Research Focus for the Matthew and Andrew Akin Foundation

Rebecca Marsh MD
10/13/15

X-linked lymphoproliferative disease type 2 (XLP2), or XIAP deficiency, is a fatal primary immune deficiency caused by mutations in the XIAP/BIRC4 gene. Patients with XLP2 are principally affected by hemophagocytic lymphohistiocytosis (HLH), hypogammaglobuliemia, and inflammatory bowel disease (IBD).

It is not currently known why patients with XIAP deficiency develop HLH. HLH is a severe, life-threatening, hyperinflammatory syndrome characterized by fevers, life threatening cytopenias, hepatosplenomegaly, hepatitis, liver failure, and can have central nervous system involvement characterized by altered mental status, focal deficits, and seizures. Most patients with genetic causes of HLH develop disease because they have mutations in genes which are known to be critical for cytotoxic lymphocyte granule-mediated cytotoxicity (Familial HLH). However, this is not the case for patients with XIAP deficiency. We and other have shown that cytotoxicity in these patients is normal. It has more recently been shown that XIAP is critical for regulation of IL-1beta production downstream of TNF receptor signaling (Yabal at el). IL-1beta secretion is a highly regulated process. Two signals are normally required for a cell to produce and secrete active IL-1beta. First, a priming signal (such as a TLR agonist or TNF alpha) induces upregulation of both pro-IL1beta and NLRP3. Second, an inflammasome activation signal is required for the inflammasome to assemble and become active, which leads to activation of caspase-1 and pro-IL1beta processing into the active form. Active IL-1beta is then secreted from the cell by an unknown mechanism. Several autoinflammatory diseases are known to be caused by mutations in inflammasome associated genes, including NLRP3.

With funding provided by the Matthew and Andrew Akin Foundation, we have made the novel observation that IL-1beta production following various toll-like receptor (TLR) agonists and TNF alpha by XIAP deficient macrophages is inhibited by NLRP3 deletion. We have also observed that IL-1beta production can be inhibited by several therapeutic agents. We hypothesize that aberrant IL-1beta production by XIAP deficient macrophages following multiple TLR agonist and TNF alpha priming is NLRP3 dependent, and that the NLRP3 inflammasome or upstream or downstream pathways represent a novel therapeutic strategy for the treatment of XIAP deficiency/XLP2. We are currently working to test these hypotheses in a mouse model of XIAP deficiency. We hope to find targeted therapies that may one day be trialed to prevent or lessen the severity of HLH in patients with XIAP deficiency.