Search

Sulforaphane has been investigated in human pathologies and preclinical models of airway diseases. To provide further mechanistic insights, we explored L-sulforaphane (LSF) in the ovalbumin (OVA)-induced chronic allergic airways murine model, with key hallmarks of asthma. Histological analysis indicated that LSF prevented or reversed OVA-induced epithelial thickening, collagen deposition, goblet cell metaplasia, and inflammation. Well-known antioxidant and anti-inflammatory mechanisms contribute to the beneficial effects of LSF. Fourier transform infrared microspectroscopy revealed altered composition of macromolecules, following OVA sensitization, which were restored by LSF. RNA sequencing in human peripheral blood mononuclear cells highlighted the anti-inflammatory signature of LSF. Findings indicated that LSF may alter gene expression via an epigenetic mechanism which involves regulation of protein acetylation status. LSF resulted in histone and α-tubulin hyperacetylation in vivo, and cellular and enzymatic assays indicated decreased expression and modest histone deacetylase (HDAC) inhibition activity, in comparison with the well-known pan-HDAC inhibitor suberoylanilide hydroxamic acid (SAHA). Molecular modeling confirmed interaction of LSF and LSF metabolites with the catalytic domain of metal-dependent HDAC enzymes. More generally, this study confirmed known mechanisms and identified potential epigenetic pathways accounting for the protective effects and provide support for the potential clinical utility of LSF in allergic airways disease. [ABSTRACT FROM AUTHOR]

In mice, the maternal microbiome influences fetal immune development and postnatal allergic outcomes. Westernized populations have high rates of allergic disease and low rates of gastrointestinal carriage of Prevotella, a commensal bacterial genus that produces short chain fatty acids and endotoxins, each of which may promote the development of fetal immune tolerance. In this study, we use a prebirth cohort (n = 1064 mothers) to conduct a nested case-cohort study comparing 58 mothers of babies with clinically proven food IgE mediated food allergy with 258 randomly selected mothers. Analysis of the V4 region of the 16S rRNA gene in fecal samples shows maternal carriage of Prevotella copri during pregnancy strongly predicts the absence of food allergy in the offspring. This association was confirmed using targeted qPCR and was independent of infant carriage of P. copri. Larger household size, which is a well-established protective factor for allergic disease, strongly predicts maternal carriage of P. copri. Incidence of food allergy in westernized populations is associated with low abundance of Prevotella. Here, the authors analyse the microbiome of a mother-infant prebirth cohort and find that maternal carriage, but not infant carriage, of P. copri during pregnancy predicts the absence of food allergy in the offspring. [ABSTRACT FROM AUTHOR]

IgE-mediated peanut allergic is common, often serious, and usually lifelong. Not all individuals who produce peanut-specific IgE will react upon consumption of peanut and can eat the food without adverse reactions, known as sensitized tolerance. Here, we employ high-dimensional mass cytometry to define the circulating immune cell signatures associated with sensitized tolerance and clinical allergy to peanut in the first year of life. Key features of clinical peanut allergic are increased frequency of activated B cells (CD19hiHLADRhi), overproduction of TNFα and increased frequency of peanut-specific memory CD4 T cells. Infants with sensitized tolerance display reduced frequency but hyper-responsive naive CD4 T cells and an increased frequency of plasmacytoid dendritic cells. This work demonstrates the utility and power of high-dimensional mass cytometry analysis to interrogate the cellular interactions that are associated with allergic sensitization and clinical food allergy in the first year of life. Food allergy is triggered by IgE, but some individuals are not allergic to peanuts despite making peanut-specific IgE, and are considered peanut-tolerant. Here, the authors identify differences in blood immune cell composition of peanut-allergic and tolerant infants using mass cytometry, which may help uncover the mechanism of allergic tolerance. [ABSTRACT FROM AUTHOR]

Beginning in 1970, a committee was constituted under the auspices of the World Health Organization (WHO) to catalog primary immunodeficiencies. Twenty years later, the International Union of Immunological Societies (IUIS) took the remit of this committee. The current report details the categorization and listing of 354 (as of February 2017) inborn errors of immunity. The growth and increasing complexity of the field have been impressive, encompassing an increasing variety of conditions, and the classification described here will serve as a critical reference for immunologists and researchers worldwide. [ABSTRACT FROM AUTHOR]

