What happens in primary HLH?
How does primary HLH develop in patients?
Primary hemophagocytic lymphohistiocytosis (HLH) arises from inherited defects in genes involved in cytotoxic immune function. These genetic abnormalities impair the ability of cytotoxic lymphocytes to regulate immune responses appropriately, creating a predisposition to uncontrolled hyperinflammation. Although the underlying genetic susceptibility is often present from birth, environmental triggers such as infections often contribute to disease onset.1,2
The threshold model of HLH
The threshold model of HLH is used to illustrate the potential for HLH to occur when a combination of factors causes a critical threshold to be reached. These factors can include genetic susceptibility and hyperinflammatory contributors such as infections, rheumatic disease, or malignancies.2.3
Consistent with the threshold model:
Infections and other immune stressors can trigger excessive immune activation in genetically susceptible individuals, pushing the immune system beyond a critical threshold and leading
to HLH.1,2
Genetic defects involved in perforin-mediated cytotoxicity and related immune regulatory pathways lower the threshold for hyperinflammation by impairing the body’s ability to terminate activated immune responses.2
Primary HLH in adults
Primary HLH has traditionally been viewed as a disease of infancy and early childhood because of its genetic basis. However, advances in genetic testing have expanded our understanding and demonstrated that primary HLH can also present in adolescents and adults.4
In some patients, hypomorphic (partial loss-of-function) variants in HLH-associated genes allow sufficient immune function for years before an infectious or other immune trigger overwhelms the body’s ability to regulate inflammation. Rather than causing disease early in life, these variants lower the threshold for developing uncontrolled hyperinflammation.4
This evolving understanding reinforces the threshold model of HLH: genetic susceptibility exists on a spectrum, and the HLH syndrome develops when inherited predisposition combines with additional inflammatory triggers to exceed the body’s capacity to maintain immune balance.3
As a result, primary HLH should remain in the differential diagnosis regardless of the patient’s age, and genetic testing should be initiated early whenever primary HLH is suspected.2
Genetic testing can help confirm the diagnosis, inform recurrence risk, and guide decisions regarding definitive therapy.5
The mechanisms of immune dysregulation in primary HLH
In primary 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.1,6
In a healthy immune system:
In patients with primary HLH:
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 primary HLH, these macrophages produce other cytokines that drive hypercytokinemia and hyperinflammation through an uncontrolled feedback loop.11,14
High IFNγ levels overactivate macrophages and increase monocyte sensitivity to IFNγ stimulation.15
Activated macrophages release proinflammatory cytokines including IL-1β, IL-6, and TNF-⍺, which are responsible for the cytokine storm in primary HLH.11
A continuous feedback loop of cytokine production and macrophage activation results in hyperinflammation and irreversible multiorgan damage.11
High IFNγ levels overactivate macrophages and increase monocyte sensitivity to IFNγ stimulation.15
Activated macrophages release proinflammatory cytokines including IL-1β, IL-6, and TNF-⍺, which are responsible for the cytokine storm in primary HLH.11
A continuous feedback loop of cytokine production and macrophage activation results in hyperinflammation and irreversible multiorgan damage.11
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. Henter JI. Hemophagocytic lymphohistiocytosis. N Engl J Med. 2025;392(6):584-598. doi:10.1056/NEJMra2314005 3. Steen EA, Hermiston ML, Nichols KE, Meyer LK. Digenic inheritance: evidence and gaps in hemophagocytic lymphohistiocytosis. Front Immunol. 2021;12:777851. doi:10.3389/fimmu.2021.777851 4. Zhang K, Jordan MB, Marsh RA, et al. Hypomorphic mutations in PRF1, MUNC13-4, and STXBP2 are associated with adult-onset familial HLH. Blood. 2011;118(22):5794-5798. doi:10.1182/blood-2011-07-370148 5. Shakoory B, Geerlinks A, Wilejto M, et al. The 2022 EULAR/ACR points to consider at the early stages of diagnosis and management of suspected haemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS). Arthritis Rheumatol. 2023;75(10):1714-1732. doi:10.1002/art.42636 6. George MR. Hemophagocytic lymphohistiocytosis: review of etiologies and management. J Blood Med. 2014;5:69-86. doi:10.2147/JBM.S46255 7. 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 8. 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 9. 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 10. Arango Duque G, Descoteaux A. Macrophage cytokines: involvement in immunity and infectious diseases. Front Immunol. 2014;5:491. doi:10.3389/fimmu.2014.00491 11. Morimoto A, Nakazawa Y, Ishii E. Hemophagocytic lymphohistiocytosis: pathogenesis, diagnosis, and management. Pediatr Int. 2016;58(9):817-825. doi:10.1111/ped.13064 12. 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 13. Canna SW, Marsh RA. Pediatric hemophagocytic lymphohistiocytosis. Blood. 2020;135(16):1332-1343. doi:10.1182/blood.2019000936 14. 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 15. 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 16. Rocco JM, Oved JH, Patel RJ, et al. CXCL9 as a novel prognostic marker to identify high-risk adults with hemophagocytic lymphohistiocytosis. Blood. 2026;147(9):960-972. doi:10.1182/blood.2025030976
