The influence of experimental gestational diabetes on expression of Aire mRNA and character of differentiation of Foxp3+ - cells in mesenteric lymph nodes in the offspring.
DOI:
https://doi.org/10.26641/1997-9665.2015.2.29-35Keywords:
experimental gestational diabetes, mesenteric lymph nodes, Aire, TregAbstract
Background. Formation of immunological tolerance to self-antigens is an important mechanism that prevents development of the autoimmune diseases. Objective. With the help of molecular genetic and immunofluorescence techniques to investigate the effects of experimental gestational diabetes on the level of mRNA expression of autoimmune regulator Aire and differentiation features of Foxp3+ cells in mesenteric lymph nodes in the offspring of Wistar rats. Methods. To determine the level of Аire mRNA RT-PCR was performed in real-time by thermocycler CFX96™ Real-Time PCR Detection Systems («Bio-RadLaboratories, Inc», USA). The relative level of gene expression were studied with rat reference genes GAPDH by the method ΔΔCt. Statistical analysis were conducted using available software «Bio-Rad СFX Manager 3.1» (Bio-Rad, USA). The immunopositive Foxp3+-lymphocytes were determined using an indirect immunofluorescence technique with using a monoclonal rat antibody. Results. The offspring of experimental gestational diabetes rats showed the reduction of autoimmune regulator Aire mRNA in 2,3-8,1 times (p <0,05) in mesenteric lymph node cells compared to control animals. The observed decrease in the transcriptional activity of Aire is accompanied by reduction in the number of regulatory Foxp3+ lymphocytes in mesenteric lymph node in the offspring of rats with experimental gestational diabetes, as well as reduction of concentration of the transcription factor Foxp3 in lymphocytes of cortical plateau. Conclusion. The revealed changes evidence the abuse of formation of peripheral immunological tolerance and can trigger the development of autoimmune disease in the offspring of mothers with experimental gestational diabetes.
References
- Akirav EM, Ruddle NH, Herold KC. The role of AIRE in human autoimmune disease. Nat. Rev. Endocrinol. 2011;7(1):25-33. PMID: 21102544.
- Laan M, Peterson P. The many faces of Aire in central tolerance. Front Immunol. 2013;4:326. PMID: 24130560.
- Semana G, Gausling R, Jackson RA, Hafler DA. T cell autoreactivity to proinsulin epitopes in diabetic patients and healthy subjects. J. Autoimmun. 1999;12:259-67. Cited in PubMed; PMID: 10330297.
- Narendran P, Neale AM, Lee BH, Ngui K, Steptoe RJ, Morahan G, Madsen O, Dromey JA, Jensen KP, Harrison LC. Proinsulin is encoded by an RNA splice variant in human blood myeloid cells. Proc. Natl. Acad. Sci. USA. 2006;103(44):16430-5. PMID: 17053071.
- Kojima H, Fujimiya M, Matsumura K, Nakahara T, Hara M, Chan L. Extrapancreatic insulin-producing cells in multiple organs in diabetes. Proc. Natl. Acad. Sci. USA. 2004;101(8):2458-63. PMID: 14983031.
- Shevach E, Thornton A. tTregs, pTregs, and iTregs: similarities and differences. Immunol. Rev. 2014;259(1):88-102. doi: 10.1111/imr.12160. PMID: 24712461.
- Macpherson A, Smith K. Mesenteric lymph nodes at the center of immune anatomy. J. Exp. Med. 2006;203(3):497-500. PMID: 16533891.
- Aschenbrenner K, D’Cruz LM, Vollmann EH, Hinterberger M, Emmerich J, Swee LK. Selection of Foxp3+ regulatory T cells specific for self antigen expressed and presented by Aire+ medullary thymic epithelial cells. Nat. Immunol. 2007;8(4):351-8. PMID: 17322887.
