Janssen Erin, Alosaimi Mohammad F, Alazami Anas M, Alsuliman Abdullah, Alaiya Ayodele, Al-Saud Bandar, Al-Mousa Hamoud, Al-Zaid Tariq Jassim, Smith Emma, Platt Craig D, Alruwaili Hibah, Albanyan Sarah, Al-Mayouf Sulaiman M, Geha Raif S
Division of Immunology, Boston Children's Hospital and Harvard Medical School, Boston, Mass.
Immunology Research Laboratory, Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
J Allergy Clin Immunol. 2023 Feb;151(2):572-578.e1. doi: 10.1016/j.jaci.2022.10.006. Epub 2022 Oct 13.
The type II transmembrane protein fibrinogen-like protein 2 (FGL2) plays critical roles in hemostasis and immune regulation. The C-terminal immunoregulatory domain of FGL2 can be secreted and is a mediator of regulatory T (Treg) cell suppression. Fgl2 mice develop autoantibodies and glomerulonephritis and have impaired Treg cell function.
Our aim was to identify the genetic underpinning and immune function in a patient with childhood onset of leukocytoclastic vasculitis, systemic inflammation, and autoantibodies.
Whole-exome sequencing was performed on patient genomic DNA. FGL2 protein expression was examined in HEK293 transfected cells by immunoblotting and in PBMCs by flow cytometry. T follicular helper cells and Treg cells were examined by flow cytometry. Treg cell suppression of T-cell proliferation was assessed in vitro.
The patient had a homozygous mutation in FGL2 (c.614_617del:p.V205fs), which led to the expression of a truncated FGL2 protein that preserves the N-terminal domain but lacks the C-terminal immunoregulatory domain. The patient had an increased percentage of circulating T follicular helper and Treg cells. The patient's Treg cells had impaired in vitro suppressive ability that was rescued by the addition of full-length FGL2. Unlike full-length FGL2, the truncated FGL2 mutant failed to suppress T-cell proliferation.
We identified a homozygous mutation in FGL2 in a patient with immune dysregulation and impaired Treg cell function. Soluble FGL2 rescued the Treg cell defect, suggesting that it may provide a useful therapy for the patient.
II型跨膜蛋白纤维蛋白原样蛋白2（FGL2）在止血和免疫调节中起关键作用。FGL2的C末端免疫调节结构域可被分泌，是调节性T（Treg）细胞抑制的介质。Fgl2基因敲除小鼠会产生自身抗体和肾小球肾炎，且Treg细胞功能受损。
我们的目的是确定一名患有儿童期白细胞破碎性血管炎、全身炎症和自身抗体的患者的遗传基础和免疫功能。
对患者基因组DNA进行全外显子组测序。通过免疫印迹法在HEK293转染细胞中检测FGL2蛋白表达，通过流式细胞术在PBMC中检测。通过流式细胞术检测T滤泡辅助细胞和Treg细胞。在体外评估Treg细胞对T细胞增殖的抑制作用。
该患者FGL2基因存在纯合突变（c.614_617del:p.V205fs），导致截短的FGL2蛋白表达，该蛋白保留N末端结构域但缺乏C末端免疫调节结构域。该患者循环T滤泡辅助细胞和Treg细胞百分比增加。患者的Treg细胞体外抑制能力受损，添加全长FGL2可使其恢复。与全长FGL2不同，截短的FGL2突变体无法抑制T细胞增殖。
我们在一名免疫失调且Treg细胞功能受损的患者中鉴定出FGL2基因的纯合突变。可溶性FGL2挽救了Treg细胞缺陷，表明它可能为该患者提供有效的治疗方法。
