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 2010, we evaluated 142 new patients and their relatives over the past year, for 508 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, last year 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. In 2010, we further characterized the clinical spectrum of disease in DOCK8 deficiency by identifying additional patients with this disorder who also have prominent features outside the immune system. 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 and their predilection for developing cancer. 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 2010, we also contributed to an expert consensus opinion in which we established updated criteria for diagnosis and classification of the autoimmune lymphoproliferative syndrome (ALPS) and related disorders, which will improve clinical practice.