Inborn errors of IFN-γ immunity can underlie tuberculosis (TB). We report three patients from two kindreds without EBV viremia or disease but with severe TB and inherited complete ITK deficiency, a condition associated with severe EBV disease that renders immunological studies challenging. They have CD4+ αβ T lymphocytopenia with a concomitant expansion of CD4−CD8− double-negative (DN) αβ and Vδ2− γδ T lymphocytes, both displaying a unique CD38+CD45RA+T-bet+EOMES− phenotype. Itk-deficient mice recapitulated an expansion of the γδ T and DN αβ T lymphocyte populations in the thymus and spleen, respectively. Moreover, the patients’ T lymphocytes secrete small amounts of IFN-γ in response to TCR crosslinking, mitogens, or forced synapse formation with autologous B lymphocytes. Finally, the patients’ total lymphocytes secrete small amounts of IFN-γ, and CD4+, CD8+, DN αβ T, Vδ2+ γδ T, and MAIT cells display impaired IFN-γ production in response to BCG. Inherited ITK deficiency undermines the development and function of various IFN-γ–producing T cell subsets, thereby underlying TB.

Multisystem inflammatory syndrome in children (MIS-C) is a rare condition following SARS-CoV-2 infection associated with intestinal manifestations. Genetic predisposition, including inborn errors of the OAS-RNAseL pathway, has been reported. We sequenced 154 MIS-C patients and utilized a novel statistical framework of gene burden analysis, “burdenMC,” which identified an enrichment for rare predicted-deleterious variants in BTNL8 (OR = 4.2, 95% CI: 3.5–5.3, P < 10−6). BTNL8 encodes an intestinal epithelial regulator of Vγ4+γδ T cells implicated in regulating gut homeostasis. Enrichment was exclusive to MIS-C, being absent in patients with COVID-19 or bacterial disease. Using an available functional test for BTNL8, rare variants from a larger cohort of MIS-C patients (n = 835) were tested which identified eight variants in 18 patients (2.2%) with impaired engagement of Vγ4+γδ T cells. Most of these variants were in the B30.2 domain of BTNL8 implicated in sensing epithelial cell status. These findings were associated with altered intestinal permeability, suggesting a possible link between disrupted gut homeostasis and MIS-C-associated enteropathy triggered by SARS-CoV-2.

Background. Common variable immunodeficiency (CVID) is a primary immunodeficiency disorder (PID) that typically presents with hypogammaglobulinemia and impaired antibody production. Objectives. This study aimed to promote the awareness of CVID, whose clinical spectrum is quite broad. Methods. The demographic, clinical, and laboratory characteristics of 12 children (seven males and five females) with CVID were analyzed retrospectively. The patients were diagnosed using the diagnostic criteria of the European Society for Primary Immunodeficiencies. Results. The median disease onset age was 7.2±4.1 years, and the mean diagnosis age was 11.6±3.7 years. The diagnosis delay was 4.3±2.6 years, and the parental consanguinity rate was 75%. Most patients presented with recurrent infections, including upper respiratory tract infections (n=8), lower respiratory tract infections (n=9), and gastroenteritis (n=5). In addition, growth retardation (n=9) and bronchiectasis (n=5) were common comorbidities. Two patients presented with autoimmune thrombocytopenia and anemia, and one patient exhibited lung empyema. All the patients had immunoglobulin G deficiencies. Conclusion. CVID is a heterogeneous disease, so the diagnosis is frequently delayed. In the CVID patients with pulmonary complications, relationships were seen with the diagnosis delay, symptom onset age, and lung infection prevalence. Overall, the early diagnosis and treatment of PIDs can preclude life-threatening complications.