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 2011, we evaluated 247 new patients and their relatives over the past year, for 804 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 and other genomic 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 new combined immunodeficiency that includes cases of what was previously termed autosomal recessive hyper-IgE syndrome. Since then, we have further expanded upon the clinical spectrum of disease in DOCK8 deficiency by identifying additional patients with this disorder who also unusual presentations, and following the natural history of their disease as well as their course during hematopoietic cell transplantation. Additionally, our studies have focused on understanding how absence of DOCK8 leads to the lymphocyte abnormalities that contribute to the problems the patients have handling viral infections. Since 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. In 2011, we also contributed to the exciting discovery of a new immunodeficiency disease, X-linked Magnesium defect with EBV infection and Neoplasia (XMEN), which results from mutations in MAGT1. This discovery has not only led to new basic knowledge that Magnesium can act as a signaling messenger that is important for T cell antiviral responses, but it has opened the door to better diagnosis and studies into potential therapy for this disease.