The University of Queensland, UQ Centre for Clinical Research, Experimental Dermatology Group, Brisbane, Australia; QIMR Berghofer Medical Research Institute, Brisbane, Australia.
The University of Queensland, UQ Centre for Clinical Research, Experimental Dermatology Group, Brisbane, Australia.
J Autoimmun. 2014 May;50:51-8. doi: 10.1016/j.jaut.2013.10.005. Epub 2013 Nov 20.
The origins of autoimmunity are not yet understood despite significant advances in immunology. The trafficking of maternal cells to the offspring represents the very first immunological event in foetal life and is reinforced during lactation. The persistence of maternal cells in offspring's tissues and circulation has been associated with several autoimmune disorders. However a direct causal effect has never been demonstrated. Maternal T cells specifically targeting foetal insulin producing cells have been shown to generate islet inflammation without directly participating in this process. Our objective was to evaluate if alloreactive maternal cells could directly trigger a graft-versus host like reaction or indirectly influence the development of the offspring's regulatory T cells favouring autoimmunity. We adopted a breeding strategy comparing genetically identical offspring from either strongly alloreactive transgenic mothers compared to immunodeficient mothers. We detected maternal alloreactive T cells in the offspring and early signs of inflammation in small intestine of 6 weeks old offspring. Interestingly, CD4(+) Foxp3(+) regulatory T cell frequency was diminished in mesenteric lymph nodes from eight months old offspring born of alloreactive mothers compared to offspring of immunodeficient mothers. Our study favours a hypothesis where highly alloreactive maternal cell microchimerism indirectly predisposes offspring to autoimmunity.
尽管免疫学取得了重大进展，但自身免疫的起源仍未被理解。母体细胞向后代的转移代表了胎儿生命中第一个免疫事件，并在哺乳期得到加强。母体细胞在后代组织和循环中的持续存在与几种自身免疫性疾病有关。然而，从未证明过直接的因果关系。已经表明，专门针对胎儿胰岛素产生细胞的母体 T 细胞会引起胰岛炎症，而不会直接参与该过程。我们的目的是评估同种异体反应性母体细胞是否可以直接引发移植物抗宿主样反应，或者是否可以间接影响后代调节性 T 细胞的发育，从而促进自身免疫。我们采用了一种繁殖策略，比较了来自强同种异体反应性转基因母亲的遗传上相同的后代与免疫缺陷母亲的后代。我们在后代中检测到了母体同种异体反应性 T 细胞，并在 6 周龄后代的小肠中发现了早期炎症迹象。有趣的是，与免疫缺陷母亲的后代相比，来自同种异体反应性母亲的 8 个月大后代的肠系膜淋巴结中 CD4(+)Foxp3(+)调节性 T 细胞频率降低。我们的研究支持这样一种假说，即高度同种异体反应性母体细胞微嵌合体间接使后代易患自身免疫。
