Defining New Human Immunodeficiency and Immunodysregulation Disorders

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications, trials & patents

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 (p110 delta activation mutation causing senescent T cells, lymphadenopathy, and immunodeficiency) disease, and CHAI (CTLA4 haploinsufficiency with autoimmune infiltration) disease. Patients with susceptibility to EBV, rhinovirus, influenza virus, respiratory syncytial virus, and other respiratory viruses 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, gene expression microarrays, 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 FY2021, 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. We extended our work on human IFIH1(MDA5) deficiency (complete or partial) to report a genetic association with very early onset inflammatory bowel disease. We also contributed to several studies that were published in FY2021, which are briefly summarized as follows: We contributed to the first report of human IL-37 deficiency as a cause of very early onset inflammatory bowel disease. We also contributed to reports of 1) CARMIL2-deficient patient cohort describing natural history, clinical laboratory testing, and cytoskeletal abnormalities; 2)GIMAP5 deficiency focusing on the liver abnormalities; and 3)anti-type I IFN autoantibodies associated with disseminated yellow fever virus.