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 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 2009, we evaluated 103 new patients and their relatives over the past year, for 350 cumulatively, using functional screening and gene sequencing to exclude known disease. About 20 are 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. Our most important advance in 2009 was the discovery that autosomal recessive loss-of-function mutations in the dedicator of cytokinesis 8 (DOCK8) gene cause a new form of combined immunodeficiency. Patients have recurrent upper and lower respiratory tract infections, severe and persistent viral infections of the skin (caused by herpes simplex virus, molluscum contagiosum, and human papillomavirus), severe food and other allergies associated with anaphylaxis, and cancers. Their peripheral blood contains low numbers of and poorly functioning lymphocytes, including the CD8 T cells that are important in fighting viral infections, as well as high levels of immunoglobulin E and eosinophils that contribute to allergy. Our discovery of this new disease and its genetic cause now facilitates the diagnosis and further study of affected patients. Moreover, 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 2009, we also contributed to two other advances focused on X-linked lymphoproliferative disease (XLP). In this disease, boys die from infection with Epstein-Barr virus (EBV), unless they receive a bone marrow transplant to replace their defective lymphocytes. EBV is a common virus that causes no symptoms or a self-limited infectious mononucleosis in healthy people. Patients with XLP can also develop lymphoproliferative disease, including lymphomas, but why this happens was not clear. Our work established that this occurs because the product of the gene that is mutated in most forms of XLP, SH2D1A (SAP), normally functions not only in activating lymphocytes but also in linking this signal to the signal for lymphocyte death. Because this signal is missing in most XLP patients, patients abnormally accumulate lymphocytes, which can predispose them to developing cancers. Finally, we also helped establish the utility of a rapid flow cytometry-based way to diagnose a form of XLP due to BIRC4 (XIAP) mutations. Because XLP mimics other diseases and requires curative bone marrow transplantation, this work will improve patient diagnosis and care.