2015年6月23日讯 /生物谷BIOON/ --近日，来自瑞典卡罗琳斯卡学院的研究人员发现男性不育与前列腺的自身免疫性炎症有关，相关研究结果发表在国际学术期刊 science translational medicine。
现在不孕不育情况的发生越来越多，其中有一半案例是由于男性不育造成的，虽然男性不育有很多可能的原因，但这种情况仍未得到完全解释。
在这项研究中，研究人员发现了导致患有I型自身免疫性多内分泌腺综合征（APS1）的男性生育能力降低的一个重要原因。患有APS1会增加自身免疫性疾病的患病风险，因此APS1也常被用作自身免疫性疾病的研究模型。
不育在患有APS1的男性和女性中都比较常见，对于患有APS1的女性来说，不孕主要是由于自身免疫系统攻击了卵巢造成的，但患有APS1的男性生育能力降低的原因并不清楚。研究人员为了调查这种不育的情况是否与自身免疫系统攻击了男性生殖器官有关，他们选取了93名患有APS1的男性和女性患者进行了相关研究。
研究人员发现许多病人的免疫系统都会对一种表达在前列腺中的酶产生应答，这种酶叫作谷氨酰胺转氨酶4，并且只有男性的免疫系统会对谷氨酰胺转氨酶4产生应答，一旦在青春期哪前列腺发育成熟，这种免疫反应就会发生，有趣的是，之前一些关于小鼠的研究发现谷氨酰胺转氨酶4在雄性小鼠生育方面发挥着一定的作用。
为进一步理解这一发现，研究人员又利用APS1小鼠模型进行了研究，发现雄性小鼠的免疫系统会对谷氨酰胺转氨酶4产生免疫反应，并在前列腺部位自发形成一种炎症性疾病--前列腺炎。
总得来说，这项研究发现了导致男性不育的新致病机制，但关于自身免疫性前列腺炎在男性不育中究竟发挥什么样的重要作用仍需大量研究证明。（生物谷Bioon.com）
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DOI: 10.1126/scitranslmed.aaa9186
Transglutaminase 4 as a prostate autoantigen in male subfertility
Nils Landegren1,2,*, Donald Sharon3,4, Anthony K. Shum5, Imran S. Khan6, Kayla J. Fasano6, ?sa Hallgren1,2, Caroline Kampf7, Eva Freyhult8, Brita Ardesj?-Lundgren9, Mohammad Alimohammadi1,2,10, Sandra Rathsman11, Jonas F. Ludvigsson12, Dan Lundh13, Ruben Motrich14, Virginia Rivero14, Lawrence Fong15, Aleksander Giwercman16, Jan Gustafsson17, Jaakko Perheentupa18, Eystein S. Husebye19, Mark S. Anderson6, Michael Snyder3 and Olle Kampe1,2
Autoimmune polyendocrine syndrome type 1 (APS1), a monogenic disorder caused by AIREgene mutations, features multiple autoimmune disease components. Infertility is common in both males and females with APS1. Although female infertility can be explained by autoimmune ovarian failure, the mechanisms underlying male infertility have remained poorly understood. We performed a proteome-wide autoantibody screen in APS1 patient sera to assess the autoimmune response against the male reproductive organs. By screening human protein arrays with male and female patient sera and by selecting for gender-imbalanced autoantibody signals, we identified transglutaminase 4 (TGM4) as a male-specific autoantigen. Notably, TGM4 is a prostatic secretory molecule with critical role in male reproduction. TGM4 autoantibodies were detected in most of the adult male APS1 patients but were absent in all the young males. Consecutive serum samples further revealed that TGM4 autoantibodies first presented during pubertal age and subsequent to prostate maturation. We assessed the animal model for APS1, the Aire-deficient mouse, and found spontaneous development of TGM4 autoantibodies specifically in males. Aire-deficient mice failed to present TGM4 in the thymus, consistent with a defect in central tolerance for TGM4. In the mouse, we further link TGM4 immunity with a destructive prostatitis and compromised secretion of TGM4. Collectively, our findings in APS1 patients and Aire-deficient mice reveal prostate autoimmunity as a major manifestation of APS1 with potential role in male subfertility.
