HLH macrophage icon

What happens in HLH?

Multiple pathways can contribute to HLH

In hemophagocytic lymphohistiocytosis (HLH), a dysregulated inflammatory immune response is triggered that cannot be shut off by the normal mechanisms of the immune system. This inflammatory state is associated with an abnormal activation of lymphocytes and macrophages, resulting in hypercytokinemia, hemophagocytosis, and multiorgan failure.1,2

In a healthy immune system:

Healthy immune system mechanism with T cells and NK cells
Healthy immune system mechanism with T cells and NK cells

CD=cluster of differentiation; IFNγ=interferon gamma; NK=natural killer.

In patients with primary HLH:

HLH mechanism of disease with T-cell dysfunction and interferon gamma overproduction
HLH mechanism of disease with T-cell dysfunction and interferon gamma overproduction

Why are high levels of IFNγ and the overactivation of macrophages important?

High IFNγ promotes a dangerous feedback loop of inflammation

IFNγ is a key cytokine that activates macrophages. In patients with HLH, these macrophages produce other cytokines that drive hypercytokinemia and hyperinflammation through an uncontrolled feedback loop.7,10

HLH feedback loop of T-cell and macrophage activation with cytokine release
HLH feedback loop of T-cell and macrophage activation with cytokine release

IL=interleukin; TNF-α=tumor necrosis factor alpha.

HLH patient icon

Signs and symptoms

Explore how the effects of HLH may appear in your patients.

See the signs

References: 1. Jordan MB, Allen CE, Weitzman S, Filipovich AH, McClain KL. How I treat hemophagocytic lymphohistiocytosis. Blood. 2011;118(15):4041-4052. doi:10.1182/blood-2011-03-278127 2. George MR. Hemophagocytic lymphohistiocytosis: review of etiologies and management. J Blood Med. 2014;5:69-86. doi:10.2147/JBM.S46255 3. Esteban YM, de Jong JLO, Tesher MS. An overview of hemophagocytic lymphohistiocytosis. Pediatr Ann. 2017;46(8):e309-e313. doi:10.3928/19382359-20170717-01 4. Steen EA, Nichols KE, Meyer LK. Insights into the cellular pathophysiology of familial hemophagocytic lymphohistiocytosis. Front Immunol. 2023;14:1147603. doi:10.3389/fimmu.2023.1147603 5. Henter JI, Horne A, Aricó M, et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48(2):124-131. doi:10.1002/pbc.21039 6. Arango Duque G, Descoteaux A. Macrophage cytokines: involvement in immunity and infectious diseases. Front Immunol. 2014;5:491. doi:10.3389/fimmu.2014.00491 7. Morimoto A, Nakazawa Y, Ishii E. Hemophagocytic lymphohistiocytosis: pathogenesis, diagnosis, and management. Pediatr Int. 2016;58(9):817-825. doi:10.1111/ped.13064 8. Martynova E, Rizvanov A, Urbanowicz RA, Khaiboullina S. Inflammasome contribution to the activation of Th1, Th2, and Th17 immune responses. Front Microbiol. 2022;13:851835. doi:10.3389/fmicb.2022.851835 9. Canna SW, Marsh RA. Pediatric hemophagocytic lymphohistiocytosis. Blood. 2020;135(16):1332-1343. doi:10.1182/blood.2019000936 10. De Benedetti F, Prencipe G, Bracaglia C, Marasco E, Grom AA. Targeting interferon-γ in hyperinflammation: opportunities and challenges. Nat Rev Rheumatol. 2021;17(11):678-691. doi:10.1038/s41584-021-00694-z 11. Pascarella A, Bracaglia C, Caiello I, et al. Monocytes from patients with macrophage activation syndrome and secondary hemophagocytic lymphohistiocytosis are hyperresponsive to interferon gamma. Front Immunol. 2021;12:663329. doi:10.3389/fimmu.2021.663329