Defining New Human Immunodeficiency and Immunodysregulation Disorders

National Institute Of Allergy And Infectious Diseases

Investigators

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Abstract

Besides unique patients with immunodeficiency and immunodysregulation disorders lacking known diagnoses, our intake includes patients with combined immunodeficiency, common variable immunodeficiency (CVID), variants of hyper-IgE syndrome or autoimmune lymphoproliferative syndrome (ALPS), Evans syndrome, caspase-8-deficiency state (CEDS), B cell expansion with NF-kB and T cell anergy (BENTA) disease, X-linked Magnesium defect with EBV infection and Neoplasia (XMEN), PASLI/APDS (p110 delta activation mutation causing senescent T cells, lymphadenopathy, and immunodeficiency / Activated PI3K delta syndrome) disease, CHAI (CTLA4 haploinsufficiency with autoimmune infiltration) disease, and MAGIS (Midline malformations of the brain, Anterior pituitary gland dysfunction, Growth retardation, Immunodysregulation/immunodeficiency, and Skeletal defects) syndrome. Patients with susceptibility to EBV, rhinovirus, influenza virus, respiratory syncytial virus, and other respiratory viruses, including those with MDA5 deficiency, are also being investigated. Our evaluation includes functional screening and gene sequencing, and a subset of patients is also being intensively studied using biochemical analyses, RNA-seq with PAR-CLIP, flow cytometric analyses, in vitro functional tests, and other technologies. These experiments have provided leads for sequencing of new candidate genes not previously associated with disease. Additionally, we are using comparative genomic hybridization (CGH) arrays, whole exome sequencing, whole genome sequencing, and other technologies to determine genetic causes of new immunological diseases in an unbiased manner. In FY2025, we continued our work on investigating the molecular pathogenesis of several as yet undescribed immunodeficiency-immunodysregulation disorders, as well as the natural history and optimal treatment of previously reported rare immunological disorders. For the former, we contributed to the report of a new inherited cause of lymphangiectasia / protein-losing enteropathy due to loss-of-function mutations in the E3 ubiquitin ligase NEDD4 that regulates autophagy. We also continued to work on understanding the physiological impact of altered G-protein signaling in MAGIS (Midline malformations of the brain, Anterior pituitary gland dysfunction, Growth retardation, Immunodysregulation / immunodeficiency, and Skeletal defects) syndrome, focusing on effects on inflammation and non-immune functioning of various organ systems. Such knowledge is important not only for improving patient diagnosis of a rare disorder, but also because it reveals new molecular target(s) for the development of potential immunomodulatory and other treatments.