IRF5 genetic risk variants drive myeloid-specific IRF5 hyperactivation and presymptomatic SLE

Inhibition of IRF5 hyperactivation protects from lupus onset and severity

“…Lyn was identified as a negative regulator of IRF5 posttranslational modification via direct binding to IRF5 (73). Given that basal IRF5 hyperactivation has been detected in multiple cohorts of patients with lupus and, more recently, in healthy donor IRF5 genetic risk carriers (69), and given our finding that IRF5 hyperactivation in NZB/W F1 and MRL/lpr lupus mice was not constitutive over the course of the disease, it is unlikely that alterations in Lyn are driving IRF5 hyperactivation. Further, since SLE serum recapitulated the IRF5 activation detected in matched SLE patients, this points to a circulating trigger or triggers that induce IRF5 activation rather than a loss in negative control regulators ( Figure 8, D and E) (19).…”

“…IRF5 genetic variants that associate with SLE risk were originally identified in 2005 (6) and only recently are studies beginning to shed light on how IRF5 genetic risk contributes to SLE pathogenesis (20,28,69,70). While these studies led to a multitude of studies in murine lupus models lacking Irf5, together, they support genetic and nongenetic roles for IRF5 in lupus disease development (21)(22)(23)(24)(25)(26)71).…”

Immunogenetics in systemic lupus erythematosus: Transitioning from genetic associations to cellular effects

“…Instead, increased basal levels of nuclear localized (ie activated) IRF5 were detected in monocytes, pDCs and neutrophils from IRF5 risk individuals 66 . Moreover, an increased frequency of pDCs in peripheral blood that produced elevated levels of type I IFN in response to TLR7/8 stimulation and increased spontaneous NETosis from neutrophils were found in IRF5 risk carriers 66 . Another study in cells from healthy individuals demonstrated increased production of TNF‐α following TLR and nucleotide‐binding oligomerization domain‐containing(NOD)2 receptor activation of monocyte‐derived dendritic cells carrying the promoter IRF5 risk alleles 67 …”

“…A recent study of healthy donor cells found no differences in IRF5 protein levels between carriers of an IRF5 risk haplotype relative to a protective haplotype. Instead, increased basal levels of nuclear localized (ie activated) IRF5 were detected in monocytes, pDCs and neutrophils from IRF5 risk individuals 66 . Moreover, an increased frequency of pDCs in peripheral blood that produced elevated levels of type I IFN in response to TLR7/8 stimulation and increased spontaneous NETosis from neutrophils were found in IRF5 risk carriers 66 .…”

Potential T Cell-Intrinsic Regulatory Roles for IRF5 via Cytokine Modulation in T Helper Subset Differentiation and Function

“…In each patient, the disease shares several common characteristics, but ultimately has a unique landscape and response to treatment. This is likely driven by a "multi-hit" scenario where dysfunction or dysregulation of a single (or multiple) master regulatory factor, like IRF5, will predispose individuals to developing a specific brand of immune dysregulation with many shared pathological characteristics (112). However, ultimately the path of development and resulting severity of the disease is determined by the addition of other risk allelic variations, thereby leading to the unique signature characterizing individual autoimmune conditions.…”