RÉSUMÉ
Background: Massive eosinophil infiltration into the esophagus is associated with subepithelial fibrosis and esophageal stricture in patients with eosinophilic esophagitis (EoE). However, the pathogenesis of esophageal fibrosis remains unclear. Objective: We sought to elucidate the cellular and molecular mechanisms underlying the induction of esophageal fibrosis. Methods: We established a murine model of EoE accompanied by fibrotic responses following long-term intranasal administration of house dust mite antigen. Using this murine model, we investigated the characteristics of immune cells infiltrating the fibrotic region of the inflamed esophagus using flow cytometry and histological analyses. We also analyzed the local inflammatory sites in the esophagus of patients with EoE using single-cell RNA sequencing, flow cytometry, and immunohistochemistry. Results: Enhanced infiltration of both amphiregulin-producing and IL-5-producing TH2 cells was detected in the fibrotic area of the esophagus in mice subjected to repeated house dust mite exposure. Deletion of amphiregulin in CD4+ T cells ameliorates esophageal fibrosis. An analysis of human esophageal biopsy samples showed that the infiltration of amphiregulin-producing CD4+ T cells was higher in patients with EoE than in control patients. Furthermore, the number of infiltrated amphiregulin-producing CD4+ T cells was associated with the degree of esophageal fibrosis in patients with EoE. Conclusions: Amphiregulin, produced by TH2 cells, contributes to esophageal fibrosis in EoE and may be a therapeutic target.
Sujet(s)
Conjonctivite allergique , Pièges extracellulaires , Kératoconjonctivite , Humains , ConjonctiveRÉSUMÉ
Uncontrolled type 2 immunity by type 2 helper T (Th2) cells causes intractable allergic diseases; however, whether the interaction of CD4+ T cells shapes the pathophysiology of allergic diseases remains unclear. We identified a subset of Th2 cells that produced the serine proteases granzyme A and B early in differentiation. Granzymes cleave protease-activated receptor (Par)-1 and induce phosphorylation of p38 mitogen-activated protein kinase (MAPK), resulting in the enhanced production of IL-5 and IL-13 in both mouse and human Th2 cells. Ubiquitin-specific protease 7 (USP7) regulates IL-4-induced phosphorylation of STAT3, resulting in granzyme production during Th2 cell differentiation. Genetic deletion of Usp7 or Gzma and pharmacological blockade of granzyme B ameliorated allergic airway inflammation. Furthermore, PAR-1+ and granzyme+ Th2 cells were colocalized in nasal polyps from patients with eosinophilic chronic rhinosinusitis. Thus, the USP7-STAT3-granzymes-Par-1 pathway is a potential therapeutic target for intractable allergic diseases.
Sujet(s)
Hypersensibilité , Lymphocytes auxiliaires Th2 , Humains , Animaux , Souris , Granzymes/génétique , Granzymes/métabolisme , Interleukine-5/métabolisme , Ubiquitin-specific peptidase 7/métabolisme , Inflammation/métabolisme , Différenciation cellulaire , Facteur de transcription STAT-3/génétique , Facteur de transcription STAT-3/métabolismeRÉSUMÉ
Allergic diseases arise from a complex interplay between immune system and environmental factors. A link between the pathogenesis of allergic diseases and type 2 immune responses has become evident, with conventional and pathogenic type 2 helper T (Th2) cells involved in both. Recently, there has been a significant development in therapeutic agents for allergic diseases: IL-5 and IL-5 receptor antagonists, Janus kinase (JAK) inhibitors, and sublingual immunotherapy (SLIT). Mepolizumab, an IL-5, and Benralizumab, an IL-5 receptor antagonist, modulate eosinophilic inflammation mediated by IL-5-producing Th2 cells. Delgocitinib shows that JAK-associated signaling is essential for the inflammatory reaction in atopic dermatitis, one of the common allergic diseases. SLIT has a significant effect on allergic rhinitis by reducing pathogenic Th2 cell numbers. More recently, novel molecules that are involved in pathogenic Th2 cell-mediated allergic diseases have been identified. These include calcitonin gene-related peptide (CGRP), reactive oxygen species (ROS) scavenging machinery regulated by the Txnip-Nrf2-Blvrb axis, and myosin light chain 9 (Myl9), which interacts with CD69. This review provides an updated view of the recent research on treatment of allergic diseases and their cause: conventional and pathogenic Th2 cells.
Sujet(s)
Eczéma atopique , Hypersensibilité , Humains , Cytokines , Interleukine-5/usage thérapeutique , Hypersensibilité/traitement médicamenteux , Lymphocytes auxiliaires Th2RÉSUMÉ
Allergic conjunctivitis is a chronic inflammatory disease that is characterized by severe itch in the conjunctiva, but how neuro-immune interactions shape the pathogenesis of severe itch remains unclear. We identified a subset of memory-type pathogenic Th2 cells that preferentially expressed Il1rl1-encoding ST2 and Calca-encoding calcitonin-gene-related peptide (CGRP) in the inflammatory conjunctiva using a single-cell analysis. The IL-33-ST2 axis in memory Th2 cells controlled the axonal elongation of the peripheral sensory C-fiber and the induction of severe itch. Pharmacological blockade and genetic deletion of CGRP signaling in vivo attenuated scratching behavior. The analysis of giant papillae from patients with severe allergic conjunctivitis revealed ectopic lymphoid structure formation with the accumulation of IL-33-producing epithelial cells and CGRP-producing pathogenic CD4+ T cells accompanied by peripheral nerve elongation. Thus, the IL-33-ST2-CGRP axis directs severe itch with neuro-reconstruction in the inflammatory conjunctiva and is a potential therapeutic target for severe itch in allergic conjunctivitis.
Sujet(s)
Conjonctivite allergique , Neuropeptides , Humains , Interleukine-33/génétique , Protéine-1 analogue au récepteur de l'interleukin-1/génétique , Peptide relié au gène de la calcitonine , Conjonctivite allergique/anatomopathologie , Lymphocytes auxiliaires Th2 , Calcitonine , Prurit/anatomopathologie , Conjonctive/anatomopathologie , NeuronesSujet(s)
Hypersensibilité , Lymphocytes auxiliaires Th2 , Cytokines , Humains , Mémoire immunologique , InflammationRÉSUMÉ
To clarify the early alterations of gene expression using a mouse model of glaucoma filtration surgery, we carried out microarray expression analysis. Using BALB/c mice, a filtration surgery model was made by incision of the limbal conjunctiva, followed by the insertion of a 33G needle tip into the anterior chamber, and 11-0 nylon sutures. Subgroups of mice were treated intraoperatively with 0.4 mg/ml mitomycin-C (MMC). At day 3 after surgery the bleb was maintained. The bleb region tissue was sampled 3 days after the filtration surgery, and gene expression analysis was carried out using a mouse Agilent 8 × 60 K array. We found 755 hyperexpressed transcripts in the bleb region compared to control conjunctiva. The hyperexpressed transcripts included epithelial cell metaplasia-related (Il1b, Krt16, Sprr1b), inflammation-related (Ccl2, Il6) and wound healing-related (Lox, Timp1) genes. We also found downregulation of a goblet cell marker gene (Gp2) in the bleb conjunctiva. MMC treatment suppressed elastin (Eln) gene expression and enhanced keratinization-related gene expression (Krt1, Lor) in the bleb region. Our results suggest the importance of epithelial wound healing after filtration surgery, and this filtration surgery model will be a useful tool for further pathophysiological analysis.