Center for Chronic Immunodeficiency (CCI), Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Faculty of Biology, University of Freiburg, Freiburg, Germany.
Center for Chronic Immunodeficiency (CCI), Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Institute for Surgical Pathology, University Medical Center Freiburg, Freiburg, Germany.
J Allergy Clin Immunol. 2018 Feb;141(2):730-740. doi: 10.1016/j.jaci.2017.04.041. Epub 2017 May 26.
A subgroup of patients with common variable immunodeficiency (CVID) experience immune dysregulation manifesting as autoimmunity, lymphoproliferation, and organ inflammation and thereby increasing morbidity and mortality. Therefore treatment of these complications demands a deeper comprehension of their cause and pathophysiology.
On the basis of the identification of an interferon signature in patients with CVID with secondary complications and a skewed follicular helper T-cell differentiation in defined monogenic immunodeficiencies, we sought to determine the profile of CD4 memory T cells in blood and secondary lymphatic tissues of these patients.
We quantified T1/T2/T17 CD4 memory T cells in blood and lymph nodes of patients with CVID using flow cytometry, analyzed their function, and correlated all findings to the burden of immune dysregulation.
Patients with CVID with immune dysregulation had a skewed memory CD4 T-cell differentiation toward a CXCR3CCR6 T1 phenotype both in blood and lymph nodes. Consistent with our phenotypic findings, we observed a higher IFN-γ production in peripheral CD4 memory T cells and lymph node-derived follicular helper T cells of patients with CVID compared with those of healthy control subjects. Increased IFN-γ production was accompanied by a poor germinal center output, an accumulation of T-box transcription factor (T-bet) B cells in lymph nodes, and an accumulation of T-betCD21 B cells in peripheral blood of affected patients.
Identification of excessive IFN-γ production by blood and lymph node-derived T cells of patients with CVID with immune dysregulation will offer new therapeutic avenues for this subgroup. CD21 B cells might serve as a marker of this IFN-γ-associated dysregulation.
一部分普通变异型免疫缺陷（CVID）患者存在免疫失调，表现为自身免疫、淋巴增生和器官炎症，从而增加发病率和死亡率。因此，治疗这些并发症需要深入了解其病因和病理生理学。
基于在具有继发性并发症的 CVID 患者中鉴定出干扰素特征，以及在明确的单基因免疫缺陷中鉴定出滤泡辅助 T 细胞分化的倾斜，我们试图确定这些患者血液和次级淋巴组织中 CD4 记忆 T 细胞的特征。
我们使用流式细胞术定量测定 CVID 患者血液和淋巴结中 T1/T2/T17 CD4 记忆 T 细胞，分析其功能，并将所有发现与免疫失调的负担相关联。
存在免疫失调的 CVID 患者在血液和淋巴结中均存在向 CXCR3CCR6 T1 表型的记忆 CD4 T 细胞分化倾斜。与我们的表型发现一致，与健康对照相比，CVID 患者外周血 CD4 记忆 T 细胞和淋巴结来源的滤泡辅助 T 细胞中观察到更高的 IFN-γ 产生。增加的 IFN-γ 产生伴随着生发中心输出减少、淋巴结中 T 框转录因子（T-bet）B 细胞积累以及受影响患者外周血中 T-betCD21 B 细胞积累。
鉴定出具有免疫失调的 CVID 患者血液和淋巴结来源的 T 细胞中过度产生 IFN-γ，将为这一组患者提供新的治疗途径。CD21 B 细胞可能作为与 IFN-γ 相关失调的标志物。
