]. Production of IFN in lupus Plasmacytoid dendritic cells (pDCs) Batimastat (BB-94) are considered Batimastat (BB-94) the main source of IFN-I in SLE because of their capacity to produce 100-1000-fold greater amounts of IFN-α than other cell types and evidence of pDC activation in SLE patients [1?]. The importance of these cells in disease pathogenesis is usually supported by the finding that in lupus mice significant disease suppression occurred either with IRF8 deficiency which arrests development of predominantly pDCs or with the mutation in the endosomal histidine transporter mice suggesting that under certain circumstances this sensor can also mediate disease [57]. Accordingly in human SLE it is possible that TLR8 which binds ssRNA in contrast to mouse TLR8 which does not may also play a role [58]. Despite the strong association of SLE with anti-double stranded DNA (dsDNA) several lines of evidence suggest TLR7 may be more important than TLR9. This was first suggested by an early Capn1 experiment showing that this interferogenic activity of nucleic acid-containing IgG immune complexes (generated by combining SLE sera with apoptotic or necrotic cells) for pDCs was more sensitive Batimastat (BB-94) to RNase than to DNase [59]. Lupus-prone mice lacking only TLR7 experienced a substantial reduction in disease albeit not as great as TLR7/9 double deficiency whereas absence of TLR9 contrary to expectations resulted in greater severity [55]. Although an in the beginning perplexing result subsequent studies have attributed this to the absence of competition from TLR9 for UNC93B1-mediated endoplasmic reticulum to endosome trafficking resulting in increased transport and activation of TLR7 [41 60 Similarly knockout of TLR8 which in mice does not bind nucleic acids but still relies on UNC93B1 for trafficking to the endosome also prospects to the development of systemic autoimmunity [61] presumably by the same mechanism. It should be pointed out that lupus-prone mouse strains produce in addition to standard ANAs species-specific anti-gp70 autoantibodies to circulating RNA-containing endogenous retroviral particles and this specificity is Batimastat (BB-94) usually TLR7-dependent and associated with disease development [62 63 It is possible that this mouse-specific response may be a factor in the TLR7 predominance in murine lupus. NA-TLR centric model of SLE autoantibody production Both.