X-linked lymphoproliferative disease is usually a rare congenital immunodeficiency that is most often caused by mutations in (encoding TAK-901 X-linked inhibitor of apoptosis XIAP) were discovered in a minority of patients with XLP phenotypes (Rigaud et al. a rapid diagnosis. These studies can also aid in the interpretation of genetic results when new or unreported sequence variants are encountered. This review will give a brief overview of the clinical manifestations and molecular basis of SAP deficiency and XIAP deficiency and will spotlight the immunologic abnormalities that are unique to these disorders which can be exploited for use in patient screening with circulation cytometry. Clinical manifestations and molecular basis of SAP deficiency and XIAP deficiency SAP deficiency XLP is usually most often caused by deficiency of SLAM-associated protein (SAP) due to mutations in the gene found on chromosome Xq24-25.(Coffey et al. 1998 Nichols et al. 1998 Sayos et al. 1998 SAP is usually a 128-amino acid protein involved in the intracellular signaling of the SLAM (signaling lymphocyte activation molecule) family of receptors.(Ma et al. 2007 XLP due to SAP deficiency usually presents in child years or adolescence and clinical manifestations include fulminant infectious mononucleosis/EBV-associated HLH (in ~60% of cases) lymphoproliferative disease including malignant lymphoma (~30%) hypo-/dys-gammaglobulinemia (~30%) and aplastic anemia (3%).(Seemayer et al. 1995 Lymphomas are typically of B-cell origin (non-Hodgkin?痵) and often occur in extra-nodal sites particularly the ileocecal region.(Harrington et al. 1987 Some patients with hypo-/dysgammaglobulinemia may be in the TAK-901 beginning diagnosed as having common variable immune deficiency.(Soresina et al. 2002 Aghamohammadi et al. 2003 Lymphocytic vasculitis macrophage activation syndrome (an HLH variant) interstitial pneumonitis and encephalitis have also been observed.(Dutz et al. 2001 Kanegane et al. 2005 Snow et al. 2009 Talaat et al. 2009 Loss of functional SAP causes several defects in lymphocyte function. In Mouse monoclonal to ESR1 brief SAP is necessary for normal T-cell-dependent humoral immune responses NK cell and CD8+ T cell cytotoxicity and development of invariant natural killer T (iNKT) cells (Ma et al. 2007 More recently SAP was found to be necessary for sustained T cell:B cell interactions that ensure proper germinal center formation and B cell help.(Qi et al. 2008 Cannons et al. 2010 Moreover SAP is also required for T cell restimulation-induced cell death (RICD) a self-regulatory mechanism of apoptosis critical for T cell homeostasis.(Nagy et al. 2009 Snow et al. 2009 Although Epstein-Barr computer virus (EBV) has been historically identified as a triggering event for infectious mononucleosis and associated hemophagocytic lymphohistiocytosis (HLH); not all disease manifestations are associated with EBV consistent with the presence of TAK-901 intrinsic lymphocyte defects. XIAP deficiency Deficiency of X-linked inhibitor of apoptosis (XIAP) caused by gene mutations was discovered to be associated with XLP phenotypes in 2006.(Rigaud et al. TAK-901 2006 In contrast to SAP deficiency over 90% of patients with XIAP deficiency develop hemophagocytic lymphohistiocytosis with or without association with EBV and recurrent HLH is usually common.(Rigaud et al. 2006 Marsh et al. 2010 Zhao et al. 2010 A minority of patents may display hypogammaglobulinemia and no cases of lymphoma have been observed in patients with XIAP deficiency to date. XIAP is an inhibitor of apoptosis (IAP) family member consisting of 3 baculovirus IAP repeat (BIR) domains and a C-terminal RING (really interesting new gene) domain name. XIAP is best known for its caspase-inhibitory and anti-apoptotic properties and BIR2 and its N-terminal linker region inhibit caspase-3 and caspase-7 while BIR3 inhibits caspase-9.(Chai et al. 2001 Huang et al. 2001 Shiozaki et al. 2003 Scott et al. 2005 The BIR regions of XIAP can also interact with non-caspase proteins such as RIP2 and TAB1. These and other XIAP interactions mediate signaling pathways including Nuclear Factor -kappa B (NF-κB) c-jun N-terminal kinase (JNK) NOD1 and NOD2 and the bone morphogenetic protein (BMP) receptors.(Sanna et al. 1998 Yamaguchi et al. 1999 Lewis et al. 2004 Kaur et al. 2005 Lu et al. 2007.