The genetics of macrophage activation syndrome

Schulert, Grant S.; Cron, Randy Q.

doi:10.1038/s41435-020-0098-4

Cited by 91Autoimmune and Inflammatory Disorders ResearchImmunodeficiency and Autoimmune DisordersInflammasome and immune disorders

The genetics of macrophage activation syndrome

Schulert, Grant S., Cron, Randy Q.·2020·Genes & Immunity

DOI 10.1038/s41435-020-0098-4

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Abstract

Macrophage activation syndrome (MAS), or secondary hemophagocytic lymphohistiocytosis (HLH), is a cytokine storm syndrome associated with multi-organ system dysfunction and high mortality rates. Laboratory and clinical features resemble primary HLH, which arises in infancy (1 in 50,000 live births) from homozygous mutations in various genes critical to the perforin-mediated cytolytic pathway employed by NK cells and cytotoxic CD8 T lymphocytes. MAS/secondary HLH is about ten times more common and typically presents beyond infancy extending into adulthood. The genetics of MAS are far less defined than for familial HLH. However, the distinction between familial HLH and MAS/secondary HLH is blurred by the finding of heterozygous perforin-pathway mutations in MAS patients, which may function as hypomorphic or partial dominant-negative alleles and contribute to disease pathogenesis. In addition, mutations in a variety of other pathogenic pathways have been noted in patients with MAS/secondary HLH. Many of these genetically disrupted pathways result in a similar cytokine storm syndrome, and can be broadly categorized as impaired viral control (e.g., SH2P1A), dysregulated inflammasome activity (e.g., NLRC4), other immune defects (e.g., IKBKG), and dysregulated metabolism (e.g., LIPA). Collectively these genetic lesions likely combine with states of chronic inflammation, as seen in various rheumatic diseases (e.g., still disease), with or without identified infections, to result in MAS pathology as explained by the threshold model of disease. This emerging paradigm may ultimately support genetic risk stratification for high-risk chronic and even acute inflammatory disorders. Moving forward, continued whole-exome and -genome sequencing will likely identify novel MAS gene associations, as well as noncoding mutations altering levels of gene expression.

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Data from mouse models of HLH and patients with cytokine storm indicate that the inability of CTLs to kill efficiently leads to prolonged activation of T cells, triggering a cascade of inflammatory tissue damage.
“Data from mouse models of HLH and patients with cytokine storm indicate that the inability of CTLs to kill efficiently leads to prolonged activation of T cells, triggering a cascade of inflammatory tissue damage.”
From Cytokine storm (2020) · cites this paper as [23]
In patients with primary HLH, various autosomal recessive monogenic abnormalities in granule-mediated cytotoxicity lead to cytokine storm.
“In patients with primary HLH, various autosomal recessive monogenic abnormalities in granule-mediated cytotoxicity lead to cytokine storm.”
From Cytokine storm (2020) · cites this paper as [23]
Common pathologic mutations in primary HLH include those in PRF1, UNC13D, STXBP1, RAB27A, STX11, SH2D1A, XIAP, and NLRC4.
“Common pathologic mutations include those occurring in PRF1, UNC13D, STXBP1, RAB27A, STX11, SH2D1A, XIAP, and NLRC4.23”
From Cytokine storm (2020) · cites this paper as [23]

