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Pam3CSK4 induces Th1/regulatory T cell responses, and as such, is a valid candidate adjuvant for sublingual allergy vaccines.

Background: IL-10-inducing adjuvants could enhance the efficacy of allergy vaccines in establishing allergen-specific tolerance.The aim of this study wasto identify such adjuvants using in vitro cultures of human and murine cells and to evaluate them in a therapeutic murine model of sublingual immunotherapy (SLIT). Methods: Adjuvants stimulating IL-10 gene expression by human or murine immune cells were tested sublingually in BALB/c mice sensitized to ovalbumin (OVA), assessing the reduction in airway hyperresponsiveness (AHR) by whole-body plethysmography. The induction of regulatory T cells (T_reg) was evaluated using phenotypic and functional assays. T-cell proliferation in cervical lymph nodes (LNs) was assessed following intravenous transfer of CFSE-labelled OVA-specific T cells and FACS analysis. Results: A combination of 1,25-dihydroxyvitamin D3 plus dexamethasone (VitD3/Dex) as well as Lactobacillus plantarum were found to induce IL-10 production by human and murine dendritic cells (DCs). The former inhibits LPS-induced DC maturation, whereas L. plantarum induces DC maturation. Following stimulation with VitD3/Dex-pretreated DCs, CD4+ naïve T cells exhibit a T_reg profile.In contrast, a Th1/T_reg pattern of differentiation is observed in the presence of DCs treated with L. plantarum. Both adjuvants significantly enhance SLIT efficacy in mice, in association with either induction of Foxp3+ T_reg cells (for VitD3/Dex) or proliferation of OVA-specific T cells in cervical LNs (for L. plantarum). Conclusions: Both VitD3/Dex and L. plantarum polarize naïve T cells towards IL-10-expressing T cells, through distinct mechanisms. As adjuvants, they both enhance SLIT efficacy in a murine asthma model.

GATA2 (n 5 1), and 22q11.2 (n 5 4) mutations and deletions, suggesting improved clinical utility of our comprehensively designed target capture.CVID is the most common PID, representing a heterogeneous group of hypogammaglobulinemias of largely unknown molecular defects. Our system established a genetic diagnosis of 22q11.2 deletion syndrome (22q11.2DS) in a patient with CVID in accordance with a previous study, reporting that a subgroup of patients with adult 22q11.2DS could have hypogammaglobinemia. 9 Moreover, the incidence of this syndrome is relatively high compared with that of other PIDs. Therefore patients with CVID should always be evaluated for the possibility of 22q11.2DS. In this context our customized design to capture this chromosomal lesion is useful.Recent studies revealed that newborn screening for T-cell receptor excision circles can efficiently detect infants with severe combined immunodeficiency and complete DiGeorge syndrome (mainly because of 22q11.2DS). 10 Our comprehensive genetic diagnostic system covering virtually all of the PID genes and 22q11.2DS, would provide an effective genetic confirmation test for infants with positive results on T-cell receptor excision circle screening tests, who require precise and rapid genetic diagnoses for appropriate clinical management.In summary, we developed an NGS-based comprehensive, rapid, and efficient PID diagnostic system that could become a first-line genetic analysis of PID-suspected patients, including infants with positive newborn screening results.We thank the patients and family who made this study possible by providing clinical samples. We also thank Ms Yoshie Miura, Ms Yuko Imanishi, and Ms Hiroe Namizaki for their valuable assistance. We acknowledge the Division for Medical Research Engineering, Nagoya University Graduate School of Medicine, for technical support for NGS. Finally, we thank Enago (www.enago.jp) for the English-language review.

Sublingual allergen-specific immunotherapy (SLIT) is a safe and efficacious treatment for type 1 respiratory allergies. Herein, we investigated the key subset(s) of antigen-presenting cells (APCs) involved in antigen/allergen capture and tolerance induction during SLIT. Following sublingual administration, fluorochrome-labeled ovalbumin (OVA) is predominantly captured by oral CD11b⁺CD11c⁻ cells that migrate to cervical lymph nodes (CLNs) and present the antigen to naive CD4⁺ T cells. Conditional depletion with diphtheria toxin of CD11b⁺, but not CD11c⁺ cells, in oral tissues impairs CD4⁺ T-cell priming in CLNs. In mice with established asthma to OVA, specific targeting of the antigen to oral CD11b⁺ cells using the adenylate cyclase vector system reduces airway hyperresponsiveness (AHR), eosinophil recruitment in bronchoalveolar lavages (BALs), and specific Th2 responses in CLNs and lungs. Oral CD11b⁺CD11c⁻ cells resemble tolerogenic macrophages found in the lamina propria (LP) of the small intestine in that they express the mannose receptor CD206, as well as class-2 retinaldehyde dehydrogenase (RALDH2), and they support the differentiation of interferon-γ/interleukin-10 (IFNγ/IL-10)-producing Foxp3⁺ CD4⁺ regulatory T cells. Thus, among the various APC subsets present in oral tissues of mice, macrophage-like cells play a key role in tolerance induction following SLIT.

Different memory CD4(+) T cell responses are elicited in the context of chronic vs. seasonal stimulation with the allergen(s). The heterogeneity in the patterns of CD4(+) T cell responses observed in patients allergic to HDMs should be taken into account for specific immunotherapy.