Ball Dimity H, Tay Hwee Kee, Bell Kara S, Coates Michelle L, Al-Riyami Lamyaa, Rzepecka Justyna, Harnett William, Harnett Margaret M
Centre for Immunobiology, Glasgow Biomedical Research Centre, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, UK.
J Parasitol Res. 2013;2013:961268. doi: 10.1155/2013/961268. Epub 2013 Feb 7.
ES-62, an immunomodulator secreted by filarial nematodes, exhibits therapeutic potential in mouse models of allergic inflammation, at least in part by inducing the desensitisation of Fc ε RI-mediated mast cell responses. However, in addition to their pathogenic roles in allergic and autoimmune diseases, mast cells are important in fighting infection, wound healing, and resolving inflammation, reflecting that mast cells exhibit a phenotypic and functional plasticity. We have therefore characterised the differential functional responses to antigen (via Fc ε RI) and LPS and their modulation by ES-62 of the mature peritoneal-derived mast cells (PDMC; serosal) and those of the connective tissue-like mast cells (CTMC) and the mucosal-like mast cells derived from bone marrow progenitors (BMMC) as a first step to produce disease tissue-targeted therapeutics based on ES-62 action. All three mast cell populations were rendered hyporesponsive by ES-62 and whilst the mechanisms underlying such desensitisation have not been fully delineated, they reflect a downregulation of calcium and PKC α signalling. ES-62 also downregulated MyD88 and PKC δ in mucosal-type BMMC but not PDMC, the additional signals targeted in mucosal-type BMMC likely reflecting that these cells respond to antigen and LPS by degranulation and cytokine secretion whereas PDMC predominantly respond in a degranulation-based manner.
ES-62是一种由丝虫线虫分泌的免疫调节剂，在过敏性炎症的小鼠模型中显示出治疗潜力，至少部分是通过诱导FcεRI介导的肥大细胞反应脱敏来实现的。然而，除了在过敏性和自身免疫性疾病中的致病作用外，肥大细胞在抵抗感染、伤口愈合和炎症消退中也很重要，这反映出肥大细胞具有表型和功能可塑性。因此，作为基于ES-62作用生产针对疾病组织的治疗药物的第一步，我们已经对成熟的腹膜来源肥大细胞（PDMC；浆膜）、结缔组织样肥大细胞（CTMC）以及源自骨髓祖细胞的粘膜样肥大细胞（BMMC）对抗原（通过FcεRI）和LPS的不同功能反应及其受ES-62的调节进行了表征。所有这三种肥大细胞群体都因ES-62而反应性降低，虽然这种脱敏的潜在机制尚未完全阐明，但它们反映了钙和PKCα信号的下调。ES-62还下调了粘膜型BMMC中的MyD88和PKCδ，但未下调PDMC中的，粘膜型BMMC中靶向的额外信号可能反映出这些细胞通过脱颗粒和细胞因子分泌对抗原和LPS作出反应，而PDMC主要以脱颗粒为基础作出反应。
