Interferon pathway lupus risk alleles modulate risk of death from acute COVID-19

Abstract

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Molecular mechanisms controlling age‐associated B cells in autoimmunity*

“…Associations with several other autoimmune diseases like multiple sclerosis, rheumatoid arthritis, and scleroderma have also been reported 170‐173 . Variants in IRF8 have also been associated with susceptibility to respiratory infections like H1N1 and, more recently together with IRF5 variants, with differences in COVID‐19 mortality 174,175 . Given the crucial role of IRF8 and IRF5 in pathogen responses, it is thus intriguing to speculate that proper control of the ABC compartment by these IRFs may exert a broad impact not only in autoimmune diseases but also in other aspects of human pathophysiology.…”

Sulfasalazine: a risk factor for severe COVID-19?

“…The realisation, over the space of a few months, that sulfasalazine is an inhibitor of type I IFN production by plasmacytoid dendritic cells and also a risk factor for death due to SARS-CoV-2 infection; 1 that autoantibodies against type I IFNs are observed in about 20% of critical COVID-19 cases and deaths; 8 and that SLE risk alleles associated with high type I IFN production are associated with asymptomatic SARS-CoV-2 infection (ie, potentially less severe disease), 9 have helped crystalise understanding of autoimmunity as it relates to anti-viral immunity. The data strongly support a role for type I IFN in resistance to SARS-CoV-2 and highlight the possibility that autoimmune diseases related to increased type I IFN production might be a consequence of evolutionary pressure to maintain genetic alleles that ensure resistance to viral pathogens.…”

Frequency of IRF5+ dendritic cells is associated with the TLR7-induced inflammatory cytokine response in SARS-CoV-2 infection

“…While in our results show coinciding cytokine and IRF5 expression, we cannot causally link IRF5 to DC functionality because we were not able to perform an IRF5 knockdown. Furthermore, multiple SNPs have been identified in the human IRF5 gene that alters the expression levels of IRF5 and hence influence the magnitude of host inflammatory responses and risk of severe COVID-19 [28] , [37] , which was not considered in this study. Future studies should further differentiate the different mDC subsets, in particular CD141+ mDCs and CD1c+ mDCs to examine potential differences in the IRF5 regulation [9] .…”