X-linked lymphoproliferative disease is caused by deficiency of a novel SH2 domain-containing signal transduction adaptor protein

X-linked lymphoproliferative disease (XLP) is an inherited immunodeficiency , involving primarily T and natural killer (NK) cells, which in the majorit y of cases exacerbates following exposure to Epstein-Barr virus (EBV). Prio r to EBV infection, most boys with the defective XLP gene appear to be clin ically healthy. EBV infection in males with the defective XLP gene leads to three main phenotypes: severe and mostly fatal infectious mononucleosis (5 8%), lymphoproliferative disorders mostly of B-cell origin (30%) and/or dys gammaglobulinemia (31%). Later in life, dysgammaglobulinemia and malignant lymphoma may also develop in about 53% and 56% of EBV-negative XLP males, r espectively. This fact suggests that EBV may only act as a potent trigger o f the earliest and most serious clinical phenotype of XLP, i.e. fatal infec tious mononucleosis. XLP has an unfavorable prognosis. Successful transplan tation of hematopoietic stem cells can cure this immunodeficiency. In the f uture, gene therapy may eventually become an additional option to prevent X LP. The gene responsible for XLP, SH2-domain containing gene 1A (SH2D1A) ha s recently been identified and sequenced. SH2D1A encodes a polypeptide of 1 28 amino acids containing a single SH2 domain. Until now, 45 different SH2D 1A gene mutations have been identified in patients with XLP. SH2D1A is thou ght to play an important role in signal transduction in T and NK cells. In vitro, SH2D1A has been shown to interact as an adaptor protein with the sig naling pathways through SLAM, a T-cell costimulatory molecule, and 2B4, an NK-cell-activating receptor Further functional studies of the SH2D1A protei n will probably provide new insights into the pathogenesis of severe infect ious mononucleosis, malignant lymphomas and immunodeficiency in patients wi th XLP.