Search

A study of 768 convalescent SARS CoV-2-infected and 500 uninfected Icelanders reveals broad and stable T-cell responses 3-8 months from infection. HLA alleles, disease severity, and age contribute to the heterogeneity of cellular immunity.

Asthma is a common allergic airway disease with significant inter-individual heterogeneity. Here, Olafsdottir et al. report a genome-wide meta-analysis of two large population-based cohorts to identify sequence variants that associate with asthma risk and perform follow-up functional analyses on a protective loss-of-function variant in TNFRSF8.

Mutations in genes encoding NAPDH oxidase subunits are known to be causative for the primary immunodeficiency chronic granulomatous disease (CGD). Here, the authors identify CYBC1 mutations in patients with CGD and show that CYBC1 is important for formation of the NADPH complex and respiratory burst.

Objectives: It has recently been shown that individuals with selective IgA deficiency (sIgAD) have defective B cell responses both to T cell dependent and independent mimicking stimulations. The complex intracellular signaling pathways from different stimuli leading to IgA isotype switching have not been fully elucidated. Thus, the main objective of this study was to delineate these pathways and their potential role in the immunopathology linked to sIgAD.Materials and Methods: PBMCs from 10 individuals with sIgAD and 10 healthy controls (HC) were activated in vitro via either a T cell dependent or independent mimicking stimulation. Intracellular phosphorylation of pSTAT3, pSTAT5, pSTAT6, and as pERK1/2 was evaluated in T and B cells using phosphoflow cytometry.Results: By evaluating T cell dependent cytokine driven pathways linked to IgA isotype induction we identified a defect involving an IL-21 driven STAT3 activation isolated to B cells in sIgAD individuals. However, all other signaling pathways studied were found to be normal compared to HC. In T cell dependent cytokine driven stimulations linked to IgA isotype induction the following patterns emerged: (i) IL-10 led to significant STAT3 activation in both T- and B cells; (ii) IL-4 stimulation was predominantly confined to STAT6 activation in both T- and B cells, with some effects on STAT3 activation in T-cells; (iii) as expected, of tested stimuli, IL-2 alone activated STAT5 and some STAT3 activation though in both cases only in T-cells; (iv) IL-21 induced significant activation of STAT3 in both T- and B cells, with some effects on STAT5 activation in T-cells; and finally (v) synergistic effects were noted of IL-4+IL-10 on STAT5 activation in T-cells, and possibly STAT6 in both T- and B cells. On the other hand, CPG induced T cell independent activation was confined to ERK1/2 activation in B cells.Conclusion: Our results indicate a diminished STAT3 phosphorylation following IL-21 stimulation solely in B cells from sIgAD individuals. This can represent aberrant germinal center reactions or developmental halt. Thus, our work provides further insight into the unraveling of the previously hypothesized role of IL-21 to reconstitute immunoglobulin production in primary antibody deficiencies.