Epstein-Barr virus persistence and infection of autoreactive plasma cells in synovial lymphoid structures in rheumatoid arthritis
Epstein-Barr virus persistence and infection of autoreactive plasma cells in synovial lymphoid structures in rheumatoid arthritis
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DOI：
10.1136/annrheumdis-2012-202352
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发表时间：
2013-09-01
影响因子：
27.4
通讯作者：
Pitzalis, Costantino
中科院分区：
文献类型：
--
作者：
Croia, Cristina;Serafini, Barbara;Pitzalis, Costantino
目的类风湿性关节炎（RA）与EB病毒（EBV）DNA载量增加、对EBV的强烈免疫应答以及对病毒和自身抗原的交叉反应性循环抗体有关。然而，EBV在RA发病机制中的作用仍然难以捉摸。在这里，我们研究了滑膜EBV感染，异位淋巴样结构（ELS）和免疫瓜氨酸自身和EBV proteins.MethodsLatent和裂解EBV感染的关系进行了研究，在43 RA滑膜组织的特点是存在/不存在的ELS和11个控制骨关节炎滑膜使用RT-PCR，原位杂交和免疫组化。抗瓜氨酸化蛋白（ACPA）和抗瓜氨酸化EBV肽的滑膜产生结果EB病毒表达异常仅见于ELS+ RA，而非骨关节炎（OA）滑膜。（LMP 2A，EBV编码的小RNA（EBER））转录物、EBER+细胞以及分别在ELS相关B细胞和浆细胞中对EBV潜伏性（LMP 1，LMP 2A）和裂解性（BFRF 1）抗原的免疫反应性。重要的是，滑膜生发中心周围大部分产生ACPA的浆细胞被EBV感染。此外，含有ELS的RA滑膜移植到SCID小鼠中支持ACPA和抗VCP 1/VCP 2抗体的产生。CD 4+和CD 8 + T细胞定位和颗粒酶B表达的分析表明，EB病毒持久性在ELS含有滑膜可能有利于排除CD 8 + T细胞从B细胞滤泡和受损的CD 8介导的cytotoxic.ConclusionsWe表现出积极的EB病毒感染ELS在RA滑膜与ACPA反应B细胞的局部分化。
ObjectivesRheumatoid arthritis (RA) is associated with an increased Epstein-Barr virus (EBV) blood DNA load, a robust immune response to EBV and cross-reactive circulating antibodies to viral and self-antigens. However, the role of EBV in RA pathogenesis remains elusive. Here, we investigated the relationship between synovial EBV infection, ectopic lymphoid structures (ELS) and immunity to citrullinated self and EBV proteins.MethodsLatent and lytic EBV infection was investigated in 43 RA synovial tissues characterised for presence/absence of ELS and in 11 control osteoarthritis synovia using RT-PCR, in situ hybridisation and immunohistochemistry. Synovial production of anti-citrullinated protein (ACPA) and anti-citrullinated EBV peptide (VCP1/VCP2) antibodies was investigated in situ and in vivo in the severe combined immunodeficiency (SCID)/RA chimeric model.ResultsEBV dysregulation was observed exclusively in ELS+ RA but not osteoarthritis (OA) synovia, as revealed by presence of EBV latent (LMP2A, EBV-encoded small RNA (EBER)) transcripts, EBER+ cells and immunoreactivity for EBV latent (LMP1, LMP2A) and lytic (BFRF1) antigens in ELS-associated B cells and plasma cells, respectively. Importantly, a large proportion of ACPA-producing plasma cells surrounding synovial germinal centres were infected with EBV. Furthermore, ELS-containing RA synovia transplanted into SCID mice supported production of ACPA and anti-VCP1/VCP2 antibodies. Analysis of CD4+ and CD8+ T-cell localisation and granzyme B expression suggests that EBV persistence in ELS-containing synovia may be favoured by exclusion of CD8+ T cells from B-cell follicles and impaired CD8-mediated cytotoxicity.ConclusionsWe demonstrated active EBV infection within ELS in the RA synovium in association with local differentiation of ACPA-reactive B cells.