- Hinterberger M, Aichinger M, da Costa O, Voehringer D, Hoffmann R, Klein L. Autonomous role of medullary thymic epithelial cells in central CD4(+) T cell tolerance. Nat. Immunol. 2010;11(6):512-9. doi: 10.1038/ni.1874. PMID: 20431619.
- Nagamine K, Peterson P, Scott HS, Kudoh J, Minoshima S, Heino M, Krohn KJ, Lalioti MD, Mullis PE, Antonarakis SE, Kawasaki K, Asakawa S, Ito F, Shimizu N. Positional cloning of the APECED gene. Nat. Genet. 1997;17(4):393-8. PMID: 9398839.
- Kont V, Laan M, Kisand K, Merits A, Scott HS, Peterson P. Modulation of Aire regulates the expression of tissue-restricted antigens. Mol. Immunol. 2008;45(1):25-33. PMID: 17599412.
- Poliani PL, Kisand K, Marrella V, Ravanini M, Notarangelo LD, Villa A, Peterson P, Facchetti F. Human peripheral lymphoid tissues contain auto-immune regulator-expressing dendritic cells. Am. J. Pathol. 2010;176(3):1104-12. doi: 10.2353/ajpath.2010.090956. PMID: 20093495.
- Suzuki E, Kobayashi Y, Kawano O, Endo K, Haneda H, Yukiue H, Sasaki H, Yano M, Maeda M, Fujii Y. Expression of AIRE in thymocytes and peripheral lymphocytes. Autoimmunity. 2008;41(2):133-9. doi: 10.1080/08916930701773941. PMID: 18324482.
- Gardner JM, Devoss JJ, Friedman RS, Wong DJ, Tan YX, Zhou X, Johannes KP, Su MA, Chang HY, Krummel MF, Anderson MS. Deletional tolerance mediated by extrathymic Aire-expressing cells. Science. 2008;321(5890):843-7. doi: 10.1126/science.1159407. PMID: 18687966.
- Fletcher AL, Lukacs-Kornek V, Reynoso ED, Pinner SE, Bellemare-Pelletier A, Curry MS, Collier AR, Boyd RL, Turley SJ. Lymph node fibro-blastic reticular cells directly present peripheral tissue antigen under steady-state and inflammatory conditions. J. Exp. Med. 2010;207(4):689-97. doi: 10.1084/jem.20092642. PMID: 20308362
- Hubert FX, Kinkel SA, Webster KE, Can-non P, Crewther PE, Proeitto AI, Wu L, Heath WR, Scott HS. A specific anti-Aire antibody reveals Aire expression is restricted to medullary thymic epithelial cells and not expressed in periphery. J. Immunol. 2008;180(6):3824-32. PMID: 18322189.
- Zheng X, Yin L, Liu Y, Zheng P. Expression of tissue-specific autoantigens in the hematopoietic cells leads to activation-induced cell death of autoreactive T cells in the secondary lymphoid organs. Eur. J. Immunol. 2004;34(11):3126-34. PMID: 15368272.
- Cohen JN, Guidi CJ, Tewalt EF, Qiao H, Rouhani SJ, Ruddell A, Farr AG, Tung KS, Engelhard VH. Lymph node-resident lymphatic endothelial cells mediate peripheral tolerance via Aire-independent direct antigen presentation. J. Exp. Med. 2010;207(4):681-8. doi: 10.1084/ jem.20092465. PMID: 20308365.
- Yang S, Fujikado N, Kolodin D, Benoist C, Mathis D. Immune tolerance. Regulatory T cells generated early in life play a distinct role in main-taining self-tolerance. Science. 2015;348(6234):589-94. doi: 10.1126/science.aaa7017. PMID: 25791085.
- Daniely D, Kern J, Cebula A, Ignatowicz L. Diversity of TCRs on natural Foxp3+ T cells in mice lacking Aire expression. J. Immunol. 2010;184(12):6865-73. PMID: 20483761.
