关键词： CELLULAR IMMUNE-RESPONSES   BOOSTER VACCINATION   MULTIPLE-SCLEROSIS   A VACCINATION   MEMORY   VACCINES   IMMUNIZATION   PERSISTENCE   EXPRESSION   SUBSETS  

摘要： Low responsiveness/nonresponsiveness is characterized by an insufficient immune response upon primary and/or booster vaccination and affects 1-10% of vaccinees. In the current study, we aimed to investigate whether nonresponsiveness is an Ag/vaccine-specific phenomenon and to clarify underlying immunological mechanisms. Nonresponders to tick-borne encephalitis (TBE) or hepatitis B Ag with a history of previous TBE vaccinations were booster vaccinated with TBE and influenza vaccine and compared with TBE high responders in terms of humoral and cellular immune response. Postboosters in TBE high responder existing TBE titers increased, and solid humoral responses to influenza vaccine were induced. In TBE nonresponders, low to undetectable prevaccination TBE titers remained low, whereas sufficient influenza Abs were induced. In both TBE groups, a positive correlation of humoral and cellular immune response was seen as high/low TBE titers were associated with sufficient/lack of Ag-specific T cell proliferation. Furthermore, responses to influenza were robust in terms of Abs and cytokine production. In contrast, in hepatitis B nonresponders, sufficient humoral responses to TBE and influenza Ags were induced despite lacking specific IL-2 and IFN-gamma production. Importantly, these patients showed high IL-10 baseline levels in vitro. HLA-DR subtypes associated with hepatitis B nonresponsiveness were overrepresented in this group, and high IL-10 levels were linked to these subtypes. Whereas TBE and hepatitis B nonresponders had increased IL-10-producing FOXP3(+) T regulatory cells upon vaccination, only in hepatitis B nonresponders, showing elevated prevaccination IL-10 levels, a prominent population of B regulatory cells was detected. We conclude that immunological pathways of nonresponsiveness follow different patterns depending both on vaccine Ag and genetic predisposition of the vaccinee.

关键词： 调节性B细胞   类风湿关节炎   IL-10   TGF-β  

摘要： 调节性B细胞(regulatory B cells,Bregs)是一类对自身免疫性炎症反应有负性调节作用的B细胞亚群。Bregs可通过产生白细胞介素-10(interleukin-10,IL-10)、转化生长因子-β(transforming growth factor,TGF-β)等抑制性细胞因子以及细胞间的接触发挥免疫调节作用。进一步研究Bregs与其他调节性免疫细胞之间的相互作用及其在类风湿关节炎(rheumatoid arthritis,RA)炎症免疫反应中的负性调节功能,有助于深入认识此亚群细胞的功能,阐明RA的发病机制,寻找新的RA治疗策略。

关键词： ULCERATIVE-COLITIS   IMMUNE-RESPONSES   LYMPHOCYTE DEPLETION   B-1B CELLS   INTERLEUKIN-10   IL-10   AUTOIMMUNITY   EXPRESSION   DISEASE   RITUXIMAB  

摘要： The spleen regulatory B cell subset with the functional capacity to express IL-10 (B10 cells) modulates both immune responses and autoimmune disease severity. However, the peritoneal cavity also contains relatively high frequencies of functionally defined IL-10-competent B10 cells. In this study, peritoneal cavity B10 cells shared similar cell surface phenotypes with their spleen counterparts. However, peritoneal cavity B10 cells were 10-fold more frequent among B cells than occurred within the spleen, intestinal tract, or mesenteric lymph nodes and were present at higher proportions among the phenotypically defined peritoneal B1a > B1b > B2 cell subpopulations. The development or localization of B10 cells within the peritoneal cavity was not dependent on the presence of commensal microbiota, T cells, IL-10 or B10 cell IL-10 production, or differences between their fetal liver or adult bone marrow progenitor cell origins. The BCR repertoire of peritoneal cavity B10 cells was diverse, as occurs in the spleen, and predominantly included germline-encoded V-H and V-L regions commonly found in either the conventional or B1 B cell compartments. Thereby, the capacity to produce IL-10 appears to be an intrinsic functional property acquired by clonally diverse B cells. Importantly, IL-10 production by peritoneal cavity B cells significantly reduced disease severity in spontaneous and induced models of colitis by regulating neutrophil infiltration, colitogenic CD4(+) T cell activation, and proinflammatory cytokine production during colitis onset. Thus, the numerically small B10 cell subset within the peritoneal cavity has regulatory function and is important for maintaining homeostasis within gastrointestinal tissues and the immune system.

