Mouse mast cell protease-6 and MHC are involved in the development of experimental asthma

• Published in: The Journal of immunology (1950) 2014-11, Vol.193 (10), p.4783-4789
• Main Authors: Cui, Yue, Dahlin, Joakim S, Feinstein, Ricardo, Bankova, Lora G, Xing, Wei, Shin, Kichul, Gurish, Michael F, Hallgren, Jenny
• Format: Article
• Language: English
• Subjects: Animals; Asthma - chemically induced; Asthma - genetics; Asthma - immunology; Asthma - pathology; Bronchial Hyperreactivity - chemically induced; Bronchial Hyperreactivity - genetics; Bronchial Hyperreactivity - immunology; Bronchial Hyperreactivity - pathology; Bronchoalveolar Lavage Fluid - chemistry; Bronchoalveolar Lavage Fluid - cytology; Chromosomes, Mammalian; Crosses, Genetic; Eosinophils - immunology; Eosinophils - pathology; Female; Gene Expression Regulation; H-2 Antigens - genetics; H-2 Antigens - immunology; Haplotypes; Immunoglobulin E - genetics; Major Histocompatibility Complex; Male; Mast Cells - immunology; Mast Cells - pathology; Mice; Mice, Inbred BALB C; Mice, Knockout; Ovalbumin; Signal Transduction; Th2 Cells - immunology; Th2 Cells - pathology; Tryptases - genetics; Tryptases - immunology
• ISSN: 0022-1767; 1550-6606; 1550-6606
• DOI: 10.4049/jimmunol.1302947

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.