Since the 1990s, the International Union of Immunological Societies (IUIS) PID expert committee (EC), now called Inborn Errors of Immunity Committee, has published every other year a classification of the inborn errors of immunity. This complete catalog serves as a reference for immunologists and researchers worldwide. However, it was unadapted for clinicians at the bedside. For those, the IUIS PID EC is now publishing a phenotypical classification since 2013, which proved to be more user-friendly. There are now 320 single-gene inborn errors of immunity underlying phenotypes as diverse as infection, malignancy, allergy, auto-immunity, and auto-inflammation. We herein propose the revised 2017 phenotypic classification, based on the accompanying 2017 IUIS Inborn Errors of Immunity Committee classification. [ABSTRACT FROM AUTHOR]

Unlabelled: The fundamental abnormality in asthma is inflammation of the airways. T-helper 2 (Th2) lymphocytes are the key orchestrators of this inflammation, initiating and propagating inflammation through the release of Th2 cytokines. Interleukins(IL)-4, IL-5 and IL-13. IL-4 and IL-13 promote IgE production by B-cells, mast cell growth and differentiation, and upregulate adhesion molecule expression on vascular endothelium. IL-4 also promotes differentiation of uncommitted Th0 lymphocytes into Th2 lymphocytes. IL-5 promotes differentiation and recruitment of eosinophils and activates them to degranulate within tissues, resulting in damage to the respiratory epithelium. Current treatment of childhood asthma relies predominantly on corticosteroids that have nonspecific anti-inflammatory activity and are associated with potential side-effects. Novel therapies that selectively target the underlying immunopathogenesis hold great promise. Disruption of the Th2 lymphocyte induced allergic inflammatory response represents a novel approach to selectively inhibiting allergic inflammation at its origin. Possible therapeutic interventions include inhibition of Th2 response (CpG oligonucleotides, vaccination, CTLA4Ig fusion protein, IL-12, IL-10), inhibition of IgE (the anti-IgE antibody rhuMAb-E25 omalizumab, which is undergoing clinical trials), inhibition of mediator activity (leukotriene modifiers, which are approved for use in childhood asthma), and targeting Th2 cytokines (soluble IL-4 receptors, IL-5 antibody, IL-13). Other therapeutic approaches targeting downstream events in the allergic inflammatory cascade are also currently under investigation (chemokine receptors CCR3, tryptase inhibitors, and inhibitors of cyclic AMP-specific phosphodiesterase 4).Conclusion: As we further understand the pathophysiology of asthma, the potential to develop novel treatments increases. This paper addresses current possible new treatments for the future. [ABSTRACT FROM AUTHOR]

Maternal immune dysregulation seems to affect fetal or postnatal immune development. Preeclampsia is a pregnancy-associated disorder with an immune basis and is linked to atopic disorders in offspring. Here we show reduction of fetal thymic size, altered thymic architecture and reduced fetal thymic regulatory T (Treg) cell output in preeclamptic pregnancies, which persists up to 4 years of age in human offspring. In germ-free mice, fetal thymic CD4+ T cell and Treg cell development are compromised, but rescued by maternal supplementation with the intestinal bacterial metabolite short chain fatty acid (SCFA) acetate, which induces upregulation of the autoimmune regulator (AIRE), known to contribute to Treg cell generation. In our human cohorts, low maternal serum acetate is associated with subsequent preeclampsia, and correlates with serum acetate in the fetus. These findings suggest a potential role of acetate in the pathogenesis of preeclampsia and immune development in offspring. Maternal immunological dysregulation might affect the immunological development of the fetus. Here the authors show that decreased maternal acetate is associated with preeclampsia, impaired fetal thymic output and regulatory T cell development. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Carbohydrate vaccines: developing sweet solutions to sticky situations," by R. D. Astronomo and D. R. Burton in the 2010 issue.