Grants Awarded

Accumulation of Heterozygous Mutations on HLH Pathogenesis

Principal Investigator
Fernando Sepulveda, PhD
Imagine Institute, Paris, France

Date of Award
December 2014

Amount of Award

Layperson Summary
Familial forms of hemophagocytic lymphohistiocytic syndrome (HLH) are severe and potentially life-threatening immune disorder characterized by impairment in the cytotoxic activity of lymphocytes and natural killer (NK) cells. We and others have established that Familial HLH is inherited as an autosomal recessive trait. Recent reports suggest that the accumulation of hypomorphic mutations in the genes responsible of FHL can be associated with the development of this disorder. Thus, we hypothesized that rare gene variants, hypomorphic mutations or subtle defects in cytotoxic activity may be deleterious for immune homeostasis and lead to HLH development only when expressed under particular genetic context. The aim of this proposal is to use the combination of different murine models of inherited HLH to investigate the impact of the accumulation of heterozygous mutations in several HLH genes i) in the cytotoxic activity of lymphocytes (CD8 and NK cells) and ii) in the susceptibility to develop HLH upon viral infection. By using in vitro and in vivo approaches, we will compare mice carrying double or triple heterozygous mutations with well-established murine models of HLH to determine the consequences of subtle defects in cytotoxic activity in immune homeostasis and HLH development.

Twelve Month Report
Hemophagocytic lymphohistiocytosis (HLH) is a rare, life‐threatening syndrome, characterized by severe hyperinflammation and severe immunopathologic processes in several tissues. These features result from organ infiltration by over‐activated CD8 T‐cells and macrophages, which produce high levels of inflammatory cytokines. HLH can affect both children and adults, and cases can be broadly classified as “primary” (with a clear autosomal recessive pattern of inheritance) and “secondary” HLH (with no hint for a genetic cause). Primary HLH is  caused by genetic defects in the perforin‐dependent granule exocytosis pathway  of cytotoxic lymphocytes. Recent  studies have suggested that mono‐orbiallelic mutations in genes encoding cytotoxic effector proteins may account for some cases of “secondary” HLH. However, this hypothesis has yet to be demonstrated. Murine models of HLH constitute a powerful tool for addressing this question. The aim of this proposal was to determine the impact of the accumulation of heterozygous mutations in genes controlling cytotoxic activity of lymphocytes in cytotoxic activity and in the susceptibility to develop HLH upon viral infection. With the support of the Histiocytosis Association, we showed that the accumulation of  heterozygous mutation along the granule‐dependent cytotoxic pathway i) impair the killing activity of lymphocytes and ii) increase the susceptibility of developing HLH syndrome. Hence, our results support the existence of polygenic inheritance in secondary HLH.