关键词： B淋巴细胞   调节性   变态反应性疾病   免疫调节  

摘要： 目前的研究发现B细胞和T细胞一样具有"调节性亚群",发挥重要的负向免疫调节功能,这种功能不仅体现在自身免疫性疾病中,也体现在接触性超敏反应、变应性气道炎性反应等多种变态反应性疾病中。对调节性B细胞在变态反应性疾病中的作用进行深入研究,将有助于进一步理解变态反应性疾病的发生机制,并为其治疗提供新思路。

关键词： cytotoxic T cells   Treg   bacterial   costimulation   CUTTING EDGE   LISTERIA-MONOCYTOGENES   CLONAL EXPANSION   HOST-DEFENSE   TOLL-LIKE   CTLA-4   MEMORY   CD28   EFFECTOR   RECEPTOR  

摘要： The activation of protective CD8 T cells requires B7-1/B7-2 costimulation, even when suppression by Tregs, and in particular, Treg intrinsic CTLA-4, is circumvented. Although T cell activation has been classically described to require distinct, positive stimulation signals that include B7-1 (CD80) and B7-2 (CD86) costimulation, overriding suppression signals that avert immune-mediated host injury are equally important. How these opposing stimulation and suppression signals work together remains incompletely defined. Our recent studies demonstrate that CD8 Teff activation in response to cognate peptide stimulation is actively suppressed by the Foxp3(+) subset of CD4 cells, called Tregs. Here, we show that the elimination of Treg suppression does not bypass the requirement for positive B7-1/B7-2 costimulation. The expansion, IFN- cytokine production, cytolytic, and protective features of antigen-specific CD8 T cells stimulated with purified cognate peptide in Treg-ablated mice were each neutralized effectively by CTLA-4-Ig that blocks B7-1/B7-2. In turn, given the efficiency whereby CTLA-4-Ig overrides the effects of Treg ablation, the role of Foxp3(+) cell-intrinsic CTLA-4 in mitigating CD8 Teff activation was also investigated. With the use of mixed chimera mice that contain CTLA-4-deficient Tregs exclusively after the ablation of WT Foxp3(+) cells, a critical role for Treg CTLA-4 in suppressing the expansion, cytokine production, cytotoxicity, and protective features of peptide-stimulated CD8 T cells is revealed. Thus, the activation of protective CD8 T cells requires positive B7-1/B7-2 costimulation even when suppression by Tregs and in particular, Treg-intrinsic CTLA-4 is circumvented.

关键词： NF-KAPPA-B   FOXO TRANSCRIPTION FACTORS   TGF-BETA   CUTTING EDGE   IN-VIVO   NEGATIVE REGULATION   IMMUNE-RESPONSES   EXPRESSION   AKT   INDUCTION  

摘要： E3 ubiquitin ligase Casitas-B-lineage lymphoma protein-b (Cbl-b) is critical for establishing the threshold for T cell activation and is essential for induction of T cell anergy. Recent studies suggest that Cbl-b is involved in the development of CD4(+)CD25(+) inducible regulatory T cells (iTregs). In this study, we report that the optimal induction of Foxp3 by naive CD4(+)CD25(-) T cells requires suboptimal TCR triggering. In the absence of Cbl-b, the TCR strength for optimal Foxp3 induction is downregulated in vitro. Using TCR-transgenic Rag(-/-) mice in combination with Cbl-b deficiency, we show that in vivo iTreg development is also controlled by Cbl-b via tuning the TCR strength. Furthermore, we show that Akt-2 but not Akt-1 regulates Foxp3 expression downstream of Cbl-b. Therefore, we demonstrate that Cbl-b regulates the fate of iTregs via controlling the threshold for T cell activation.

