title: Knockdown of the antiapoptotic Bcl-2 family member A1/Bfl-1 protects mice from anaphylaxis.
abstract: Many forms of hypersensitivity reactions and allergic responses depend on deregulated mast cell activity. Several reports suggested that the antiapoptotic Bcl-2 family protein Bcl2a1/Bfl-1/A1 plays a critical role in mast cell survival upon activation. However, its in vivo relevance is poorly understood because of quadruplication of the Bcl2a1 gene locus in mice, hindering conventional knockout studies. In this study, we used a mouse model allowing traceable constitutive knockdown of all A1 isoforms expressed in the hematopoietic system by RNA interference. Knockdown of A1 reduced mast cell numbers in the skin and impaired connective tissue-like mast cell survival upon FcεRI-mediated activation in vitro. In contrast, A1 was dispensable for mucosa-like mast cell differentiation and survival. Moreover, knockdown of A1 prevented IgE-mediated passive systemic and cutaneous anaphylaxis in vivo. Our findings demonstrate that A1 is essential for the homeostasis of connective tissue mast cells, identifying A1 as a possible therapeutic target for therapy of certain types of mast cell-driven allergy symptoms.
authors.affiliation: Division of Developmental Immunology, Biocenter, Medical University Innsbruck, A-6020 Innsbruck, Austria; and.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Ottina
authors.affiliation: Clinical Immunology and Allergy Unit, Department of Medicine, Karolinska Institute and Karolinska University Hospital, S-17176 Stockholm, Sweden.
authors.forename: Katarina
authors.initials: K
authors.lastname: Lyberg
authors.affiliation: Division of Developmental Immunology, Biocenter, Medical University Innsbruck, A-6020 Innsbruck, Austria; and.
authors.forename: Maja
authors.initials: M
authors.lastname: Sochalska
authors.affiliation: Division of Developmental Immunology, Biocenter, Medical University Innsbruck, A-6020 Innsbruck, Austria; and andreas.villunger@i-med.ac.at gunnar.p.nilsson@ki.se.
authors.forename: Andreas
authors.initials: A
authors.lastname: Villunger
authors.affiliation: Clinical Immunology and Allergy Unit, Department of Medicine, Karolinska Institute and Karolinska University Hospital, S-17176 Stockholm, Sweden andreas.villunger@i-med.ac.at gunnar.p.nilsson@ki.se.
authors.forename: Gunnar P
authors.initials: GP
authors.lastname: Nilsson
mesh_terms: D000707:Anaphylaxis / Q000235:genetics* / Q000276:immunology*; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006410:Hematopoiesis / Q000235:genetics; D007073:Immunoglobulin E / Q000276:immunology; D008407:Mast Cells / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D015778:Minor Histocompatibility Antigens; D011401:Promoter Regions, Genetic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D051567:Proto-Oncogene Proteins c-vav / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D017455:Receptors, IgE / Q000378:metabolism
chemical_list: C096816:BCL2-related protein A1; D015778:Minor Histocompatibility Antigens; D019253:Proto-Oncogene Proteins c-bcl-2; D051567:Proto-Oncogene Proteins c-vav; D034741:RNA, Small Interfering; D017455:Receptors, IgE; D007073:Immunoglobulin E