Abstract In viral infections, complement activation can contribute to viral clearance, but excessive activation, as observed in severe COVID-19, may drive immunopathology. While much is known about complement-activating factors in COVID-19, insight into the role of endogenous complement inhibitors remains limited. We performed a longitudinal analysis within the BEAT-COVID cohort, comprising hospitalized patients with SARS-CoV-2 infection admitted to the intensive care unit (ICU) or ward, and age-matched healthy controls. Serum levels of the complement activation marker soluble membrane attack complex (sC5b-9) and soluble inhibitors C1-Inhibitor (C1-INH), C4b-Binding Protein (C4BP), Factor H, and Factor I were measured by ELISA. In vitro endothelial complement sensitivity was assessed by flow cytometry. Soluble inhibitors were also measured in a cohort of patients with long COVID. Patients admitted to the ICU showed elevated sC5b-9 levels compared to patients admitted to the ward and controls, correlating with disease severity, length of hospitalization, and need for mechanical ventilation, but not mortality. Unexpectedly, levels of all soluble complement inhibitors were elevated, particularly in patients admitted to the ICU. Factor H levels positively correlated with sC5b-9. Endothelial cells pre-incubated with serum from patients admitted to the ICU became more susceptible to complement attack. In patients with long COVID, Factor H and C4BP levels remained elevated compared to pre-pandemic healthy controls. Severe COVID-19 is characterized by extensive complement activation despite elevated circulating inhibitor levels, suggesting impaired local complement regulation at the cell surface, potentially amplified by overwhelming systemic activation, rather than inhibitor deficiency.
Hereditary angioedema (HAE) is a rare genetic disorder characterised by recurrent episodes of swelling, which can potentially be life-threatening, resulting in substantial physical, psychological, educational and occupational burden. Treatment of HAE is divided into on-demand treatment for acute attacks and long-term prophylaxis for prevention of attacks, and there are now several effective therapies available. However, in the UK, use of on-demand therapy is intended for attacks defined as clinically significant, and access to long-term prophylaxis is determined primarily by frequency-based criteria. In this policy-focused review, we compare UK access criteria with international guidelines on best practice. We conclude that UK access criteria result in a group of HAE patients with persisting unmet need, and this may have a greater impact in children and young people. In view of this, we recommend greater flexibility in access criteria, allowing clinical judgement, shared decision-making, and broader measures of disease burden to inform treatment eligibility, so we can individualise care and fully meet the needs of these patients.
INTRODUCTION:Thyroid peroxidase (TPO) autoantibodies are defining features of autoimmune thyroid disease (AITD), yet the relationship between epitope specificity and antibody function remains incompletely understood. METHODS:In this study, we generated patient-derived human monoclonal anti-TPO antibodies from a single donor with AITD (T-011) and characterized their competition-defined epitope relationships, reporter-based Fcγ receptor activity, and direct effects on TPO enzymatic function. RESULTS:Although the antibodies exhibited comparable FcγRIIIa reporter activation, FcγRIIa reporter responses varied according to epitope specificity. Notably, TPO036 demonstrated enhanced FcγRIIa reporter signaling and, following conversion to an F(ab')2 format, competitively inhibited Fc-mediated reporter activation. Direct TPO activity assays demonstrated that representative antibodies produced either no or only minimal inhibition of TPO enzymatic activity under the conditions tested. These findings indicate that competition-defined anti-TPO antibody groups within a single-donor repertoire can exhibit distinct functional profiles, particularly with respect to Fc-mediated reporter responses, without evidence of broad inhibition of TPO catalytic activity. CONCLUSION:Overall, our results support the existence of intra-individual, epitope-associated functional heterogeneity among anti-TPO antibodies and provide a proof-of-concept foundation for future studies evaluating epitope-targeted and Fc-modulating strategies in physiologically relevant models.
