Hemophagocytic lymphohistiocytosis (HLH): A heterogeneous spectrum of cytokine-driven immune disorders

The cytotoxic T lymphocyte immune synapse at a glance

“…Malfunctioning of this machinery as a result of genetic defects in its components leads to the devastating immune deficiency condition familial haemophagocytic lymphohistiocytosis (FHL) with five subtypes (FHL1 to FHL5), and the related conditions Griscelli syndrome type 2 (GS2), Hermansky-Pudlak syndrome type 2 (HPS2) and Chediak-Higashi syndrome (CHS) (Chediak, 1952;Farquhar and Claireaux, 1952;Griscelli et al, 1978;Hermansky and Pudlak, 1959;Higashi, 1954). Mouse models of these conditions show that upon pathogen challenge, the genetic mutation impairs the secretion of pro-apoptotic factors from CTL (and natural killer) granules, whereas the production of cytokines and their release through a different secretory pathway appears to be enhanced (Brisse et al, 2015;de Saint Basile et al, 2015 preprint;Jenkins et al, 2015;Reefman et al, 2010). The inability of CTLs and natural killer cells to clear the infection whilst continuously secreting cytokines promotes the activity of effector immune cells, leading to a life-threatening hyperinflammatory state (haemophagocytic lymphohistiocytosis, HLH) that requires immunosuppressive therapy and ultimately bonemarrow transplantation (Sieni et al, 2014).…”

Janus kinase inhibition lessens inflammation and ameliorates disease in murine models of hemophagocytic lymphohistiocytosis

“…Prf1 2/2 mice fail to clear infection with LCMV, and instead develop a pathological expansion and activation of CD8 1 T cells that secrete a plethora of proinflammatory cytokines. 21,22 To define the therapeutic effects of JAK inhibition in this model of primary HLH, Prf1 2/2 mice were treated with PBS or infected with 2 3 10 5 PFU LCMV Armstrong. Beginning on day 4 postinfection, animals were treated or not with ruxolitinib twice daily by oral gavage ( Figure 3A).…”

A xenograft model of macrophage activation syndrome amenable to anti-CD33 and anti–IL-6R treatment

“…Numerous mouse models now exist that fulfill as few as 0 and as many as all 8 of the HLH diagnostic criteria (8). Many are built upon genetic KO of the key genes identified in primary HLH cases.…”