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Update on Lysinuric Protein Intolerance, a Multi-faceted Disease Retrospective cohort analysis from birth to adulthood
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Mutations of the hemophagocytic lymphohistiocytosis–associated gene UNC13D in a patient with systemic juvenile idiopathic arthritis
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Macrophage activation syndrome in systemic juvenile rheumatoid arthritis
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X‐linked lymphoproliferative syndrome: a genetic condition typified by the triad of infection, immunodeficiency and lymphoma
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A Heterozygous <i>RAB27A</i> Mutation Associated with Delayed Cytolytic Granule Polarization and Hemophagocytic Lymphohistiocytosis
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Highly elevated serum levels of interleukin‐18 in systemic juvenile idiopathic arthritis but not in other juvenile idiopathic arthritis subtypes or in Kawasaki disease: Comment on the article by Kawashima et al
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Three Hypothetical Inflammation Pathobiology Phenotypes and Pediatric Sepsis-Induced Multiple Organ Failure Outcome*
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A Multicenter Network Assessment of Three Inflammation Phenotypes in Pediatric Sepsis-Induced Multiple Organ Failure
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Reaching the Threshold: A Multilayer Pathogenesis of Macrophage Activation Syndrome
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Hemophagocytic lymphohistiocytosis in 2 patients with underlying IFN-γ receptor deficiency
Tesi, B., Sieni, E., Neves, C., Romano, F., Cetica, V., Cordeiro, A. I., Chiang, S. C. C., Schlums, H., Galli, L., Avenali, S., et al. (2015) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2014.11.030 · Cited by 85 · see citing works
Lysinuric protein intolerance: mechanisms of pathophysiology
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Secondary hemophagocytic lymphohistiocytosis in zoonoses. A systematic review.
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Graded Defects in Cytotoxicity Determine Severity of Hemophagocytic Lymphohistiocytosis in Humans and Mice
Jessen, B., Kögl, T., Sepulveda, F. E., Basile, G. D. S., Aichele, P., & Ehl, S. R. (2013) · Frontiers in Immunology · doi:10.3389/fimmu.2013.00448 · Cited by 77 · see citing works
NEMO Links Nuclear Factor-κB to Human Diseases
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Convergent pathways of the hyperferritinemic syndromes
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Interleukin 1 receptor antagonist to treat cytophagic histiocytic panniculitis with secondary hemophagocytic lymphohistiocytosis.
Behrens, E. M., Kreiger, P. A., Cherian, S., & Cron, R. Q. (2006) · PubMed · Cited by 75 · see citing works
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Association of GATA2 Deficiency With Severe Primary Epstein-Barr Virus (EBV) Infection and EBV-associated Cancers
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Macrophage activation syndrome in the course of monogenic autoinflammatory disorders
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Pathogenic Gene Mutations or Variants Identified by Targeted Gene Sequencing in Adults With Hemophagocytic Lymphohistiocytosis
Miao, Y., Zhu, H., Qiao, C., Xia, Y., Kong, Y.-L., Zou, Y., Miao, Y., Chen, X., Cao, L., Wu, W., et al. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.00395 · Cited by 69 · see citing works
Association ofIRF5Polymorphisms with Susceptibility to Macrophage Activation Syndrome in Patients with Juvenile Idiopathic Arthritis
Yanagimachi, M. D., Naruto, T., Miyamae, T., Hara, T., Kikuchi, M., Hara, R., Imagawa, T., Mori, M., Sato, H., Goto, H., et al. (2011) · The Journal of Rheumatology · doi:10.3899/jrheum.100655 · Cited by 68 · see citing works
Pediatric macrophage activation syndrome, recognizing the tip of the Iceberg
Crayne, C. B., & Cron, R. Q. (2019) · European Journal of Rheumatology · doi:10.5152/eurjrheum.2019.19150 · Cited by 67 · see citing works
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Regulation and role of the transcription factor IRF5 in innate immune responses and systemic lupus erythematosus
Ban, T., Sato, G. R., & Tamura, T. (2018) · International Immunology · doi:10.1093/intimm/dxy032 · Cited by 64 · see citing works
