Background The genetic etiologies of the hyper-IgE syndromes are diverse. Approximately 60-70% of patients with hyper-IgE syndrome have dominant mutations in STAT3, and a single patient was reported to have a homozygous TYK2 mutation. In the remaining hyper-IgE syndrome patients, the genetic etiology has not yet been identified. Methods We performed genome-wide single nucleotide polymorphism analysis for nine subjects with autosomal recessive hyper-IgE syndrome to locate copy number variations and homozygous haplotypes. Homozygosity mapping was performed with twelve subjects from seven additional families. The candidate gene was analyzed by genomic and cDNA sequencing to identify causative alleles in a total of 27 patients with autosomal recessive hyper-IgE syndrome. Findings Subtelomeric microdeletions were identified in six subjects at the terminus of chromosome 9p. In all patients the deleted interval involved DOCK8, encoding a protein implicated in the regulation of the actin cytoskeleton. Sequencing of subjects without large deletions revealed 16 patients from nine unrelated families with distinct homozygous mutations in DOCK8 causing premature termination, frameshift, splice site disruption, single exon- and micro-deletions. DOCK8 deficiency was associated with impaired activation of CD4+ and CD8+ T cells. Interpretation Autosomal recessive mutations in DOCK8 are responsible for many, though not all, cases of autosomal recessive hyper-IgE syndrome. DOCK8 disruption is associated with a phenotype of severe cellular immunodeficiency characterized by susceptibility to viral infections, atopic eczema, defective T cell activation and TH17 cell differentiation; and impaired eosinophil homeostasis and dysregulation of IgE.

Background Commensal microbiota play a critical role in maintaining oral tolerance. The effect of food allergy on the gut microbial ecology remains unknown. Objective We sought to establish the composition of the gut microbiota in experimental food allergy and its role in disease pathogenesis. Methods Food allergy–prone mice with a gain-of-function mutation in the IL-4 receptor α chain (Il4raF709) and wild-type (WT) control animals were subjected to oral sensitization with chicken egg ovalbumin (OVA). Enforced tolerance was achieved by using allergen-specific regulatory T (Treg) cells. Community structure analysis of gut microbiota was performed by using a high-density 16S rDNA oligonucleotide microarrays (PhyloChip) and massively parallel pyrosequencing of 16S rDNA amplicons. Results OVA-sensitized Il4raF709 mice exhibited a specific microbiota signature characterized by coordinate changes in the abundance of taxa of several bacterial families, including the Lachnospiraceae, Lactobacillaceae, Rikenellaceae, and Porphyromonadaceae. This signature was not shared by similarly sensitized WT mice, which did not exhibit an OVA-induced allergic response. Treatment of OVA-sensitized Il4raF709 mice with OVA-specific Treg cells led to a distinct tolerance-associated signature coincident with the suppression of the allergic response. The microbiota of allergen-sensitized Il4raF709 mice differentially promoted OVA-specific IgE responses and anaphylaxis when reconstituted in WT germ-free mice. Conclusion Mice with food allergy exhibit a specific gut microbiota signature capable of transmitting disease susceptibility and subject to reprogramming by enforced tolerance. Disease-associated microbiota may thus play a pathogenic role in food allergy.

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Adoptive transfer of mature T cells (ATMTC) through bone marrow (BM) transplantation, first attempted over 20 years ago, has recently emerged as a successful therapy for complete 22q deletion syndrome (22qDS). This provides a potential option to thymic transplantation (TT) for immune reconstitution in 22qDS. Compared to thymic transplant, ATMTC is an easier procedure to accomplish and is available at more centers. However, there are differences in the nature of the T-cell reconstitution that results. Predictably, more naïve T cells and recent thymic emigrants are present in patients treated with thymus transplant. There are no significant differences in mortality between the two procedures, but the number of patients is too limited to conclude that the procedures are equally effective. Adoptive transfer should be pursued as a reasonable treatment for 22qDS patients requiring immune reconstitution when thymus transplant is not available.

The current global epidemic of atopy and asthma has been related to the changes in environmental exposures brought about by the development and expansion of industrialized societies. This article reviews the evidence supporting the fundamental role of air pollutants in fostering allergic inflammation of the airways, with emphasis on the molecular and genetic pathways that link ambient particulate matter (PM) exposure to the induction of proinflammatory changes and proallergic effects in the respiratory tract. We propose that the link between PM exposure and proallergic effects involves organic PM components that generate oxygen radicals capable of perturbing the redox equilibrium mucosal immune cells.

Following completion of clinical trials for food allergy (FA) therapies, many patients/families wish to maintain desensitization. We describe the results of follow-up of participants transitioned to real food equivalents following epicutaneous (EPIT) and oral immunotherapy (OIT) clinical trials. METHODS: Post-study participants were offered the option to transition to daily ingestion of real food equivalents based upon their OFC outcomes upon study completion. Charts of those who transitioned to ingestion of daily doses of real food equivalents from January 2016-May 2019 were reviewed. Participants without recent follow-up were contacted by telephone. This study was IRB approved. RESULTS: Thirty-seven patients (65% male; median age 8.8 years, range 4-24 years) from 8 studies (milk and peanut EPIT; egg, wheat, and peanut OIT; multi-food OIT+omalizumab) underwent transition to ingestion of daily doses of real food equivalents for milk, baked/lightly-cooked egg, wheat, peanut, tree nuts, sesame, and/or shrimp; 35 patients had follow-up. Thirty-one patients continued dosing for at least one year or were confirmed to be actively dosing if transitioned in the past year, with 22 patients contacted in the prior 4 months confirmed to be actively dosing (median of 2.6 years). Five patients discontinued dosing after a median of 0.2 years, with reasons including dosing-related side effects (gastrointestinal, hives, wheezing; n53), eosinophilic esophagitis (n51), or unknown (n51). CONCLUSIONS: Most post-study participants (88.6%) who transitioned to real food equivalents continued dosing long-term. This suggests that transitioning to real food equivalents may be a desirable and sustainable option for patients/families wishing to maintain desensitization achieved during FA therapeutic studies.

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