Background/Purpose: The pathogenesis of systemic lupus erythematosus (SLE) is thought to be strongly influenced by the interferon (IFN) signaling pathway, particularly type I IFNs (IFNα/β). However, recent work suggests a significant role for type II IFN (IFNγ) and type III (IFNλ) in SLE. While anifrolumab was recently approved for the treatment of SLE, response rates were ~16% above placebo for lupus patients in general, and for LN, complete remission rates were ~10% over placebo, reaching under 28%. Thus, while efficacious, this suggests an opportunity to understand why these patients were not more responsive to therapy. One potential reason is that nearly 2/3 of type I IFN genes are also regulated by IFNγ, suggesting that there may be compensatory or redundant mechanisms by which IFNs regulate lupus pathogenesis.

Methods: We created two knock-out alleles, one targeting the type I IFN receptor (Ifnar1) and one targeting the type II IFN receptor (Ifngr1) on the MRL/lpr lupus-prone background. We then intercrossed these alleles to develop a cohort comprising four separate genotypes: WT, Ifngr1-/-, Ifnar-/-, and Ifngr-/-Ifnar1-/- (DKO) mice. These cohorts were analyzed for disease pathology, including proteinuria, renal histology, autoantibodies, and immune cell activation. To corroborate our murine findings, we also assessed 3 published datasets derived from human lupus nephritis patients to evaluate gene signatures for type I vs. type II IFN activation profiles.

Results: Here, we demonstrate that deficiency of Ifnar1 has limited effects on disease endpoints in the MRL/lpr model, whereas deficiency of Ifngr1 exhibits a dominant protective effect. However, when Ifnar1 was deleted in concert with Ifngr1, we observed an additive effect. Both Ifngr1-/- and DKO MRL/lpr mice had increased survival compared to WT or Ifnar-/- mice, and this was accompanied by ameliorated lupus nephritis. Given the survival advantage of the DKO and Ifngr1-/- deficient MRL/lpr mice, we aged these mice to 27 weeks (far beyond the standard survival age of WT MRL/lpr mice). At this delayed time point, DKO mice showed improvement in glomerular disease, reduced lymphoproliferation with markedly reduced lymphadenopathy, and improved survival. When examining immune activation, we found a substantial B cell phenotype, with DKO mice exhibiting reduced age-associated B cell numbers, reduced autoantibodies, and suppressed germinal centers compared to Ifngr1 deficiency alone. In human cohorts, we examined the unique type I and II IFN signatures and found that both were associated with the presence of lupus nephritis but, in fact, the type II IFN signature in kidney parenchymal cells is more significantly associated with the presence of lupus nephritis.

Conclusion: This data suggests that type I IFNs do, in fact, regulate disease activation in MRL/lpr mice. However, due to redundant and overlapping transcriptional regulation and the strong type II IFN signature seen in many mouse models and likely patients, blocking type I IFNs alone may not be sufficient to ameliorate disease. Furthermore, both type I and type II IFNs are responsible for regulating B cell phenotypes, which are instrumental in driving both human and murine lupus.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/type-i-and-type-ii-ifns-have-both-independent-and-overlapping-effects-on-sle-disease-severity/