Defining New Human Immunodeficiency and Immunodysregulation Disorders

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Besides unique patients with immunodeficiency and immunodysregulation disorders lacking known diagnoses, our intake includes patients with combined immunodeficiency, variants of hyper-IgE syndrome, variants of autoimmune lymphoproliferative syndrome (ALPS) or caspase-8-deficiency state (CEDS), common variable immunodeficiency (CVID), X-linked lymphoproliferative syndrome (XLP), and Evans syndrome. In 2013, we evaluated 240 new patients and their relatives over the past year, for 1217 cumulatively, using functional screening and gene sequencing. A subset is 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 started using comparative genomic hybridization (CGH) arrays, whole exome sequencing, and other technologies to determine genetic causes of new immunological diseases in an unbiased manner. Using these technologies, in 2009 we discovered that DOCK8 mutations are associated with a combined immunodeficiency that includes cases of what was previously termed autosomal recessive hyper-IgE syndrome. Since then, our studies have focused on understanding how absence of DOCK8 leads to the lymphocyte abnormalities that contribute to the problems the patients have in handling viral infections. Because little is known about DOCK8, studying how it normally works to regulate immune cells in preventing infections, allergies, and cancers, may help us better understand why patients in the general population suffer similar problems. As part of this effort, we have contributed to a study in 2013 showing that invariant NK T cells show a survival defect that impairs their normal functions. In 2012, we contributed to the discovery of a new disease that results from gain-of-function CARD11 mutations, which we term B cell expansion with NF-κB and T cell anergy (BENTA) disease. Whereas somatic mutations in the same gene are associated with B cell lymphomas, germline mutations cause a polyclonal, non-malignant B cell expansion driven by NF-κB activation. However, patients unexpectedly have a mild immunodeficiency accompanied by T cell anergy, suggesting an unappreciated role of constitutive CARD11 expression in regulating T cell homeostasis. In 2011, we contributed to the discovery of X-linked Magnesium defect with EBV infection and Neoplasia (XMEN), a disease that results from mutations in MAGT1. We have defined further the clinical spectrum of disease as being hallmarked by EBV-related lymphoproliferative disease. In doing so, in 2013 we helped to establish that defects in NK cell function are crucial for the impairment in EBV control and that such defects can be reversed by treatment with magnesium supplementation, which has important therapeutic implications.