Signal transducer and activator of transcription 1 (STAT1) gain-of-function (GOF) mutations underlie an inborn error of immunity called chronic mucocutaneous candidiasis. Beyond the fungal susceptibility, attributed to Th17 failure, over half of the reported patients suffer from autoimmune manifestations, the mechanism of which has not been explained yet. Dendritic cells (DCs) have been implicated in the pathogenesis of various autoimmune disorders, however, to date they have not been studied in STAT1 GOF CMC. We hypothesized that the STAT1 mutations would affect DCs’ properties and alter their inflammatory and tolerogenic functions. To test the hypothesis, we generated monocyte-derived DCs (moDCs) and tolerogenic DCs (tDCs) from freshly isolated STAT1 GOF patients’ monocytes cultivated in the presence of IL-4 and GM-CSF (moDCs), and tolerogenic factors vitamin D2 and dexamethasone (tDCs). Functional and signaling studies, co-culture experiments and RNA sequencing demonstrated that STAT1 GOF DCs were profoundly altered in their phenotype and functions, characterized by defective autophagy, proinflammatory skew and loss of tolerogenic functions. The results suggested that DCs play an important role in the immune dysregulation in STAT1 GOF CMC and may contribute to the disease-associated autoimmune manifestations via alteration in various cellular mechanism, including autophagic processes.

Background: Common variable immunodeficiency (CVID) is characterized by an impaired post-vaccination response, high susceptibility to respiratory tract infections, and a broad spectrum of non-infectious complications. Thus, patients with CVID are at high risk of coronavirus disease 2019 (COVID-19), and vaccination’s role in prevention is questionable. The main aim of this study was to evaluate the clinical outcomes, safety, and dynamics of humoral and T-cell immune responses induced by the mRNA vaccine BNT162b2 in CVID. Methods: This prospective observational cohort study focused on the clinical outcomes (proportion of infected patients, disease severity), safety (adverse-event incidence, laboratory-parameter changes), and dynamics of humoral (specific post-vaccination and virus-neutralizing-antibody assessment) and T-cell immune responses (anti-SARS-CoV-2 specific T-cell detection) in 21 patients with CVID after a two-dose administration of BNT162b2. The patients were followed for 6 months. Results: Humoral response was observed in 52% (11/21) of patients at month 1 post-vaccination but continuously decreased to 33.3% (5/15) at month 6. Nevertheless, they had a remarkably lower anti-SARS-CoV-2 neutralizing antibody titer than healthy controls. The T-cell response was measurable in 33% (6/17) of patients with CVID at month 1, and it persisted for the study period. Mild infection occurred in three patients (14.3%) within the follow-up period. The vaccine also exhibited a favorable safety profile. Conclusions: The BNT162b2 vaccine elicited a measurable antibody response in a high proportion of patients, but it was limited by low titer of the virus-neutralizing antibodies and rapid waning of anti-RBD SARS-CoV-2 specific antibodies. T-cell response was detected in one-third of the patients and remained stable within the follow-up period. Vaccination has favorable safety and clinical-related outcomes in preventing severe COVID-19.

Adam Klocperk1, M.D., Ph.D., Zuzana Paračková1, MSc., Jitka Dissou2, M.D., Hana Malcová3, M.D., Ph.D., Petr Pavlíček4, M.D., Tomáš Vymazal4, M.D., As. Prof., Pavla Doležalová5, M.D., Prof., Anna Šedivá1, M.D., Prof.1Department of Immunology, 2ndFaculty of Medicine, Charles University in Prague and University Hospital in Motol, Prague, Czech Republic2Emergency Department for Children, University Hospital in Motol, Prague, Czech Republic3Department of Children and Adult Rheumatology, University Hospital in Motol , Prague, Czech Republic4Department of Anesthesiology and Intensive Care Medicine, 2nd Faculty of Medicine, Charles University in Prague and University Hospital in Motol, Prague, Czech Republic5Centre for Paediatric Rheumatology and Autoinflammatory Diseases, Department of Paediatrics and Adolescent Medicine, General University Hospital in Prague and 1st Faculty of Medicine, Charles University in Prague, Prague, Czech Republic