Talreja Jaya, Peng Changya, Zhang Kezhong, Samavati Lobelia
Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, Detroit Medical Center, and.
Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, Michigan.
Am J Respir Cell Mol Biol. 2025 Jul;73(1):135-146. doi: 10.1165/rcmb.2024-0428OC.
Numerous chronic human disorders are associated with immune activation by an obscure antigen (or antigens). We identified ChainA, a novel sarcoidosis epitope, by immunoscreening of a novel T7 phage library and confirmed an abundance of ChainA IgG antibody in sarcoidosis. We tested whether the ChainA epitope elicits immune responses through B-cell activation, plasma cell differentiation, and antibody production. Peripheral blood mononuclear cells (PBMCs) from healthy control participants and patients with sarcoidosis were challenged by chemically synthesized ChainA epitope, and cellular activation markers of B cells, T cells, major histocompatibility complex (MHC) classes, plasma cell differentiation, and unfolded protein response (UPR) transcription factors were assessed. ChainA increased the expression of MHC Class II (MHCII) and CD80/CD86 costimulatory molecules. ChainA significantly augmented the transition of naive B cells to memory B cells and plasma cells in PBMCs from patients with sarcoidosis compared with those from healthy control participants. B cell differentiation to antibody-secreting plasma cells requires the activation of UPR, B lymphocyte-induced maturation protein 1 (or, Blimp-1), and X-box binding protein 1 (XBP-1). ChainA treatment upregulated the expression of Blimp-1 and the spliced form of XBP-1, a transcriptional activator of endoplasmic reticulum stress response. Furthermore, the transition of B cells to plasma cells in response to ChainA induced the production of anti-ChainA IgG. In parallel to human PBMCs, utilizing murine splenocytes, we validated our observations that ChainA challenge augments MHCII expression, robust UPR responses, and an increased production of IgG-specific antibody against ChainA. These results indicate that the ChainA epitope may be involved in the pathogenesis of sarcoidosis, as it activates MHCII, memory B cells, plasma cell differentiation, and the production of ChainA-specific IgG.
许多慢性人类疾病都与一种不明抗原（或多种抗原）引发的免疫激活有关。我们通过对一个新型T7噬菌体文库进行免疫筛选，鉴定出了一种新型结节病表位ChainA，并证实结节病患者体内存在大量的ChainA IgG抗体。我们测试了ChainA表位是否通过B细胞激活、浆细胞分化和抗体产生来引发免疫反应。用化学合成的ChainA表位刺激健康对照参与者和结节病患者的外周血单个核细胞（PBMC），并评估B细胞、T细胞、主要组织相容性复合体（MHC）类别的细胞激活标志物、浆细胞分化和未折叠蛋白反应（UPR）转录因子。ChainA增加了MHC II类（MHCII）和CD80/CD86共刺激分子的表达。与健康对照参与者相比，ChainA显著增强了结节病患者PBMC中幼稚B细胞向记忆B细胞和浆细胞的转变。B细胞分化为分泌抗体的浆细胞需要激活UPR、B淋巴细胞诱导的成熟蛋白1（或Blimp-1）和X盒结合蛋白1（XBP-1）。ChainA处理上调了Blimp-1的表达以及XBP-1的剪接形式，XBP-1是内质网应激反应的转录激活因子。此外，B细胞对ChainA的反应向浆细胞的转变诱导了抗ChainA IgG的产生。与人类PBMC类似，利用小鼠脾细胞，我们验证了我们的观察结果，即ChainA刺激可增强MHCII表达、强烈的UPR反应以及针对ChainA的IgG特异性抗体产量增加。这些结果表明，ChainA表位可能参与结节病的发病机制，因为它激活了MHCII、记忆B细胞、浆细胞分化以及ChainA特异性IgG的产生。
