Grants Awarded

Investigations into the Clinical and Molecular Pathogenesis of XIAP Deficiency

Principal Investigator and Co-Investigators
Rebecca Marsh MD (PI); Jack J. H. Bleesing MD, PhD; Kimberly Risma MD, PhD;
Lisa Filipovich MD
Cincinnati Children’s Hospital Medical Center – Cincinnati, Ohio USA

Date of Award
December 2007

Amount of Award

Layperson Summary
Primary Hemophagocytic Lymphohistiocytosis (HLH) is a rare, life-threatening disease typically caused by defects in the ability of killer lymphocytes to effectively clear viral infection. There is essentially overactivation of the faulty immune system which then leads to systemic inflammation and multi-organ failure if left untreated. There are several known genetic defects which lead to HLH, though the underlying genetic cause of HLH in many patients remains unknown. Recently, a newly identified X-linked genetic defect has been reported to be the cause of HLH in three families, with 11/12 of these patients developing HLH, 4 of whom died. The defect is in the gene encoding the X-Linked Inhibitor of Apoptosis, or XIAP. XIAP is known to inhibit cell death by interacting with several proteins which are involved in apoptotic cell death, and also has lesser understood roles in certain cell signaling pathways. It is unclear why a deficiency of XIAP leads to HLH.

We have recently diagnosed XIAP deficiency in 5 patients from 4 families with variable manifestations of primary immune deficiency, evidence of immune dysfunction/dysregulation, and propensity to develop HLH. The work we propose involves three major areas of research related to the understanding of this new disease. The first area is the detailed characterization of affected patients. Features of interest include patient lymphocyte populations and specialized characterization of those cells, along with monitoring of their function over time. Monitoring of HLH-specific markers at baseline and with relapse and remission will also be performed. We also have begun work to develop a screening diagnostic test. The second area is the determination of both intact and compromised XIAP protein sequences expressed by our XIAP deficient patients and correlation with functional assays relevant to XIAP function. Third, we will further investigate the reason for the development of HLH in XIAP deficient patients, including analysis of the function of cytotoxic cells, which is a well-described mechanism of HLH development in many of the other causes of primary HLH.


A Rapid Flow Cytometric Screening Test for X-Linked Lymphoproliferative Disease due to XIAP Deficiency