News Beyond Our Pages
Authors: Marc E. Rothenberg, Jean Bousquet
Journal: Journal of Allergy and Clinical Immunology (2020)

GATA3 is a predominant transcription factor driving TH2 immunity, but the molecular mechanisms underlying its regulation in vivo are incompletely understood. He at al (J Exp Med 2020 Jul 6;217(7). https://pubmed.ncbi.nlm.nih.gov/32399548/) discovered an unexpected critical regulatory role for the transcriptional repressor Blimp-1. Blimp-1 was markedly induced by the anti-inflammatory cytokine IL-10, but not the proinflammatory cytokines IL-6 or IL-21, and indirectly promoted GATA3 expression by inhibiting the known GATA3 repressor Bcl-6. Notably, Blimp-1 was required for development of TH2 responses to aeroallergens but did not affect the response to systemically delivered allergens or production of IgE. Overall, these results demonstrate that Blimp-1 promotes allergic airway disease through direct action on lung T cells. We asked senior author Amanda C. Poholek, PhD, of the University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, to comment on the study. She writes: “Our study highlights an unappreciated signaling pathway where IL-10 induces Blimp-1 in T cells to drive TH2 cells in the lung and promote inflammation. This pathway was specific to allergens introduced via the lung, suggesting the existence of tissue-specific pathways driving TH2 cell differentiation which has important therapeutic implications for allergic asthma.” Autosomal dominant hyper-IgE syndrome (AD-HIES) is classically thought to be a result of dominant negative STAT3 mutations. Béziat et al (J Exp Med 2020;217(6). https://pubmed.ncbi.nlm.nih.gov/32207811/) have identified dominant-negative mutations in IL6ST, which encodes the gp130 signaling receptor subunit used by members of the IL-6 cytokine family, in patients without STAT3 mutations and with the classical AD-HIES presentation of skin and lung infections, severe allergy, elevated IgE levels, and skeletal abnormalities. The mutations led to loss of all tyrosine residues that normally allow for STAT3 recruitment and resulted in impaired responsiveness to multiple IL-6 cytokine family members in primary cells ex vivo. Overall, these findings expand the known causes of hyper-IgE syndrome, autosomal dominant STAT3, autosomal recessive ZNF341, and autosomal recessive partial IL6ST deficiencies, to include autosomal dominant IL6ST deficiency. We asked first author Vivien Béziat, PhD, of the Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale (INSERM), in Paris, France, to comment on the study. He writes: “We show that specific heterozygous truncating mutations in IL6ST cause hyper-IgE syndrome. These patients seem unusually susceptible to develop severe sequel following lung infections and should be managed accordingly.” Scientists have known for years that certain humoral factors may mediate the metabolic effects of exercise. Knudsen et al (Science 2020;368(6490). https://pubmed.ncbi.nlm.nih.gov/32355002/) have identified that IL-13 protein is produced by immune cells, such as type 2 innate lymphoid cells in skeletal muscle during exercise and increases endurance capacity. IL-13 signaling induced metabolic reprogramming including promoting fatty acid oxidation and mitochondrial respiration to preserve glycogen, with downstream improvements in running distance, glucose tolerance, and mitochondrial activity. Notably, IL-13 did not exert appreciable effects in resting muscle. In total, these findings show that IL-13 has a potential important role in the muscle during exercise and underscore the effects of immune responses on tissue metabolic fitness. We asked senior author Chih-Hao Lee, PhD, of the Harvard T.H. Chan School of Public Health, Boston, Massachusetts, to comment on the study. He writes: “Although well-recognized for its role in allergic reactions, our study suggests that localized, physiological levels of IL-13 orchestrate an adaptive response to the increasing energetic demand of exercising muscle, highlighting the importance of interplay between immune and metabolic signaling in maintaining tissue homeostasis. Anti-IL-13 antibodies have been evaluated in clinical trials for asthma therapy. It will be interesting to see whether those biologics affect muscle function.” Dietary antigen-specific IgA is thought to be tolerogenic, but the regulation of its production is poorly understood. Food-specific gut IgA is presumed to be produced during homeostasis upon repeated dietary exposure. However, Zhang et al (Sci Immunol 2020;5(47). https://pubmed.ncbi.nlm.nih.gov/32385053/) identified that daily food exposure in the absence of a mucosal adjuvant only induced low-level production of cross-reactive IgA. Further, when adjuvant was present, generation of peanut-specific IgA was independent of follicular TH cells but still required T cells and CD40L. This is in contrast to generation of food-specific IgG1 and IgE, which required follicular TH cells. Collectively, these results highlight the differences in the regulation of food-specific IgA and IgE production, raising the exciting possibility of therapeutic isotype-selective modulation of antibodies to dietary antigens. We asked senior author Stephanie C. Eisenbarth, MD, PhD, of Yale University School of Medicine, Cambridge, Massachusetts, to comment on the study. She writes: “These findings on IgA presented in this paper surprised us on 2 fronts: first, we detected highly specific and high-titer gut IgA to peanut in healthy nonallergic adults, yet mice failed to make a similar IgA response unless peanut was accompanied by an adjuvant. This raises the question of how humans make IgA to dietary antigens. Second, most studies on IgA to bacteria or other antigens have concluded that T follicular helper (Tfh) cells drive this antibody response, yet when we eliminated Tfh cells in mice, IgA production to peanut was unimpaired. We are working to address the questions raised by both of these unexpected findings.” Although 17q12-21 is a major risk locus for asthma, the culprit gene and underlying disease mechanisms remain unclear. Previous studies implicating ORMDL sphingolipid biosynthesis regulator 3 (ORMDL3) in asthma have predominantly focused on subjects with European ancestry, Ober et al (Lancet Respir Med 2020;8:482-92. https://doi.org/10.1016/S2213-2600(20)30011-4) have now re-examined this locus to assess for ancestry-specific differences. Consistent with prior studies, broad association with increased asthma risk were found within the European ancestry cohort. In contrast, only 2 single nucleotide polymorphisms (SNPs) were significant in the African ancestry cohort. Both SNPs regulated the expression of gasdermin B, but not ORMDL3, in primary cells derived from patients with African ancestry. These collective results suggest gasdermin B, a protein involved in epithelial apoptosis, is the leading asthma-related gene within the 17q21 locus. Further investigation is required to clarify the underlying disease mechanism and reconcile these findings with prior studies implicating ORMDL3. Figure attribution by user M. Kamran Ikram et al / CC BY (https://creativecommons.org/licenses/by/2.5). News items were written by medical writer Jared Travers, MD, PhD. News items were written by medical writer Jared Travers, MD, PhD.