Dysregulated invertebrate tropomyosin–dectin-1 interaction confers susceptibility to allergic diseases

Abstract

The key factors underlying the development of allergic diseases—the propensity for a minority of individuals to develop dysfunctional responses to harmless environmental molecules—remain undefined. We report a pathway of immune counter-regulation that suppresses the development of aeroallergy and shrimp-induced anaphylaxis. In mice, signaling through epithelially expressed dectin-1 suppresses the development of type 2 immune responses through inhibition of interleukin-33 (IL-33) secretion and the subsequent recruitment of IL-13–producing innate lymphoid cells. Although this homeostatic pathway is functional in respiratory epithelial cells from healthy humans, it is dramatically impaired in epithelial cells from asthmatic and chronic rhinosinusitis patients, resulting in elevated IL-33 production. Moreover, we identify an association between a single-nucleotide polymorphism (SNP) in the dectin-1 gene loci and reduced pulmonary function in two cohorts of asthmatics. This intronic SNP is a predicted eQTL (expression quantitative trait locus) that is associated with reduced dectin-1 expression in human tissue. We identify invertebrate tropomyosin, a ubiquitous arthropod-derived molecule, as an immunobiologically relevant dectin-1 ligand that normally serves to restrain IL-33 release and dampen type 2 immunity in healthy individuals. However, invertebrate tropomyosin presented in the context of impaired dectin-1 function, as observed in allergic individuals, leads to unrestrained IL-33 secretion and skewing of immune responses toward type 2 immunity. Collectively, we uncover a previously unrecognized mechanism of protection against allergy to a conserved recognition element omnipresent in our environment.

The mammalian mycobiome: A complex system in a dynamic relationship with the host

“…In support of a role for intestinal fungi in modulating the risk of allergic disease in humans, Candida and Rhodotorula species were found to be enriched in the fecal microbiotas of neonates who went on to develop multisensitized atopy and asthma (Fujimura et al, ). A recent study also identified an SNP in CLEC7A that is associated with reduced dectin‐1 expression and diminished lung function in asthmatic subjects (Gour et al, ). While the authors linked the CLEC7A polymorphism to impaired immune responses to tropomyosin, a conserved invertebrate determinant, it seems plausible that anomalous sensing of symbiotic fungi and the ensuing alterations in the mycobiota might also be a contributing factor (Gour et al, ).…”

Future research trends in understanding the mechanisms underlying allergic diseases for improved patient care

“…However, very few studies on why only susceptible individuals raise an allergic immune response have come forward. They indicate that genetic susceptibility is based on altered signal processing and mutations of pattern recognition receptors How to expand the understanding of allergens and allergic sensitization? Provide structures of homologous allergens to study cross‐reactivity Provide structures of hypoallergenic variants to visualize the effects of allergen design Provide structures for all major allergen types Provide structures for allergens complexed with IgE Fabs, IgG Fabs, or single‐chain antibodies Provide structures of allergens with their ligands Perform studies on the effect of the biological function of allergens on innate immune cells Perform studies on signal transduction initiated by allergens in innate immune cells Define pattern recognition receptors, membrane constituents, or other cellular binding partners of allergens Define “susceptibility to allergic sensitization” at the molecular and mechanistic level …”

“…30 Unequivocally, these authors [27][28][29][30] argue that it is a common misconception to regard allergens as generally harmless environmental substances. Allergens interact with innate immune receptors (eg, TLR4, 31 protease-activated receptor-2, 32 dectin-1 33 ), disrupt the integrity of membranes (eg, phospholipase A2, 34,35 defensins 36,37 ), or degrade connective tissues (eg, hyaluronidases 38 ). However, very few studies on why only susceptible individuals raise an allergic immune response have come forward.…”

“…They indicate that genetic susceptibility is based on altered signal processing 39 and mutations of pattern recognition receptors. 33 F I G U R E 1 Molecular mechanisms in allergic inflammation. Epithelial leakiness and activation and their proinflammatory cytokine and chemokine (TNF-α, IL-13, TSLP, IL-25, IL-33) production induce inflammation and contribute to the Th2 response.…”

Laser-facilitated epicutaneous immunotherapy with hypoallergenic beta-glucan neoglycoconjugates suppresses lung inflammation and avoids local side effects in a mouse model of allergic asthma

“…As a prominent member of the CTL family, Dectin-1 is functionally equivalent in mice and humans 8 . It recognizes β-glucans and some proteins such a tropomyosin 9 , and upon ligand binding activates innate immune responses. Murine dectin-1 is expressed on macrophages, neutrophils and dermal dendritic cells 10 .…”