Background B-cell-depleting therapies increase the risk of morbidity and mortality due to COVID-19. Evidence-based SARS-CoV-2 vaccination strategies for patients on B-cell-depleting therapies are scarce. We aimed to investigate humoral and cell-mediated immune responses to SARS-CoV-2 mRNA-based vaccines in patients receiving CD20-targeted B-cell-depleting agents for autoimmune disease, malignancy, or transplantation. Methods The RituxiVac study was an investigator-initiated, single-centre, open-label study done at the Bern University Hospital (Bern, Switzerland). Patients with a treatment history of anti-CD20-depleting agents (rituximab or ocrelizumab) and with no previous history of SARS-CoV-2 infection were enrolled between April 26 and June 30, 2021, for analysis of humoral and cell-mediated immune responses (by interferon-γ [IFNγ] release assay) at least 4 weeks after completing vaccination against SARS-CoV-2. Healthy controls without a history of SARS-CoV-2 infection were also enrolled at least 4 weeks after completing vaccination against SARS-CoV-2. All study participants received two doses of either the Pfizer–BioNTech BNT162b2 vaccine or the Moderna mRNA-1273 vaccine. The primary outcome was the proportion of patients with a history of anti-CD20 treatment who showed a humoral immune response against the SARS-CoV-2 spike protein in comparison with immunocompetent controls. Prespecified secondary endpoints were the effect of anti-CD20 therapy (including time since last treatment and cumulative dose) on humoral or cell-mediated immune responses to SARS-CoV-2 vaccination, and biomarkers of immunocompetence. This study is registered with ClinicalTrials.gov , NCT04877496 . Findings The final study population comprised 96 patients and 29 immunocompetent controls. The median age of patients was 67 years (IQR 57–72) and of controls was 54 years (45–62), and 51 (53%) of 96 patients and 19 (66%) of 29 controls were female. The median time since last anti-CD20 treatment was 1·07 years (IQR 0·48–2·55) and the median cumulative dose of an anti-CD20 depleting agent was 2·80 g (1·50–5·00). Anti-spike IgG antibodies were detected in 47 (49%) of 96 patients 1·79 months (IQR 1·16–2·48) after the second vaccine dose compared to 29 (100%) of 29 controls 1·81 months (1·17–2·48) after the second vaccine dose (p<0·001). SARS-CoV-2-specific IFNγ release was detected in 13 (20%) of 66 patients and 21 (75%) of 28 of healthy controls (p<0·001). Only nine (14%) of 66 patients were double positive for anti-SARS-CoV-2 spike IgG and cell-mediated responses, compared with 21 (75%) of 28 healthy controls (p<0·001). Time since last anti-CD20 therapy (>7·6 months; positive predictive value 0·78), peripheral CD19 + cell count (>27 cells per μL; positive predictive value 0·70), and CD4 + lymphocyte count (>653 cells per μL; positive predictive value 0·71) were ...

Urticaria is a common, mast cell-driven disease presenting with wheals or angioedema or both. In the last years, urticaria has increasingly attracted notice to clinicians and researchers, last but not least inspired by the approval of omalizumab, an anti-IgE antibody, for urticaria treatment. There is wide consensus on the clinical classification based on duration and elicitation. However, the pathogenesis is incompletely understood. This review summarizes current guidelines for the management and novel insights in the pathogenesis of urticaria with special focus on their impact on clinical praxis. The classification of urticaria subgroups is mainly based on clinical criteria: acute and chronic urticaria (CU). Chronic urticaria comprises both chronic spontaneous urticaria (CSU) and chronic inducible urticaria (CIndU) that includes physical and non-physical urticarias. Recent research focused on characterizing the role of cells and mediators involved in the pathogenesis of urticaria, identifying the mechanisms of mast cell activation, and investigating underlying autoimmune processes in chronic spontaneous urticarial. Currently, non-sedating antihistamines and omalizumab, an antiimmunoglobulin E antibody, are recommended for the therapy of chronic urticaria, as both exhibit a favorable efficacy and safety profile. Novel therapeutic strategies aim at specifically targeting cells and mediators involved in the pathogenesis of urticaria.

SUMMARY Eosinophils are white blood cells that function in innate immunity and participate in the pathogenesis of various inflammatory and neoplastic disorders. Their secretory granules contain four cytotoxic proteins, including the eosinophil major basic protein (MBP-1). How MBP-1 toxicity is controlled within the eosinophil itself and activated upon extracellular release is unknown. Here we show how intragranular MBP-1 nanocrystals restrain toxicity, enabling its safe storage, and characterize them with an X-ray-free electron laser. Following eosinophil activation, MBP-1 toxicity is triggered by granule acidification, followed by extracellular aggregation, which mediates the damage to pathogens and host cells. Larger non-toxic amyloid plaques are also present in tissues of eosinophilic patients in a feedback mechanism that likely limits tissue damage under pathological conditions of MBP-1 oversecretion. Our results suggest that MBP-1 aggregation is important for innate immunity and immunopathology mediated by eosinophils and clarify how its polymorphic self-association pathways regulate toxicity intra- and extracellularly.