X-linked severe combined immunodeficiency disease (X-SCID) is a rare inherited disease caused by mutations in the interleukin 2 receptor subunit gamma gene (IL2RG), which encodes the common γ chain protein, a subunit of the receptor for lymphocytes. X-SCID is characterized by profound defects in T-cell, B-cell, and natural killer cell function. Here, we report a Chinese cohort of nine X-SCID patients with six novel IL2RG mutations. Among those, the two adolescent patients with an atypical immunotype were confirmed by further analyzing IL-2-JAK-STAT5 signaling, T cell proliferation, and T cell receptor excision circles (Trecs). Interestingly, Bacillus Calmette-Guérin (BCG) disease occurred commonly in this cohort. Although allogeneic hematopoietic stem-cell transplantation is curative for the disease, it is not available to all patients due to the lack of suitable matched donors. Autologous gene therapy using a self-inactivating lentiviral vector (SIN-LV) technology has provided an alternative therapy for such mono-genetic diseases. Here, we performed the pre-clinical studies to assess our SIN-LV carrying IL2RG on human ED7R cells deficient in IL2RG and CD34⁺ stem cells derived from the bone marrow of a healthy donor and a patient with X-SCID. This work is done complied with the established “Good Manufacturing Practice” (GMP) used in the clinical trials. In addition, a safety study is performed using the transduced CD34⁺ cells implanted into the axilla of nude mice in vivo. Overall, our studies have demonstrated the efficiency and safety of SIN-IL2RG-LV, which paves the way for conducting X-SCID gene therapy clinical trials in China in the near future.

Germline heterozygous gain-of-function (GOF) mutation of NFKBIA, encoding IκBα, would affect the activation of NF-κB pathway and cause an autosomal dominant (AD) form of anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID). Here we reported a Chinese patient with a heterozygous N-terminal truncation mutation of NFKBIA/IκBα. She presented recurrent fever, infectious pneumonia and chronic diarrhea with EDA-ID. Impaired NF-κB translocation and IL1R and TLR4 pathway activation were revealed in this patient. The findings suggested that the truncation mutation of IκBα caused medium impaired of activation of NF-κB but the early death. Furthermore, we reviewed all the reported patients with NFKBIA mutation to learn more about this disease.

Activated phosphoinositide 3-kinase δ syndrome 1 (APDS1) is a primary immunodeficiency disease caused by gain-of-function mutations in PIK3CD. Clinical features of autoimmune disease have been reported in patients with APDS1. In this study, we reported three patients with APDS1 presenting with systemic lupus erythematosus (SLE) phenotype. The clinical manifestations included recurrent respiratory tract infection, lymphoproliferation, Coombs-positive hemolytic anemia, decreased complement fractions, positive antinuclear antibodies, renal complications related to SLE associated diseases, which met the clinical spectrum of APDS1 and the classification criteria of SLE. The immunological phenotype included an inversion in the CD4:CD8 ratio, an increase in both non-circulating Tfh CD4⁺ memory T and circulating Tfh populations, a low level of recent thymic emigrant T cells, overexpression of CD57 on T cells, and a decrease in B cells with fewer antibody class switch recombination. These phenotypes detected in patients with APDS1 presenting with SLE were resemble that in patients with APDS1 presenting without SLE. Meanwhile, we described the effect of glucocorticoids and rapamycin therapy on patients with APDS1. The phosphorylation of S6 at Ser235/236 was inhibited in patients with APDS1 who underwent glucocorticoids therapy, including two who presented with SLE phenotype. The phosphorylation of AKT at Ser473 and phosphorylation of S6 at Ser235/236 were inhibited in other patients with APDS1 who underwent rapamycin therapy. Here, we showed the coexistence of immunodeficiency and SLE phenotype in APDS1, and the inhibition of rapamycin in activated Akt-mTOR signaling pathway.

CTLA4 deficiency and LRBA deficiency are a group disorders of immune dysregulation that affect CTLA4 pathway. The patients mainly present with autoimmunity, antibody deficiency and recurrent infections. Here we reported three Chinese patients with LRBA and CTLA4 mutations. They all presented with chronic diarrhea, hypokalemia, organomegaly, recurrent infections, and hypogammaglobulinemia. Reduced Treg cells and increased percentage of circulating follicular helper T (cTfh) cells were revealed in these patients. Although steroid and immunoglobulin therapy were given, the enteropathy was persistent. Therefore, abatacept treatment was provided to these patients. They showed a marked improvement of enteropathy and gastrointestinal endoscopy showed alleviated inflammatory lesion and follicular hyperplasia. Furthermore, the frequency of cTfh cells was reduced after abatacept therapy. Taken together, targeted therapy with abatacept is a promising treatment modality for patients with LRBA and CTLA4 deficiency. The findings also suggest that the frequency of cTfh cells could serve as a marker for tracking disease activity and the response to abatacept therapy.

Mutations in the gene encoding transfer RNA (tRNA) nucleotidyltransferase, CCA-adding 1 (TRNT1), an enzyme essential for the synthesis of the 3′-terminal CCA sequence in tRNA molecules, are associated with a rare syndrome of congenital sideroblastic anemia, B cell immunodeficiency, periodic fevers, and developmental delay (SIFD). Clinical manifestations and immunological phenotypes were assessed in a Chinese patient with novel compound heterozygous mutations in TRNT1. The patient required multiple hospitalizations starting at the age of 2 years for recurrent fevers without an infective cause. During the febrile episode, the patient was found to have microcytic hypochromic anemia, B cell lymphopenia, and hypogammaglobulinemia. Targeted gene sequencing identified novel compound heterozygous mutations in the TRNT1 gene (c.525delT, p.Leu176X; c.938T>C, p.Leu313Ser). Immunophenotyping revealed increased CD8⁺ T cells, CD4⁺ terminally differentiated effector memory helper T lymphocytes (CD4 TEMRA), and CD4⁺ effector memory lymphocytes (CD4 EM). Analysis of CD4⁺ T subsets identified decreased T follicular helper cells (Tfh) with a biased phenotype to Th2-like cells. The patient also showed a lower percentage of switched memory B (smB) cells. Additionally, defects in the cytotoxicity of the patient’s NK and γδT cells were shown by CD107alpha expression. In conclusion, TRNT1 mutations may lead to multiple immune abnormality especially humoral and cytotoxicity defects, which indicate that SIFD is not only suffered ‘Predominantly antibody deficiencies’ in IUIS classification system, and further studies are needed to understand the pathogenesis of immunodeficiency in these patients.