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Darragh Duffy

Publications and source records attributed to Darragh Duffy.

3 recordsLinked to original sources
PubMed2026

NAP1 switches from an activator to a limiter of interferon induction by trapping TBK1 in condensates.

TBK1 kinase is a central regulator of type I IFN production. Upon activation of the IFN-β induction pathway, TBK1-adaptor proteins (NAP1, SINTBAD, TANK) form liquid condensates. We show that NAP1 condensates concentrate TBK1. Using NAP1KO cell lines, we demonstrate that NAP1 exerts a dual effect on TBK1 activity. Initially, NAP1 binds TBK1 and increases its activity, promoting IFN pathway activation. Subsequently, TBK1-mediated phosphorylation of NAP1 induces the formation of condensates. These NAP1 condensates concentrate both TBK1 and the phosphatase PP2A, which dephosphorylates and consequently deactivates TBK1, thus limiting IFN induction. Additionally, in patients with lupus or interferonopathies, we identify NAP1 variants unable to form condensates upon danger signal exposure, which sustain TBK1 activation without limiting its activity. This study reveals a mode of regulating a signaling pathway through condensate formation and provides a potential molecular explanation for immune dysregulation associated with NAP1 variants in certain patients with interferonopathies.

Protein Serine-Threonine Kinases↗
PubMed2026

Affinity-matured B cell responses neutralizing type-I interferons underlie severe viral infections.

Autoantibodies neutralizing type-I interferons (AAN-I-IFNs) emerge as global, common, and strong determinants of a growing number of severe viral diseases. We report that AAN-I-IFNs+ patients with life-threatening COVID-19 pneumonia harbor circulating type-I IFN-specific B cells indistinguishable from patients bearing T cell tolerance defects of genetic origin. This autoimmune response mobilizes a highly diverse and stable circulating B cell response that is detected prior to severe viral infection and acquires high affinity and neutralization potential to type-I IFNs through extended somatic hypermutation. X-ray crystallography and AlphaFold3 structural analysis of hundreds of patient-derived monoclonal antibodies reveals the extended breadth of this response, targeting three major B cell epitopes covering all facets of type-I IFNs. These findings support a model in which a germinal-center-derived memory B cell response directed against type-I IFNs is established before severe viral infection, providing a core mechanism linking T cell tolerance defect to pathogenic AAN-I-IFNs underlying severe viral diseases.

Humans↗
PubMed2025

Endogenous Retroelement Activation is Implicated in Interferon-α Production and Anti-Cyclic Citrullinated Peptide Autoantibody Generation in Early Rheumatoid Arthritis.

OBJECTIVE: Endogenous retroelements (EREs) stimulate type 1 interferon (IFN-I) production but have not been explored as potential interferonogenic triggers in rheumatoid arthritis (RA). We investigated ERE expression in early RA (eRA), a period in which IFN-I levels are increased. METHODS: ERE expression (long terminal repeat [LTR] 5, long interspersed nuclear element 1 [LINE-1], and short interspersed nuclear element [SINE]) in disease-modifying treatment-na&#xef;ve eRA whole-blood and bulk synovial tissue samples was examined by reverse transcription-polymerase chain reaction and NanoString alongside IFN-&#x3b1; activity. Circulating lymphocyte subsets, including B cell subsets, from patients with eRA and early psoriatic arthritis (ePsA) were flow cytometrically sorted and similarly examined. Existing established RA and osteoarthritis (OA) synovial single-cell sequencing data were reinterrogated to identify repeat elements, and associations were explored. RESULTS: There was significant coexpression of all ERE classes and IFNA in eRA synovial tissue samples (n = 22, P < 0.0001) and significant positive associations between whole-blood LINE-1 expression (n = 56) and circulating IFN-&#x3b1; protein (P = 0.018) and anti-cyclic citrullinated peptide (anti-CCP) titers (P < 0.0001). ERE expression was highest in circulating eRA B cells, particularly na&#xef;ve B cells compared with ePsA, with possible ERE regulation by SAM and HD Domain Containing Deoxynucleoside Triphosphate Triphosphohydrolase 1 transcription (SAMDH1) implicated and associations with IFNA again observed. Finally, in established RA synovium, LTRs, particularly human endogenous retroviral sequence K (HERVK), were most increased in RA compared with OA, in which, for all synovial subsets (monocytes, B cells, T cells, and fibroblasts), ERE expression associated with increased IFN-I signaling (P < 0.001). CONCLUSION: Peripheral blood and synovial ERE expression is examined for the first time in eRA, highlighting both a potential causal relationship between ERE and IFN-I production and an intriguing association with anti-CCP autoantibodies. This suggests EREs may contribute to RA pathophysiology with implications for future novel therapeutic strategies.

Humans↗