Akarsu Ayşegül, Halaçlı Sevil, Tan Çağman, Kuşkonmaz Barış, Küpesiz Alphan, Çetinkaya Duygu, Sanal Özden, Tezcan İlhan, Çağdaş Deniz
Hacettepe University Faculty of Medicine, Department of Pediatric Immunology, Ankara, Turkey.
Hacettepe University, Health Science Institute, Institute of Child Health, Department of Pediatric Immunology, Ankara, Turkey.
Scand J Immunol. 2022 Nov;96(5):e13213. doi: 10.1111/sji.13213. Epub 2022 Sep 1.
Isotype class-switch recombination (CSR), somatic hypermutation (SHM), B cell signalling and DNA repair mechanisms defects are responsible for high IgM. The hyperimmunoglobulin M (HIGM) phenotype and CSR-related defects are now classified under primary antibody defects, combined immunodeficiencies or syndromic immunodeficiencies groups. The aim of the study is to evaluate the diverse phenotypic/genotypic/laboratory characteristics and outcome of patients with CSR defects and HIGM-related defects. We enrolled 50 patients. The most common gene defect was Activation-induced cytidine deaminase (AID) deficiency (n = 18), followed by CD40 Ligand (CD40L) (n = 14) and CD40 (n = 3) deficiency. Median ages at first symptom and diagnosis were significantly lower in CD40L deficiency (8.5 and 30 months, respectively) than AID deficiency (30 and 114 months, respectively) (p = .001 and p = .008, respectively). Frequent clinical symptoms were recurrent (66%) and severe (14.9%) infections, and/or autoimmune/non-infectious inflammatory features (48.4%). Eosinophilia and neutropenia were at a higher rate in CD40L deficiency patients (77.8%, p = .002 and 77.8%, p = .002, respectively) when compared to AID deficiency. Median serum IgM level was low in 28.6% of CD40L deficiency patients. It was significantly lower when compared to AID deficiency (p < 0.001). Six patients (CD40L deficiency n = 4, CD40 deficiency n = 2) underwent hematopoietic stem cell transplantation. Five were alive at the last visit. Four patients two patients with CD40L deficiency, one with CD40 deficiency and one with AID deficiency had novel mutations. In conclusion; patients with CSR defects and HIGM phenotype may present with a wide range of clinical manifestations and laboratory findings. Low IgM, neutropenia and eosinophilia were prominent in patients with CD40L deficiency. Characterization of genetic defect-specific clinical and laboratory features may ease the diagnosis, prevent the underdiagnoses of patients and ameliorate the outcome.
同种型类别转换重组（CSR）、体细胞高频突变（SHM）、B细胞信号传导和DNA修复机制缺陷是导致高IgM的原因。高免疫球蛋白M（HIGM）表型和与CSR相关的缺陷现在被归类于原发性抗体缺陷、联合免疫缺陷或综合征性免疫缺陷组。本研究的目的是评估具有CSR缺陷和与HIGM相关缺陷患者的不同表型/基因型/实验室特征及预后。我们招募了50名患者。最常见的基因缺陷是活化诱导胞苷脱氨酶（AID）缺乏（n = 18），其次是CD40配体（CD40L）（n = 14）和CD40（n = 3）缺乏。CD40L缺乏患者首次出现症状和诊断时的中位年龄（分别为8.5个月和30个月）显著低于AID缺乏患者（分别为30个月和114个月）（p分别为0.001和0.008）。常见的临床症状是反复感染（66%）和严重感染（14.9%），和/或自身免疫/非感染性炎症特征（48.4%）。与AID缺乏患者相比，CD40L缺乏患者的嗜酸性粒细胞增多症和中性粒细胞减少症发生率更高（分别为77.8%，p = 0.002和77.8%，p = 0.002）。28.6%的CD40L缺乏患者血清IgM水平中位数较低。与AID缺乏患者相比，其显著更低（p < 0.001）。6名患者（4名CD40L缺乏、2名CD40缺乏）接受了造血干细胞移植。最后一次随访时有5名存活。4名患者（2名CD40L缺乏、1名CD40缺乏和1名AID缺乏）有新的突变。总之，具有CSR缺陷和HIGM表型的患者可能表现出广泛的临床表现和实验室检查结果。CD40L缺乏患者中低IgM、中性粒细胞减少症和嗜酸性粒细胞增多症较为突出。对基因缺陷特异性临床和实验室特征的描述可能有助于诊断，防止患者漏诊并改善预后。
