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

Abstract

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) is 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 lymphocytic choriomeningitis virus 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 natural killer 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. (Blood. 2016;127(17):2113-2121

Advances in the pathogenesis of primary and secondary haemophagocytic lymphohistiocytosis: differences and similarities

“…Heterozygous mutations that each partially impair cytotoxic function may generate a 'gene dosage' effect through synergy (Zhang et al, , 2014a. This was corroborated by the generation of polygenic mouse models, in which the accumulation of heterozygous mutations in Rab27a, Prf1 and/or Stx11 reduced cytotoxic function and increased the risk of developing virus-induced HLH (Sepulveda et al, 2016). Heterozygous mutations in X-linked genes may also cause HLH in female patients, depending on the percentage of wild-type X-chromosome inactivation (Holle et al, 2015;Yang et al, 2015).…”

Macrophage Activation Syndrome: different mechanisms leading to a one clinical syndrome

“…Three out of 31 patients (9.7%) carried a mutation in 2 genes. Interestingly, it has been recently reported that mice carrying heterozygous mutation in more than one gene involved in pHLH carry a significant higher risk to develop HLH following viral infection [16]. Overall, clinical and laboratory feature of MAS in patients carrying the mutations were not different from those of patients who do not carry the mutation.…”

Macrophage activation syndrome: early diagnosis is key

“…These abnormalities occur by altering the protein variants of the various genes, including PRF1, MUNC13-14, STX11, STXBP2, LYST , and RAB27A , which are involved in the granule-mediated cytotoxic pathway 21–24. Heterozygous mutations in some of these genes might be associated with the development of MAS, especially if triggered by infections 25. Moreover, hyperinflammation, especially in SJIA, results in high levels of interleukin (IL)-6.…”