Grants Awarded

The Pathogenesis of XLP Due to XIAP Deficiency

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

Date of Award
September 2008

Amount of Award

Layperson Summary
The disease X-linked lymphoproliferative disease (XLP) can be caused by mutations in a gene called BIRC4.  Patients with this disease are prone to develop Hemophagocytic Lymphohistiocytosis (HLH), a very severe condition that is often fatal.  These children are deficient in a protein call XIAP. XIAP deficiency is newly discovered, and the underlying reason for the development of HLH is not well understood in these patients.  Most other patients with HLH have an underlying defect in the way that natural killer cells deliver toxic granules to target cells. This is not true of patients with XIAP deficiency.  Another reason that is thought to contribute to the pathogenesis of HLH occurs in patients with XLP due to SAP deficiency, who have absent iNKT cells, a special cell type that is thought to be involved in immunoregulation.  We have found normal iNKT cell populations in patients with XIAP deficiency.  A third reason possibly related to a propensity to develop HLH is secondary to lymphocytes having a defect which causes them to be more likely to undergo cell death when stimulated than normal.  This has been suggested in patients with XIAP deficiency.  However, how this specifically relates to a propensity to develop HLH is not fully understood.

The work that we propose to do seeks to determine the underlying reason for HLH in these patients.  We are looking to see if there is a problem with XIAP-deficient NK cell survival following initial activation and effector function.  We are also working to test patient iNKT cell function.  In addition, we are working to further study lymphocyte homeostasis in patients with XIAP deficiency, and determine if deficits truly exist, or if cells are able to compensate for the lack of XIAP through upregulation of other genes related to cell survival.  We are also studying the effects of acute suppression of XIAP on the apoptosis of normal lymphocytes.  We expect that this work will lead to a better understanding of the pathogenesis of HLH in these patients, and will help us to develop new treatments.

Twelve Month Report


Patients with X-linked Lymphoproliferative Disease due to BIRC4 Mutation have Normal Invariant Killer T-cell Population