关键词： 大鼠   间质干细胞   B淋巴细胞   免疫耐受  

摘要： 目的研究骨髓间充质干细胞（MSC）诱导调节性B淋巴细胞（Breg细胞）的免疫负调节作用。方法取DA大鼠MSC和Lewis大鼠B淋巴细胞共培养后，酶联免疫吸附试验（EUSA）检测MSC和B淋巴细胞混合培养组上清液中白细胞介素10（IL-10）的水平和分泌因子的变化；采用流式细胞技术分析B淋巴细胞增殖、凋亡、表型的变化和对抗原特异性T淋巴细胞增殖的影响，采用激光共聚焦显微镜观察Breg细胞对免疫复合物吞噬能力的变化。结果MS（2成功诱导产生高分泌IL-10的Breg细胞产生，表型为CDl9＋CDld＋CD5＋，MSC显著抑制B淋巴细胞的增殖，Breg细胞能抑制抗原特异性T淋巴细胞的增殖，并增加对免疫复合物的吞噬能力。结论MS（2诱导的Breg细胞具有明显的免疫负调节作用。

关键词： 调节性B细胞   自身免疫性疾病   感染性疾病   肿瘤  

摘要： B细胞主要通过递呈抗原和分泌各种抗体发挥免疫学作用。近来研究发现,在B细胞中存在一种新的细胞亚群调节性B细胞,它们可以通过分泌白细胞介素-10和转化生长因子-β1等抑制性细胞因子抑制获得性免疫介导的炎症反应发展和(或)加快炎症的恢复。相关研究表明这种细胞在感染性疾病、自身免疫性疾病、肿瘤中发挥重要作用。本文综述了调节性B细胞的发现与来源、免疫调节作用机制及其与相关疾病的研究进展。

关键词： 约氏疟原虫   Tim-1   T细胞   调节性B细胞  

摘要： Tim-1分子表达在T细胞和调节性B细胞表面,具有促进Th2应答的作用。为探讨Tim-1分子在抗疟疾免疫应答中的作用,利用致死型约氏疟原虫(Plasmodium yoelii)感染鼠疟模型研究了Tim-1分子表达与小鼠感染结局和免疫应答模式的关系。结果显示,BALB/c小鼠对***易感,在感染后6～7 d全部死亡,感染后第3、5天脾内细胞因子IFN-γmRNA水平明显低于对***抵抗的DBA2小鼠,而脾IL-10 mRNA水平显著高于DBA2小鼠。BALB/c小鼠脾内Tim-1+T、B细胞百分比在感染后第3、5天显著升高,而DBA2小鼠感染前后脾内Tim-1+T、B细胞百分比没有显著变化。结果提示,Tim-1分子参与抗***免疫应答的调节,可能与易感鼠产生高水平Th2型细胞因子有关。

关键词： 淋巴瘤,非霍奇金   CD163   Foxp3   巨噬细胞   T淋巴细胞   免疫组织化学   预后  

摘要： 目的分析弥漫性大B细胞淋巴瘤（DLBCL）患者肿瘤组织中M2型巨噬细胞和调节性T细胞（Tregs）的含量及其对预后的影响。方法回顾性分析经病理确诊并有完整的临床和随访资料的92例DLBCL患者资料。以CD163作为M2型巨噬细胞标记，以Foxp3作为Tregs细胞标记，采用免疫组化sP法检测肿瘤组织和癌旁组织中CD163和Foxp3蛋白的表达，分析CD163和Foxp3蛋白的表达与DLBCL临床病理特征的关系及其对患者预后的影响。结果CD163蛋白在DLBCL组织中的高表达率为59．8％，明显高于癌旁组织（15．2％，P=0．02）。Foxp3蛋白在DLBCL组织中的高表达率为41．3％，明显高于癌旁组织（20．7％，P=0．04）。在DLBCL组织中，CD163蛋白与Foxp3蛋白的表达呈正相关（r=2．012，P〈0．05）。单因素分析的结果显示，CD163和Foxp3蛋白的表达均与DLBCL的结外受侵有关。Cox多因素分析的结果显示，CD163和Foxp3蛋白的表达水平均为影响DLBCL患者预后的独立因素（均P〈0．05）。结论联合检测DLBCL组织中CD163和Foxp3蛋白的表达，进而评价M2型巨噬细胞和Tregs的含量可更准确地预测DLBCL患者的预后。