Involvement of Mast Cells in Eosinophilic Esophagitis

Abstract

RATIONALE: Allergen specific immunotherapy (SIT), the only disease modifying treatment for allergic disorders, suppresses allergic manifestations by poorly characterized mechanism(s). Recently, we demonstrated that the immunoregulatory enzyme indoleamine2,3-dioxygenase(IDO) plays a role in tolerance induction during SIT. B7-CTLA4 interaction has been shown to activate the alternative NF-kB pathway leading to increased IDO expression in DCs. Here, we test whether activation of the alternative NF-kB pathway by B7 ligation is critically required for and limiting in the suppression of asthma manifestations by SIT in a mouse model. METHODS: BALB/c mice were sensitized with OVA/Alum followed by 3 subcutaneous injections of saline (Sham) or OVA (SIT). After a series of 3inhalation challenges, airway responsiveness to methacholine was measured then serum and bronchoalveolar lavage fluid(BALF) were obtained. Blocking antibodies to CTLA4 or hamster IgG were injected before optimal SIT(1 mg). CTLA4-Ig or human IgG, alone or in combination with a general NF-kB inhibitor(IKK16) were co-injected with sub-optimal SIT(100 ug). RESULTS: Inhibition of B7 signaling partially reversed the suppression of BALF eosinophilia and airway hyperreactivity(AHR) by SIT. Interestingly, B7 ligation by CTLA4-Ig treatment strongly potentiated the suppressive effects of SIT on AHR, BALF eosinophilia and OVA-specific IgE, which could be reversed by NF-kB inhibition. CONCLUSIONS: Although B7 ligation contributes to the beneficial effects of SIT, it is not critically required. However, the activation of NF-kB upon B7 ligation by CTLA4-Ig is rate-limiting for the suppressive effects of SIT in vivo, indicating that adjuvants stimulating the alternative NF-kB pathway in DCs can be used to improve the efficacy of SIT.

Role of prostaglandin D2 in mast cell activation-induced sensitization of esophageal vagal afferents

“…Clinical studies suggest that increased eosinophil and MC infiltration into the esophagus might contribute to abnormal esophageal sensation, such as heartburn, in patients with eosinophilic esophagitis (1,11,16). The present study provides the first evidence that PGD 2 , one of the important MC mediators, displays distinctive sensitization effects on esophageal sensory afferents, which contributes to MC activation-induced sensitization of esophageal afferents.…”

Protease phenotype of constitutive connective tissue and of induced mucosal mast cells in mice is regulated by the tissue

“…Recently, the reported protease exclusivity of these two phenotypes in human MCs has been challenged by the findings of increased transcripts for tryptase and CPA3 but relatively fewer chymase transcripts in bronchial mucosal biopsies from asthmatic patients showing increased MMCs and a high Th2 transcript phenotype (18). Similarly, in patients with eosinophilic esophagitis, the associated MC hyperplasia correlated with increased transcripts for tryptase and CPA3 but not chymase (19).…”

La mystérieuse œsophagite à éosinophiles garde encore quelques secrets

“…Ce caractère non-essentiel aa ussi été suggéré chez des souris déficientes en IL-13, qui étaient résistantes dans un modèle expérimental classique d'EoE [38], ainsi que des souris traitées avec un anticorps anti-IL-13 (A. Vicari, données non publiées). Finalement, à ce profilc lassique Th2/éosinophiles, il convient d'ajouter d'autres populations de leucocytes fréquemment impliquées dans les réactionsi n fl ammatoiresa llergiques :l es basophiles et les mastocytes, qui pourraient jouer un rôle spécifique important dans la pathogénie de l'EoE [31,39,40], et peut-être permettre de distinguer l'EoE des formes d'éosinophilie oesophagienne répondante aux IPP [41].…”