Department of Periodontology, University of Tennessee Health Science Center, Memphis, TN, United States of America.
Memphis VA Medical Center, Memphis, TN, United States of America.
PLoS One. 2021 Apr 15;16(4):e0250177. doi: 10.1371/journal.pone.0250177. eCollection 2021.
Our previous studies have shown that inoculation of the oral cavity of "humanized" B6.DR1/4 mice with the periodontal pathogen Porphyromonas gingivalis results in an increase in the percentage of circulating Th17 cells, loss of bone and an exacerbation of experimental autoimmune arthritis. The aim of this study was to assess the role played by the human HLA-DRβ molecule containing the shared epitope supplied as a transgene to I-A˚ (murine class II null) C57BL/6 (B6) mice in driving these findings. We compared various immune response parameters as well as alveolar and peri-articular bone loss between humanized B6.DR1 (or B6.DR4) mice and their WT (B6) counterparts. We found that the presence of the shared epitope in the context of inoculation with P. gingivalis enhanced the percentage of Th17 cells generated, dramatically enhanced bone loss and importantly allowed for the generation of CCP2⁺ ACPAs that are not found in C57BL/6 or DBA/1 arthritic mouse serum. Due to the exceedingly complex nature of environmental factors impacting on genetic elements, it has been difficult to unravel mechanisms that drive autoimmune arthritis in susceptible individuals. The findings in this study may provide one small piece of this puzzle that can help us to better understand part of this complexity.
我们之前的研究表明，将牙周致病菌牙龈卟啉单胞菌接种到“人源化”B6.DR1/4 小鼠的口腔中，会导致循环 Th17 细胞比例增加、骨质流失和实验性自身免疫性关节炎恶化。本研究旨在评估作为转基因提供给 I-A˚（鼠类 II 类缺失）C57BL/6（B6）小鼠的含有共享表位的人类 HLA-DRβ 分子在驱动这些发现中所起的作用。我们比较了人源化 B6.DR1（或 B6.DR4）小鼠及其 WT（B6）对照之间的各种免疫反应参数以及肺泡和关节周围骨丢失。我们发现，在接种牙龈卟啉单胞菌的情况下，共享表位的存在增强了产生的 Th17 细胞的比例，显著增强了骨质流失，并且重要的是允许产生在 C57BL/6 或 DBA/1 关节炎小鼠血清中未发现的 CCP2⁺ ACPAs。由于影响遗传因素的环境因素极其复杂，因此很难揭示驱动易感个体自身免疫性关节炎的机制。本研究中的发现可能提供了这个难题的一小部分，有助于我们更好地理解其中的一部分复杂性。
