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

Allergic asthma is a complex disease with a strong genetic component where mast cells play a major role by the release of pro-inflammatory 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. While OVA-sensitized and challenged wild type mice displayed a striking airway hyperresponsiveness (AHR), mMCP-6−/− mice had less AHR that was comparable to 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 (BAL) 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 while mMCP-6 plays a key role in the development of AHR.

过敏性哮喘是一种具有强烈遗传因素的复杂疾病，其中肥大细胞通过释放促炎介质发挥主要作用。在小鼠中，肥大细胞蛋白酶 - 6（mMCP - 6）与人类肥大细胞类胰蛋白酶β - 类胰蛋白酶非常相似。编码mMCP - 6的基因Tpsb2位于17号染色体上的H - 2复合体（主要组织相容性复合体基因）附近。因此，当最初的mMCP - 6基因敲除小鼠与BALB/c品系回交时，这些小鼠携带主要组织相容性复合体的129/Sv单倍型（mMCP - 6 - / - /H - 2bc）。进一步回交产生了具有BALB/c主要组织相容性复合体基因座的mMCP - 6 - / - 小鼠。在一个实验性哮喘小鼠模型中，将BALB/c小鼠与mMCP - 6 - / - 小鼠和mMCP - 6 - / - /H - 2bc小鼠进行了比较。虽然卵清蛋白致敏和激发的野生型小鼠表现出显著的气道高反应性（AHR），但mMCP - 6 - / - 小鼠的AHR较低，与mMCP - 6 - / - /H - 2bc小鼠相当，这表明mMCP - 6是完全发展的AHR所必需的。在致敏和激发后，mMCP - 6 - / - /H - 2bc小鼠的肺部炎症、IgE反应和Th2细胞反应显著降低，而mMCP - 6 - / - 小鼠的反应与野生型小鼠相似，但支气管肺泡灌洗液（BAL）中的嗜酸性粒细胞略有减少。这些发现表明，炎症性Th2反应高度依赖于主要组织相容性复合体单倍型，并且它们基本上可以不依赖于mMCP - 6而发展，而mMCP - 6在AHR的发展中起关键作用。