Polygenic mutations in the cytotoxicity pathway increase susceptibility to develop HLH immunopathology in mice

Fernando E. Sepulveda, Alexandrine Garrigue, Sophia Maschalidi, Meriem Garfa-Traore, Gaël Ménasché, Alain Fischer and Genevieve de Saint Basile

Key points

  • The accumulation of monoallelic mutations in HLH-causing genes, impairs lymphocyte cytotoxicity contributing to HLH immunopathology in mice.

  • A polygenic model may account for some of the cases of secondary HLH observed in humans.


Hemophagocytic lymphohistiocytosis (HLH) consists in a life-threatening hyperinflammatory disease. Inherited forms of HLH are caused by biallelic mutations in several effectors of granule-dependent lymphocyte-mediated cytotoxicity. A small proportion of patients with a so-called "secondary" form of HLH, which develops in the aftermath of infection, autoimmunity or cancer, carry a monoallelic mutation in one or more HLH-associated genes. Although this observation suggests that HLH may have a polygenic mode of inheritance, the latter is very difficult to prove in humans. In order to determine whether the accumulation of partial genetic defects in lymphocyte-mediated cytotoxicity can contribute to the development of HLH, we generated mice that were doubly or triply heterozygous for mutations in HLH-associated genes, those coding for perforin, Rab27a and syntaxin-11. We found that the accumulation of monoallelic mutations did indeed increase the risk of developing HLH immunopathology after LCMV infection. In mechanistic terms, the accumulation of heterozygous mutations in the two degranulation genes Rab27a and syntaxin-11, impaired the dynamics and secretion of cytotoxic granules at the immune synapse of T lymphocytes. In addition, the accumulation of heterozygous mutations within the three genes impaired NK lymphocyte cytotoxicity in vivo. The genetic defects can be ranked in terms of the severity of the resulting HLH manifestations. Our results form the basis of a polygenic model of the occurrence of secondary HLH.

  • Submitted December 21, 2015.
  • Accepted February 6, 2016.