Advances in the pathogenesis of primary and secondary haemophagocytic lymphohistiocytosis: differences and similarities
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Summary: Haemophagocytic lymphohistiocytosis ( HLH ) comprises a heterogeneous spectrum of hyperinflammatory conditions that are inherited (primary HLH ) or acquired in a context of infections, malignancies or autoimmune/autoinflammatory disorders (secondary HLH ). Genetic defects in the cytotoxic machinery of natural killer and CD 8 + T cells underlie primary HLH , with residual cytotoxicity determining disease severity. Improved sequencing techniques have expanded the range of causal mutations and have redefined many cases of secondary HLH as primary HLH and vice versa, blurring the distinction between both subtypes. These insights allow HLH to be conceptualized as a threshold disease, in which interplay between various genetic and environmental factors causes progressive inflammation into a critical point, beyond which uncontrolled activation of immune cells and excessive cytokine production give rise to the cardinal symptoms of HLH . Various pathogenic pathways may thus converge to a common end stage of fulminant HLH .
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Three HEM1-deficient patients with features such as fever, splenomegaly, hyperferritinemia, hypertriglyceridemia, hypofibrinogenemia, and increased soluble IL-2 receptor met diagnostic criteria for hemophagocytic lymphohistiocytosis.
“Three patients with features such as fever, splenomegaly, hyperferritinemia, hypertriglyceridemia, hypofibrinogenemia, and increased soluble IL-2 receptor met diagnostic criteria for hemophagocytic lymphohistiocytosis (HLH) [8, 10, 28, 29]”
From HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions (2022) · cites this paper as [28]
Prolonged pathogen exposure resulting from impaired adaptive immune cell activation contributes to chronic inflammation and HLH development, potentially explaining the HLH-like phenotypes observed in patients.
“Prolonged pathogen exposure resulting from impaired adaptive immune cell activation is known to contribute to chronic inflammation and HLH development, potentially explaining the HLH-like phenotypes observed in patients [28, 42].”
From HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions (2022) · cites this paper as [28]
In familial HLH in which granules lack functional perforin, CD107a levels are normal or elevated.
“This draws an interesting comparison to the normal or elevated CD107a levels observed in the form of familial HLH in which granules lack functional perforin [28].”
From HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions (2022) · cites this paper as [28]
Cites
Hypomorphic mutations in PRF1, MUNC13-4, and STXBP2 are associated with adult-onset familial HLH
Zhang, K., Jordan, M. B., Marsh, R. A., Johnson, J. A., Kissell, D., Meller, J., Villanueva, J., Risma, K. A., Wei, Q., Klein, P. S., et al. (2011) · Blood · doi:10.1182/blood-2011-07-370148 · Cited by 428 · see citing works
Kaufman, K. M., Linghu, B., Szustakowski, J. D., Husami, A., Yang, F., Zhang, K., Filipovich, A. H., Fall, N., Harley, J. B., Nirmala, N. R., et al. (2014) · Arthritis & Rheumatology · doi:10.1002/art.38793 · Cited by 207 · see citing works
Schulert, G. S., Zhang, M., Fall, N., Husami, A., Kissell, D., Hanosh, A., Zhang, K., Davis, K., Jentzen, J. M., Napolitano, L., et al. (2016) · Journal of Infectious Diseases · doi:10.1093/infdis/jiv550 · Cited by 170 · see citing works
Zhang, M., Bracaglia, C., Prencipe, G., Bemrich-Stolz, C. J., Beukelman, T., Dimmitt, R. A., Chatham, W. W., Zhang, K., Li, H., Walter, M. R., et al. (2016) · The Journal of Immunology · doi:10.4049/jimmunol.1501284 · Cited by 99 · see citing works
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Wang, A., Pope, S. D., Weinstein, J. S., Yu, S., Zhang, C., Booth, C. J., & Medzhitov, R. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1820704116 · Cited by 67 · see citing works
HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions
Cook, S., Lenardo, M. J., & Freeman, A. F. (2022) · Journal of Clinical Immunology · doi:10.1007/s10875-022-01327-0 · Cited by 24 · see citing works
- Authors
- Brisse, E., Wouters, C. H., & Matthys, P.
- Affiliations
- Rega Institute for Medical Research (BE)
- KU Leuven (BE)
- Corresponding author
- Matthys, Patrick
- Venue
- British Journal of Haematology
- Publisher
- Wiley
- Published
- 2016-06-05
- Volume
- 174
- Issue
- 2
- Pages
- 203-217
- ISSN
- 0007-1048 (ISSN-L)
- 1365-2141
- OpenAlex
- W2417595397
- Cited by
- 197
- References
- 4
- Citations by year
- 2026: 24 · 2025: 30 · 2024: 13 · 2023: 22 · 2022: 23 · 2021: 17 · 2020: 22 · 2019: 23 · 2018: 12 · 2017: 9 · 2016: 1
- FWCI
- 2.11
- Type
- journal article
- Language
- en
- Open access
- green
- lirias.kuleuven.be
- Licence
- Locations
- British Journal of Haematology (publishedVersion)
- PubMed (publishedVersion)
- Lirias (KU Leuven) (submittedVersion, other-oa)
- Funders
- Agentschap voor Innovatie door Wetenschap en Technologie
- Topics
- Health Sciences › Medicine › Hematology › Autoimmune and Inflammatory Disorders Research
- Life Sciences › Immunology and Microbiology › Immunology › Immunodeficiency and Autoimmune Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Keywords
- hemophagocytic lymphohistiocytosis, secondary hemophagocytic lymphohistiocytosis, hyperinflammation, natural killer cells, CD8+ T cells, genetic mutations, cytokine production, immune cell activation, autoinflammatory disease
- MeSH terms
- Diagnosis, Differential, Humans, Inflammation, Mutation, Sequence Analysis, DNA, CD8-Positive T-Lymphocytes, Lymphohistiocytosis, Hemophagocytic, Natural Killer T-Cells
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