title: Mouse mast cell protease-6 and MHC are involved in the development of experimental asthma.
abstract: Allergic asthma is a complex disease with a strong genetic component where mast cells play a major role by the release of proinflammatory mediators. In the mouse, mast cell protease-6 (mMCP-6) closely resembles the human version of mast cell tryptase, β-tryptase. The gene that encodes mMCP-6, Tpsb2, resides close by the H-2 complex (MHC gene) on chromosome 17. Thus, when the original mMCP-6 knockout mice were backcrossed to the BALB/c strain, these mice were carrying the 129/Sv haplotype of MHC (mMCP-6(-/-)/H-2bc). Further backcrossing yielded mMCP-6(-/-) mice with the BALB/c MHC locus. BALB/c mice were compared with mMCP-6(-/-) and mMCP-6(-/-)/H-2bc mice in a mouse model of experimental asthma. Although OVA-sensitized and challenged wild type mice displayed a striking airway hyperresponsiveness (AHR), mMCP-6(-/-) mice had less AHR that was comparable with that of mMCP-6(-/-)/H-2bc mice, suggesting that mMCP-6 is required for a full-blown AHR. The mMCP-6(-/-)/H-2bc mice had strikingly reduced lung inflammation, IgE responses, and Th2 cell responses upon sensitization and challenge, whereas the mMCP-6(-/-) mice responded similarly to the wild type mice but with a minor decrease in bronchoalveolar lavage eosinophils. These findings suggest that inflammatory Th2 responses are highly dependent on the MHC-haplotype and that they can develop essentially independently of mMCP-6, whereas mMCP-6 plays a key role in the development of AHR.
authors.affiliation: Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
authors.forename: Yue
authors.initials: Y
authors.lastname: Cui
authors.affiliation: Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
authors.forename: Joakim S
authors.initials: JS
authors.lastname: Dahlin
authors.affiliation: Department of Pathology and Wildlife Diseases, The National Veterinary Institute, Uppsala, Sweden.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Feinstein
authors.affiliation: Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital and Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Lora G
authors.initials: LG
authors.lastname: Bankova
authors.affiliation: Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital and Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Xing
authors.affiliation: Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital and Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Kichul
authors.initials: K
authors.lastname: Shin
authors.affiliation: Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital and Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Gurish
authors.affiliation: Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
authors.forename: Jenny
authors.initials: J
authors.lastname: Hallgren
mesh_terms: D000818:Animals; D001249:Asthma / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D033481:Chromosomes, Mammalian; D003433:Crosses, Genetic; D004804:Eosinophils / Q000276:immunology / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D006183:H-2 Antigens / Q000235:genetics / Q000276:immunology; D006239:Haplotypes; D007073:Immunoglobulin E / Q000235:genetics; D008285:Major Histocompatibility Complex; D008297:Male; D008407:Mast Cells / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D010047:Ovalbumin; D015398:Signal Transduction; D018418:Th2 Cells / Q000276:immunology* / Q000473:pathology; D053802:Tryptases / Q000235:genetics / Q000276:immunology*
chemical_list: D006183:H-2 Antigens; C509190:Tpsb2 protein, mouse; D007073:Immunoglobulin E; D010047:Ovalbumin; D053802:Tryptases