Article

X-linked lymphoproliferative syndromes: brothers or distant cousins?

Division of Bone Marrow Transplantation and Immunodeficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA.
Blood (impact factor: 9.9). 11/2010; 116(18):3398-408. DOI:10.1182/blood-2010-03-275909 pp.3398-408
Source: PubMed

ABSTRACT X-linked lymphoproliferative disease (XLP1), described in the mid-1970s and molecularly defined in 1998, and XLP2, reported in 2006, are prematurely lethal genetic immunodeficiencies that share susceptibility to overwhelming inflammatory responses to certain infectious triggers. Signaling lymphocytic activation molecule-associated protein (SAP; encoded by SH2D1A) is mutated in XLP1, and X-linked inhibitor of apoptosis (XIAP; encoded by BIRC4) is mutated in XLP2. XLP1 is a disease with multiple and variable clinical consequences, including fatal hemophagocytic lymphohistiocytosis (HLH) triggered predominantly by Epstein-Barr virus, lymphomas, antibody deficiency, and rarer consequences of immune dysregulation. To date, XLP2 has been found to cause HLH with and without exposure to Epstein-Barr virus, and HLH is commonly recurrent in these patients. For both forms of XLP, the only curative therapy at present is allogeneic hematopoietic cell transplantation. Beyond their common X-linked locus and their requirement for normal immune responses to certain viral infections, SAP and XIAP demonstrate no obvious structural or functional similarity, are not coordinately regulated with respect to their expression, and do not appear to directly interact. In this review, we describe the genetic, clinical, and immunopathologic features of these 2 disorders and discuss current diagnostic and therapeutic strategies.

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Keywords

2 disorders
 
antibody deficiency
 
certain infectious triggers
 
certain viral infections
 
common X-linked locus
 
curative therapy
 
Epstein-Barr virus
 
functional similarity
 
immune dysregulation
 
immunopathologic features
 
normal immune responses
 
obvious structural
 
overwhelming inflammatory responses
 
share susceptibility
 
Signaling lymphocytic activation molecule-associated protein
 
variable clinical consequences
 
X-linked inhibitor
 
X-linked lymphoproliferative disease
 
XIAP
 
XLP2