Department of Pediatrics, Dalhousie University, Halifax, NS, Canada.
CSL Behring Research, CSL Biologics Research Center, Bern, Switzerland.
Front Immunol. 2021 May 19;12:660506. doi: 10.3389/fimmu.2021.660506. eCollection 2021.
Intravenous immunoglobulin (IVIG) is an effective immunomodulatory treatment for immune dysregulation diseases. However, the mechanisms by which it reduces systemic inflammation are not well understood. NK cell cytotoxicity is decreased by IVIG in women with reduced fertility, but IVIG effects on NK cells in immune dysregulation are less clear. We hypothesized that IVIG modulation of lymphocyte function, especially in NK cells, is important for resolution of inflammation. Our aim was to identify IVIG-induced changes in a cohort of patients with Kawasaki disease (KD) and those that occur broadly in pediatric patients with various immune dysregulatory diseases. Peripheral blood mononuclear cells (PBMCs) of patients with KD or autoimmune/inflammatory diseases were phenotyped pre and post high dose IVIG treatment by flow cytometry. In KD patients, after IVIG infusion T cell frequency and the proportion of activated CD25 immunoregulatory CD56 NK cells was increased, and multiple lymphocyte subsets showed increased expression of the lymphoid tissue homing receptor CD62L. Importantly, IVIG treatment decreased the frequency of cells expressing the degranulation marker CD107a among cytotoxic CD56 NK cells, which was reflected in a significant reduction in target cell killing and in decreased production of multiple pro-inflammatory mediators. Interestingly, the activating receptor CD336 was expressed on a higher proportion of CD56 NK cells after IVIG in both KD and autoimmune/inflammatory patients while other NK receptors were increased differentially in each cohort. In autoimmune/inflammatory patients IVIG induced the proliferation marker CD71 on a higher percentage of CD56 NK cells, and in contrast to KD patients, CD107a cells were increased in this subset. Furthermore, when PBMCs were stimulated with IL-2 or antigen in autologous plasma, more of the CD4 T cells of KD patients expressed CD25 after IVIG therapy but fewer cytotoxic T cells were degranulated based on CD107a expression. In summary, IVIG treatment in patients with immune dysregulation has multiple effects, especially on NK cell subsets and CD4 T cells, which are compatible with promoting resolution of inflammation. These novel findings provide insight into the immunomodulatory actions of IVIG in autoimmune and inflammatory conditions.
静脉注射免疫球蛋白（IVIG）是一种有效的免疫调节治疗方法，可用于治疗免疫失调疾病。然而，其降低全身炎症的机制尚不清楚。IVIG 可降低生育能力降低的女性的 NK 细胞细胞毒性，但 IVIG 对免疫失调患者 NK 细胞的影响尚不清楚。我们假设 IVIG 对淋巴细胞功能的调节，尤其是 NK 细胞，对于炎症的消退很重要。我们的目的是确定 IVIG 在川崎病（KD）患者亚群以及在具有各种免疫失调疾病的儿科患者中引起的变化。通过流式细胞术对 KD 患者或自身免疫性/炎症性疾病患者的外周血单个核细胞（PBMC）进行表型分析，在接受高剂量 IVIG 治疗前后进行分析。在 KD 患者中，IVIG 输注后 T 细胞频率和活化的 CD25 免疫调节性 CD56 NK 细胞的比例增加，并且多个淋巴细胞亚群表达的淋巴细胞组织归巢受体 CD62L 增加。重要的是，IVIG 治疗降低了细胞毒性 CD56 NK 细胞中表达脱颗粒标记物 CD107a 的细胞的频率，这反映在靶细胞杀伤能力显著降低和多种促炎介质的产生减少。有趣的是，在 KD 和自身免疫性/炎症性患者中，IVIG 后 CD56 NK 细胞上表达的激活受体 CD336 的比例更高，而其他 NK 受体在每个队列中都以不同的方式增加。在自身免疫性/炎症性患者中，IVIG 诱导更高比例的 CD56 NK 细胞上的增殖标记物 CD71，与 KD 患者不同，该亚群中 CD107a 细胞增加。此外，当用 IL-2 或自体血浆中的抗原刺激 PBMC 时，KD 患者的更多 CD4 T 细胞在接受 IVIG 治疗后表达 CD25，但基于 CD107a 表达，更少的细胞毒性 T 细胞脱颗粒。总之，免疫失调患者的 IVIG 治疗具有多种作用，尤其是对 NK 细胞亚群和 CD4 T 细胞，这与促进炎症消退一致。这些新发现为 IVIG 在自身免疫和炎症状态下的免疫调节作用提供了新的见解。
