Gain-of-function (GOF) mutations in PIK3CD, encoding the p110δ subunit of phosphatidylinositide 3-kinase (PI3K), cause a primary immunodeficiency. Affected individuals display impaired humoral immune responses following infection or immunization. To establish mechanisms underlying these immune defects, we studied a large cohort of patients with PIK3CD GOF mutations and established a novel mouse model using CRISPR/Cas9-mediated gene editing to introduce a common pathogenic mutation in Pik3cd. In both species, hyperactive PI3K severely affected B cell development and differentiation in the bone marrow and the periphery. Furthermore, PI3K GOF B cells exhibited intrinsic defects in class-switch recombination (CSR) due to impaired induction of activation-induced cytidine deaminase (AID) and failure to acquire a plasmablast gene signature and phenotype. Importantly, defects in CSR, AID expression, and Ig secretion were restored by leniolisib, a specific p110δ inhibitor. Our findings reveal key roles for balanced PI3K signaling in B cell development and long-lived humoral immunity and memory and establish the validity of treating affected individuals with p110δ inhibitors.

The development of food allergy has been reported to be related with the changes in the gut microbiome, however the specific microbe associated with the pathogenesis of food allergy remains elusive. This study aimed to comprehensively characterize the gut microbiome and identify individual or group gut microbes relating to food-allergy using 16S rRNA gene sequencing with network analysis. Faecal samples were collected from children with IgE-mediated food allergies (n = 33) and without food allergy (n = 27). Gut microbiome was profiled by 16S rRNA gene sequencing. OTUs obtained from 16S rRNA gene sequencing were then used to construct a co-abundance network using Weighted Gene Co-expression Network Analysis (WGCNA) and mapped onto Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. We identified a co-abundance network module to be positively correlated with IgE-mediated food allergy and this module was characterized by a hub taxon, namely Ruminococcaceae UCG-002 (phylum Firmicutes). Functional pathway analysis of all the gut microbiome showed enrichment of methane metabolism and glycerolipid metabolism in the gut microbiome of food-allergic children and enrichment of ubiquinone and other terpenoid-quinone biosynthesis in the gut microbiome of non-food allergic children. We concluded that Ruminococcaceae UCG-002 may play determinant roles in gut microbial community structure and function leading to the development of IgE-mediated food allergy.

It is 20 years since the 10 Warning Signs of primary immunodeficiency (PID) were first published and with over 180 PIDs now identified it is timely to evaluate their effectiveness, given the broadening clinical spectrum of PID. Two recent studies have sought to define the features that best identify patients with PID and compare these with the 10 Warning Signs. They suggest the 10 Warning Signs discriminate poorly between those with and without PID, and that other features identify about one-third of patients with PID in whom none of the 10 Warning Signs was present. Recent literature describes the diverse presenting features that may assist in more accurately identifying those with PID. Further development and refinement of early warning signs in light of the growing knowledge of how PIDs manifest clinically may allow relatively simple yet effective guidelines targeted at different groups to better detect PID.

This open-label, non-randomized, multicenter trial (Registration: NCT 03661736) aimed to assess if an amino acid-based formula (AAF) supplemented with two human milk oligosaccharides (HMO) supports normal growth and is well tolerated in infants with a cow’s milk protein allergy (CMPA). Term infants aged 1–8 months with moderate-to-severe CMPA were enrolled. The study formula was an AAF supplemented with 2′-fucosyllactose (2′-FL) and lacto-N-neotetraose (LNnT). Infants were fed the study formula for 4 months and were offered to remain on the formula until 12 months of age. Tolerance and safety were assessed throughout the trial. Out of 32 infants (mean age 18.6 weeks; 20 (62.5%) male), 29 completed the trial. During the 4-month principal study period, the mean weight-for-age Z score (WAZ) increased from −0.31 at the baseline to +0.28 at the 4-months’ follow-up. Linear and head growth also progressed along the WHO child growth reference, with a similar small upward trend. The formula was well tolerated and had an excellent safety profile. When comparing the microbiome at the baseline to the subsequent visits, there was a significant on-treatment enrichment in HMO-utilizing bifidobacteria, which was associated with a significant increase in fecal short-chain fatty acids. In addition, we observed a significant reduction in the abundance of fecal Proteobacteria, suggesting that the HMO-supplemented study formula partially corrected the gut microbial dysbiosis in infants with CMPA.