Showing papers by "Frederic Geissmann published in 2022"

Inborn errors of OAS–RNase L in SARS-CoV-2–related multisystem inflammatory syndrome in children

Abstract: Multisystem inflammatory syndrome in children (MIS-C) is a rare and severe condition that follows benign COVID-19. We report autosomal recessive deficiencies of OAS1, OAS2, or RNASEL in five unrelated children with MIS-C. The cytosolic double-stranded RNA (dsRNA)–sensing OAS1 and OAS2 generate 2′-5′-linked oligoadenylates (2-5A) that activate the single-stranded RNA–degrading ribonuclease L (RNase L). Monocytic cell lines and primary myeloid cells with OAS1, OAS2, or RNase L deficiencies produce excessive amounts of inflammatory cytokines upon dsRNA or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) stimulation. Exogenous 2-5A suppresses cytokine production in OAS1-deficient but not RNase L–deficient cells. Cytokine production in RNase L–deficient cells is impaired by MDA5 or RIG-I deficiency and abolished by mitochondrial antiviral-signaling protein (MAVS) deficiency. Recessive OAS–RNase L deficiencies in these patients unleash the production of SARS-CoV-2–triggered, MAVS-mediated inflammatory cytokines by mononuclear phagocytes, thereby underlying MIS-C. Description Is the OAS–RNase L pathway the “MIS-C”ing link? Multisystem inflammatory syndrome in children (MIS-C) is a severe complication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that affects one in 10,000 infected children. MIS-C is reminiscent of Kawasaki disease and its etiology remains unknown. Lee et al. performed whole-exome and whole-genome sequencing on a cohort of MIS-C patients and uncovered autosomal-recessive deficiencies of OAS1, OAS2, or RNASEL in around 1% of the cohort (see the Perspective by Brodin). These genes are components of a signaling pathway that suppresses inflammation in double-stranded RNA–stimulated mononuclear phagocytes. Thus, single-gene recessive inborn errors of the OAS–RNase L pathway can result in uncontrolled inflammatory cytokine production by mononuclear phagocytes after SARS-CoV-2 infection, potentially explaining the origins of MIS-C in some children. —STS Autosomal-recessive deficits in RNA sensing can result in SARS-CoV-2–triggered Kawasaki-like disease. INTRODUCTION Multisystem inflammatory syndrome in children (MIS-C) is a severe, unexplained complication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection with an estimated prevalence of ~1 per 10,000 infected children. It typically occurs 4 weeks after infection, without hypoxemic pneumonia. Affected children present with fever, rash, abdominal pain, myocarditis, and other clinical features reminiscent of Kawasaki disease, including lymphadenopathy, coronary aneurysm, and high levels of biological markers of acute inflammation. Sustained monocyte activation is consistently reported as a key immunological feature of MIS-C. A more specific immunological abnormality is the polyclonal expansion of CD4+ and CD8+ T cells bearing the T cell receptor Vβ21.3. The root cause of MIS-C and its immunological and clinical features remains unknown. RATIONALE We hypothesized that monogenic inborn errors of immunity to SARS-CoV-2 may underlie MIS-C in some children. We further hypothesized that the identification of these inborn errors would provide insights into the molecular and cellular mechanisms underlying its immunological and clinical phenotypes. Finally, we hypothesized that a genetic and mechanistic understanding of a few patients would provide a proof of principle that would facilitate studies in other patients. We performed whole-exome or whole-genome sequencing on 558 internationally recruited patients with MIS-C (aged 3 months to 19 years). We searched for rare nonsynonymous biallelic variants of protein-coding genes, testing a hypothesis of genetic homogeneity. RESULTS We found autosomal recessive deficiencies of OAS1 (2′-5′-oligoadenylate synthetase 1), OAS2, or RNase L (ribonuclease L) in five unrelated children of four different ancestries with MIS-C (~1% of our cohort). There were no similar defects in a cohort of 1288 individuals (aged 6 months to 99 years) with asymptomatic or mild infection (P = 0.001) or 334 young patients (aged 0 to 21 years) with asymptomatic or mild infection or COVID-19 pneumonia (P = 0.046). The estimated cumulative frequency of these defects in the general population was ~0.00013. The type I interferon (IFN)–inducible double-stranded RNA (dsRNA)–sensing proteins OAS1 and OAS2 generate 2′-5′-linked oligoadenylates (2-5A), which activate the antiviral single-stranded RNA (ssRNA)–degrading RNase L, particularly in mononuclear phagocytes. Consistent with the absence of pneumonia in these patients, epithelial cells and fibroblasts defective for this pathway restricted SARS-CoV-2 normally. This contrasted with interferon alpha and beta receptor subunit 1 (IFNAR1)–deficient cells from patients prone to hypoxemic pneumonia without MIS-C. Monocytic cell lines with genetic deficiencies of OAS1, OAS2, or RNase L displayed excessive inflammatory cytokine production in response to intracellular dsRNA. Cytokine production by RNase L–deficient cells was impaired by melanoma differentiation-associated protein 5 (MDA5) or retinoic acid–inducible gene I (RIG-I) deficiency and abolished by mitochondrial antiviral-signaling protein (MAVS) deficiency. Exogenous 2-5A suppressed inflammatory responses to these stimuli in control and OAS1-deficient cells but not in RNase L–deficient cells. Finally, monocytic cell lines, primary monocytes, and monocyte-derived dendritic cells with genetic deficiencies of OAS1, OAS2, or RNase L displayed exaggerated inflammatory responses to SARS-CoV-2 as well as SARS-CoV-2–infected cells and their RNA. CONCLUSION We report autosomal recessive deficiencies of OAS1, OAS2, or RNase L in ∼1% of an international cohort of MIS-C patients. The cytosolic OAS–RNase L pathway suppresses RIG-I/MDA5–MAVS–mediated inflammation in dsRNA-stimulated mononuclear phagocytes. Single-gene recessive inborn errors of the OAS–RNase L pathway unleash the production of SARS-CoV-2–triggered inflammatory cytokines by mononuclear phagocytes, thereby underlying MIS-C. OAS–RNase L deficiency in MIS-C. dsRNAs from SARS-CoV-2 or SARS-CoV-2–permissive cells engulfed by mononuclear phagocytes simultaneously activate the RIG-I/MDA5–MAVS pathway, inducing inflammatory cytokine production, and the OAS–RNase L pathway, exerting posttranscriptional control over inflammatory cytokine production. OAS–RNase L deficiency results in excessive inflammatory cytokine production by myeloid cells, triggering MIS-C, including lymphoid cell activation and multiple tissue lesions. NK, natural killer; IRF3, interferon regulatory factor 3; NF-κB, nuclear factor κB.

RA-MAP, molecular immunological landscapes in early rheumatoid arthritis and healthy vaccine recipients

Abstract: Rheumatoid arthritis (RA) is a chronic inflammatory disorder with poorly defined aetiology characterised by synovial inflammation with variable disease severity and drug responsiveness. To investigate the peripheral blood immune cell landscape of early, drug naive RA, we performed comprehensive clinical and molecular profiling of 267 RA patients and 52 healthy vaccine recipients for up to 18 months to establish a high quality sample biobank including plasma, serum, peripheral blood cells, urine, genomic DNA, RNA from whole blood, lymphocyte and monocyte subsets. We have performed extensive multi-omic immune phenotyping, including genomic, metabolomic, proteomic, transcriptomic and autoantibody profiling. We anticipate that these detailed clinical and molecular data will serve as a fundamental resource offering insights into immune-mediated disease pathogenesis, progression and therapeutic response, ultimately contributing to the development and application of targeted therapies for RA.