A Novel CD3G Mutation in a Taiwanese Patient With Normal T Regulatory Function Presenting With the CVID Phenotype Free of Autoimmunity-Analysis of all Genotypes and Phenotypes
Authors: Wen-I Lee, Wen-Lang Fan, Chun-Hao Lu, Shih-Hsiang Chen, Ming-Ling Kuo, Syh-Jae Lin, Weng-Sheng Tsai, Tang-Her Jaing, Li-Chen Chen, Kuo-Wei Yeh, Tsung-Chieh Yao, Jing-Long Huang
Journal: Front Immunol (2019)
Keywords: cd3g, t-cell receptor, autoimmune thyroiditis, combined t and b immunodeficiency, common variable immunodeficiency
MeSH terms: Autoimmunity, CD3 Complex / genetics, Common Variable Immunodeficiency / etiology, Common Variable Immunodeficiency / metabolism, Mutation, T-Lymphocytes, Regulatory / immunology, T-Lymphocytes, Regulatory / metabolism, Case Reports, Research Support, Non-U.S. Gov't, Biomarkers, Combined Modality Therapy, Common Variable Immunodeficiency / diagnosis, Common Variable Immunodeficiency / mortality, Disease Susceptibility, Genotype, Humans, Immunologic Memory, Kaplan-Meier Estimate, Lymphocyte Activation / genetics, Lymphocyte Activation / immunology, Male, Pedigree, Phenotype, Treatment Outcome, Biomarkers, CD3 Complex, CD3 antigen, gamma chain

The T-cell receptor (TCR)/CD3 complex is crucial for T-cell development and regulation. In humans, CD3D, CD3E, and CD3Z gene defects cause severe combined T- and B-cell immunodeficiency. However, CD3G mutations alone lead to a less severe condition, which is mainly characterized by autoimmunity. In the present study, we report the case of a 36-year-old male who presented with recurrent sinopulmonary infections without opportunistic infections; this was compatible with hypogammaglobulinemia, but normal PHA-lymphocyte proliferation. This patient had the common variable immunodeficiency (CVID) phenotype and received regular immunoglobulin infusions over 20-years; he gradually developed nodular regenerative hyperplasia over a 5-year period. Distinct from the previously reported CD3G mutations, which mainly present as autoimmunity, the novel CD3G deletion (c.del213A) in our patient caused an obvious decrease in switched memory B cells and diminished CD40L expression. However, sufficient Treg suppression function was maintained so that he remained free of autoimmune thyroiditis (AIT), inflammatory bowel disease (IBD), and autoimmune pancytopenia. A PubMed search for this rare disease entity revealed seven Turkish and two Spanish patients (five unrelated families). Among a total of 20 alleles, there were 14 splicing mutations (80(-1)G>C), two missense mutations (c.1G>A), two nonsense mutations (c.250A>T), and two deletions (c.del213A). Three patients presented with isolated AIT without significant infections. Three patients died, one from a severe infection at 31 months, one from post-transplant respiratory failure due to viral pneumonia at 17 months, and one from graft-vs.-host disease at 47 months. Those experiencing opportunistic infections, severe life-threatening infections in need of hematopoietic stem cell transplantation, and IBD-like diarrhea had a significantly higher mortality rate compared with those without these features (p = 0.0124, p = 0.01, and p = 0.0124, respectively). The patients with AIT had a significantly better prognosis (p = 0.0124) to those without AIT. Our patient with the novel CD3G mutation presented with predominant B-cell deficiency overlapping with the CVID phenotype but without recognizable autoimmunity, which was consistent with his normal Treg suppression function.