Department of Pathology and Beirne B Carter Center of Immunology, University of Virginia, Charlottesville, VA 22908, USA.
Proc Natl Acad Sci U S A. 2011 May 3;108(18):7511-6. doi: 10.1073/pnas.1017615108. Epub 2011 Apr 18.
Vasectomy is a well accepted global contraceptive approach frequently associated with epididymal granuloma and sperm autoantibody formation. To understand the long-term sequelae of vasectomy, we investigated the early immune response in vasectomized mice. Vasectomy leads to rapid epithelial cell apoptosis and necrosis, persistent inflammation, and sperm granuloma formation in the epididymis. Vasectomized B6AF1 mice did not mount autoimmune response but instead developed sperm antigen-specific tolerance, documented as resistance to immunization-induced experimental autoimmune orchitis (EAO) but not experimental autoimmune encephalomyelitis. Strikingly, tolerance switches over to pathologic autoimmune state following concomitant CD4(+)CD25(+)Foxp3(+) regulatory T cell (Treg) depletion: unilaterally vasectomized mice produce dominant autoantibodies to an orchitogenic antigen (zonadhesin), and develop CD4 T-cell- and antibody-dependent bilateral autoimmune orchitis. Therefore, (i) Treg normally prevents spontaneous organ-specific autoimmunity induction by persistent endogenous danger signal, and (ii) autoantigenic stimulation with sterile autoinflammation can lead to tolerance. Finally, postvasectomy tolerance occurs in B6AF1, C57BL/6, and A/J strains. However, C57BL/6 mice resisted EAO after 60% Treg depletion, but developed EAO after 97% Treg reduction. Therefore, variance in intrinsic Treg function--a possible genetic trait--can influence the divergent tolerogenic versus autoimmune response to vasectomy.
输精管切除术是一种被广泛接受的全球避孕方法，常与附睾肉芽肿和精子自身抗体形成有关。为了了解输精管切除术的长期后果，我们研究了输精管切除小鼠的早期免疫反应。输精管切除术导致附睾上皮细胞迅速凋亡和坏死、持续炎症和精子肉芽肿形成。B6AF1 小鼠在输精管切除后不会产生自身免疫反应，而是发展出精子抗原特异性耐受，表现为对免疫诱导的实验性自身免疫性睾丸炎（EAO）的抵抗力，但对实验性自身免疫性脑脊髓炎（EAE）没有抵抗力。引人注目的是，在同时耗尽 CD4+CD25+Foxp3+调节性 T 细胞（Treg）后，耐受会转变为病理性自身免疫状态：单侧输精管切除小鼠产生针对睾丸炎抗原（Zonadhesin）的优势自身抗体，并发展为 CD4 T 细胞和抗体依赖性双侧自身免疫性睾丸炎。因此，（i）Treg 通常通过持续的内源性危险信号来防止自发性器官特异性自身免疫的诱导，（ii）无菌性自身炎症中的自身抗原刺激可导致耐受。最后，B6AF1、C57BL/6 和 A/J 品系在输精管切除后都发生了耐受。然而，C57BL/6 小鼠在 60%的 Treg 耗竭后抵抗 EAO，但在 97%的 Treg 减少后发展为 EAO。因此，内在 Treg 功能的差异（一种可能的遗传特征）可能会影响输精管切除术导致的不同的耐受与自身免疫反应。
