Project description:Dysregulation of DNA double-strand break (DSB) repair leads to adaptive immunodeficiency, while the remaining lymphocytes are aberrantly activated and provoke inflammation. To clarify the biological impact of the LIG4 W447C variant identified in our patient, we generated the mutant mice of DNA ligase IV (LIG4), which is critical for DSB repair. Lig4_W447C/W447C mice showed severe intestinal inflammation under adaptive immunodeficiency. The inflammation was featured by a marked infiltration of T helper type 1 (Th1) cells and macrophages. We used scRNA-seq to analyse the detailed splenocyte population and T cell receptor repertoire in Lig4_W447C/W447C mice. Evaluation of the T cell receptor repertoire in Lig4_W447C/W447C mice revealed activated oligoclonal Th1 cells with restricted Vα diversity. Thus, our present results with our novel hypomorphic Lig4 mutant mice show that defective DSB repair leads to Th1-dependent intestinal inflammation under severe adaptive immunodeficiency.
2026-08-18 | GSE294169 | GEO
Project description:A de novo mutation in ITPR3 causes severe combined immunodeficiency
Project description:Loss of function mutations of ORAI1 suppress store-operated Ca2+ entry (SOCE) and cause an immunodeficiency disorder called Ca2+ release-activated Ca2+ (CRAC) channelopathy. An infant patient who is compound heterozygous for His134Pro and Leu194Pro mutations in the ORAI1 gene had strongly reduced SOCE in response to T cell receptor stimulation. He suffered from a severe form of combined immunodeficiency (CID) resulting in fatal chronic cytomegalovirus infection. Single cell transcriptomics revealed an overall strong activation of the patient's T cells but attenuated CD8+ effector memory T cell function.
Project description:Overall, this work describes the largest cohort of patients with RAG mutations and an associated phenotype consisting of combined immunodeficiency and granulomatous lesions and/or autoimmunity (CID-G/AI). By using multiple methods (microarray, ELISA and multiplex bead technology), we have consistently identified a distinctive signature of anti-cytokine antibodies in patients with RAG-dependent immunodeficiencies, especially in those with CID-G/AI and a history of severe viral infections. These autoantibodies were not detected in a large panel of patients with other forms of primary immunodeficiency, and may therefore represent a novel biomarker panel of this condition. Known autoantigens, cytokines, chemokines, growth factors and receptors were printed onto microarrays. All targets were printed in triplicate. Arrays were probed with diluted plasma and autoantibodies were detected with a AF647 conjugated anti-human IgG secondary.
Project description:Overall, this work describes the largest cohort of patients with RAG mutations and an associated phenotype consisting of combined immunodeficiency and granulomatous lesions and/or autoimmunity (CID-G/AI). By using multiple methods (microarray, ELISA and multiplex bead technology), we have consistently identified a distinctive signature of anti-cytokine antibodies in patients with RAG-dependent immunodeficiencies, especially in those with CID-G/AI and a history of severe viral infections. These autoantibodies were not detected in a large panel of patients with other forms of primary immunodeficiency, and may therefore represent a novel biomarker panel of this condition.
Project description:Reticular Dysgenesis (RD) is a rare but devastating form of severe combined immunodeficiency, characterized by a maturation arrest of the myeloid and lymphoid lineages paired with sensorineural hearing loss. RD is caused by biallelic loss-of-function mutations in the mitochondrial enzyme adenylate kinase 2 (AK2). To study the effect of AK2 depletion on HSPC differentiation, we developed a biallelic AK2 CRISPR knock-out model using human HSPCs. AK2 depleted HSPCs display severe proliferation and myeloid differentiation defects, recapitulating RD patient phenotype.