Expansion of extrafollicular B and T cell subsets in childhood-onset systemic lupus erythematosus.
Expansion of extrafollicular B and T cell subsets in childhood-onset systemic lupus erythematosus.
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儿童期发病的系统性红斑狼疮中叶外 B 细胞和 T 细胞亚群的扩增。
DOI：
10.3389/fimmu.2023.1208282
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发表时间：
2023
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
--
作者：
大多数儿童期发作的SLE患者（cSLE）发展为狼疮性肾炎（cLN），但只有一小部分对目前的治疗达到完全反应。LN和终末期肾病患儿的预后尤其可怕。在肾脏替代治疗的前五年内，死亡率可能达到22%。因此，迫切需要破译和靶向驱动cLN的免疫机制。尽管自身抗体产生在SLE中的作用明确，但靶向B细胞疗法如利妥昔单抗（抗CD 20）和贝利木单抗（抗BAFF）在cLN中仅显示出适度的疗效。虽然许多研究已经将生发中心形成的失调与SLE发病机制联系起来，但其他工作支持滤泡外B细胞活化在产生致病性抗体分泌细胞中的作用。然而，滤泡外B细胞亚群及其T细胞合作者是否在cLN的特定器官参与和/或疾病活动性的轨迹中发挥作用仍然未知。我们分析了24例初治cSLE患者在诊断时和纵向的高维质谱细胞计数和基因表达数据，应用新型计算工具来识别与临床表现（cLN）和疾病活动（SLEDAI）相关的异常。cSLE患者具有滤泡外B细胞扩增特征，i）DN 2、ii）Bnd 2、iii）浆母细胞和iv）外周T辅助细胞的频率增加。最重要的是，我们发现这种滤泡外标记与cLN的疾病活动相关，支持滤泡外T/B相互作用作为儿童肾脏发病机制的基础。本研究整合了SLE中滤泡外B细胞参与的既定和新出现的主题，通过提供证据证明滤泡外B和外周T辅助细胞扩增，沿着升高的1型IFN活化，在一个同质队列的初治cSLE患者中，他们应该表现出最极端的免疫失调状态。
Most childhood-onset SLE patients (cSLE) develop lupus nephritis (cLN), but only a small proportion achieve complete response to current therapies. The prognosis of children with LN and end-stage renal disease is particularly dire. Mortality rates within the first five years of renal replacement therapy may reach 22%. Thus, there is urgent need to decipher and target immune mechanisms that drive cLN. Despite the clear role of autoantibody production in SLE, targeted B cell therapies such as rituximab (anti-CD20) and belimumab (anti-BAFF) have shown only modest efficacy in cLN. While many studies have linked dysregulation of germinal center formation to SLE pathogenesis, other work supports a role for extrafollicular B cell activation in generation of pathogenic antibody secreting cells. However, whether extrafollicular B cell subsets and their T cell collaborators play a role in specific organ involvement in cLN and/or track with disease activity remains unknown. We analyzed high-dimensional mass cytometry and gene expression data from 24 treatment naïve cSLE patients at the time of diagnosis and longitudinally, applying novel computational tools to identify abnormalities associated with clinical manifestations (cLN) and disease activity (SLEDAI). cSLE patients have an extrafollicular B cell expansion signature, with increased frequency of i) DN2, ii) Bnd2, iii) plasmablasts, and iv) peripheral T helper cells. Most importantly, we discovered that this extrafollicular signature correlates with disease activity in cLN, supporting extrafollicular T/B interactions as a mechanism underlying pediatric renal pathogenesis. This study integrates established and emerging themes of extrafollicular B cell involvement in SLE by providing evidence for extrafollicular B and peripheral T helper cell expansion, along with elevated type 1 IFN activation, in a homogeneous cohort of treatment-naïve cSLE patients, a point at which they should display the most extreme state of their immune dysregulation.
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影响因子：
27.4
作者：
Bertsias GK;Tektonidou M;Amoura Z;Aringer M;Bajema I;Berden JH;Boletis J;Cervera R;Dörner T;Doria A;Ferrario F;Floege J;Houssiau FA;Ioannidis JP;Isenberg DA;Kallenberg CG;Lightstone L;Marks SD;Martini A;Moroni G;Neumann I;Praga M;Schneider M;Starra A;Tesar V;Vasconcelos C;van Vollenhoven RF;Zakharova H;Haubitz M;Gordon C;Jayne D;Boumpas DT;European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association
通讯作者：
European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association
影响因子：
7
作者：
Andreakos E;Zanoni I;Galani IE
通讯作者：
Galani IE
影响因子：
3.7
作者：
Lugar PL;Love C;Grammer AC;Dave SS;Lipsky PE
通讯作者：
Lipsky PE
影响因子：
4.7
作者：
Hahn, Bevra H.;McMahon, Maureen A.;Wilkinson, Alan;Wallace, W. Dean;Daikh, David I.;Fitzgerald, John D.;Karpouzas, George A.;Merrill, Joan T.;Wallace, Daniel J.;Yazdany, Jinoos;Ramsey-Goldman, Rosalind;Singh, Karandeep;Khalighi, Mazdak;Choi, Soo-In;Gogia, Maneesh;Kafaja, Suzanne;Kamgar, Mohammad;Lau, Christine;Martin, William J.;Parikh, Sefali;Peng, Justin;Rastogi, Anjay;Chen, Weiling;Grossman, Jennifer M.
通讯作者：
Grossman, Jennifer M.
影响因子：
2.5
作者：
Ardoin, Stacy P.;Daly, R. Paola;Hersh, Aimee O.
通讯作者：
Hersh, Aimee O.