- Malchow S, Leventhal DS, Nishi S, Fischer BI, Shen L, Paner GP, Amit AS, Kang C, Geddes JE, Allison JP, Socci ND, Savage PA. Aire-dependent thymic development of tumor-associated regulatory T cells. Science. 2013;339(6124):1219-24. doi: 10.1126/science.1233913. PMID: 23471412.
- Sun J, Fu H, Wu J, Zhu W, Li Y, Yang W. Macrophages overexpressing Aire induce CD4+Foxp3+ T cells. Mol. Med. Rep. 2013;7(1):159-65. doi: 10.3892/mmr.2012.1150. PMID: 23128958.
- Gardner JM, Metzger TC, McMahon EJ, Au-Yeung BB, Krawisz AK, Lu W, Price JD, Jo-hannes KP, Satpathy AT, Murphy KM, Tarbell KV, Weiss A, Anderson MS. Extrathymic Aire-expressing cells are a distinct bone marrow-derived population that induce functional inactivation of CD4⁺ T cells. Immunity. 2013; 39(3):560-72. doi: 10.1016/j.immuni.2013.08.005. PMID: 23993652.
- Pomié C, Vicente R, Vuddamalay Y, Lundgren BA, van der Hoek M, Enault G, Kagan J, Fazilleau N, Scott HS, Romagnoli P, van Meerwijk JP. Autoimmune regulator (AIRE)-deficient CD8+CD28low regulatory T lymphocytes fail to control experimental colitis. Proc. Natl. Acad. Sci. USA. 2011;108(30):12437-42. doi: 10.1073/pnas.1107136108. PMID: 21746930.
- Nakajima A, Negishi N, Tsurui H, Kadowaki-Ohtsuji N, Maeda K, Nanno M, Yamagu-chi Y, Shimizu N, Yagita H, Okumura K, Habu S. Commensal bacteria regulate thymic Aire expression. PLoS One. 2014;9(8):e105904. doi: 10.1371/journal.pone.0105904. PMID: 25157574.
- Zhu W, Yang W, He Z, Liao X, Wu J, Sun J, Yang Y, Li Y. Overexpressing autoimmune regulator regulates the expression of toll-like receptors by interacting with their promoters in RAW264.7 cells. Cell Immunol. 2011;270(2):156-63. doi: 10.1016/j.cellimm.2011.05.002. PMID: 21628060.
Downloads
How to Cite
Issue
Section
License
Copyright (c) 2018 Morphologia

This work is licensed under a Creative Commons Attribution 4.0 International License.
The authors reserve the right to authorship of their work and transfer to the Journal the right to the first publication of this work under the terms of a license Creative commons Attribution 4.0 International (CC BY 4.0), which allows other people to freely distribute the published work with a mandatory reference to the authors of the original work and the first publication of the work in this journal.By submitting a manuscript to the editorial office of the Journal ‘Morphologia’ authors agree to transfer the rights to protect and use the manuscript (all supplemental materials, particularly protected objects such as photos, drawings, diagrams, tables, etc.), including the reproduction in the press and distribution via the Internet; translation of the manuscript into any language; export and import of journal copies with the Authors’ article in order to make it available for public. Authors convey the rights mentioned above to the editorial office without any temporal or territorial limitation all over the world.
The Authors guarantee that they have the exclusive rights to use the material transferred to editorial office. Editors are not responsible to third parties for contraventions of warranty given by the Authors. The considered rights are transferred to the editorial office since the moment when the current issue is signed for publishing. Reproduction of materials published in the Journal by other individuals and legal entities is possible only with the consent of Editorial office, with the obligatory indication of the full bibliographic reference of the primary publication. The Authors reserve the right to use the published material, its fragments and parts for teaching materials, oral presentations, dissertation thesis prepararion with obligatory bibliographic citation of the original paper. Electron copy of the published article, downloaded from official journal web-site in .pdf format may be put by authors on the official web-site of their institutions, any other official resources with open access.