IFN-γ and CD25 drive distinct pathologic features during hemophagocytic lymphohistiocytosis
Humblet‐Baron, S., Franckaert, D., Dooley, J., Ailal, F., Bousfiha, A. A., Deswarte, C., Oleaga‐Quintas, C., Casanova, J., Bustamante, J. C., & Liston, A. (2018) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2018.10.068 · Cited by 62 · see citing works
Polygenic mutations in the cytotoxicity pathway increase susceptibility to develop HLH immunopathology in mice
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Hemophagocytic lymphohistiocytosis in children with chronic granulomatous disease
Parekh, C., Hofstra, T. C., Church, J. A., & Coates, T. D. (2010) · Pediatric Blood & Cancer · doi:10.1002/pbc.22830 · Cited by 56 · see citing works
Loss of circulating CD27+ memory B cells and CCR4+ T cells occurring in association with elevated EBV loads in XLP patients surviving primary EBV infection
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Heterozygosity for the common perforin mutation, p.A91V, impairs the cytotoxicity of primary natural killer cells from healthy individuals
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Brief Report: Novel UNC13D Intronic Variant Disrupting an NF‐κB Enhancer in a Patient With Recurrent Macrophage Activation Syndrome and Systemic Juvenile Idiopathic Arthritis
Schulert, G. S., Zhang, M., Husami, A., Fall, N., Brunner, H. I., Zhang, K., Cron, R. Q., & Grom, A. A. (2018) · Arthritis & Rheumatology · doi:10.1002/art.40438 · Cited by 51 · see citing works
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Genetic variant spectrum in 265 Chinese patients with hemophagocytic lymphohistiocytosis: Molecular analyses of PRF1 , UNC13D , STX11 , STXBP2 , SH2D1A , and XIAP
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Intravenous Immunoglobulin Treatment for Macrophage Activation Syndrome Complicating Chronic Granulomatous Disease
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Effects of HLA-DRB1 alleles on susceptibility and clinical manifestations in Japanese patients with adult onset Still’s disease
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IKBKG (nuclear factor-κB essential modulator) mutation can be associated with opportunistic infection without impairing Toll-like receptor function
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IFN-γR1 defects: Mutation update and description of theIFNGR1variation database
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Adults with septic shock and extreme hyperferritinemia exhibit pathogenic immune variation
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Performance of an Automated Screening Algorithm for Early Detection of Pediatric Severe Sepsis*
Eisenberg, M., Madden, K., Christianson, J. R., Melendez, E., & Harper, M. B. (2019) · Pediatric Critical Care Medicine · doi:10.1097/pcc.0000000000002101 · Cited by 41 · see citing works
Chronic Granulomatous Disease Presenting as Hemophagocytic Lymphohistiocytosis: A Case Report
Valentine, G. C., Thomas, T., Nguyen, T. C., & Lai, Y. (2014) · PEDIATRICS · doi:10.1542/peds.2014-2175 · Cited by 39 · see citing works
Expanding the spectrum of A20 haploinsufficiency in two Chinese families: cases report
Li, G., Liu, H., Guan, W., Xu, H. M., Wu, B., & Sun, L. (2019) · BMC Medical Genetics · doi:10.1186/s12881-019-0856-1 · Cited by 38 · see citing works
Association of IRF5 Polymorphisms with Susceptibility to Hemophagocytic Lymphohistiocytosis in Children
Yanagimachi, M. D., Goto, H., Miyamae, T., Kadota, K., Imagawa, T., Mori, M., Sato, H., Yanagisawa, R., Kaneko, T., Morita, S., et al. (2011) · Journal of Clinical Immunology · doi:10.1007/s10875-011-9583-x · Cited by 33 · see citing works
Does Viral Hemorrhagic Fever Represent Reactive Hemophagocytic Syndrome?
Cron, R. Q., Behrens, E. M., Shakoory, B., Ramanan, A. V., & Chatham, W. W. (2015) · The Journal of Rheumatology · doi:10.3899/jrheum.150108 · Cited by 30 · see citing works
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Fatal hemophagocytic lymphohistiocytosis in X‐linked chronic granulomatous disease associated with a perforin gene variant
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Multifocal Recurrent Osteomyelitis and Hemophagocytic Lymphohistiocytosis in a Boy with Partial Dominant IFN-γR1 Deficiency: Case Report and Review of the Literature
Staines‐Boone, A. T., Deswarte, C., Montoya, E. V., Sánchez‐Sánchez, L. M., Campos, J. A. G., Muñiz‐Ronquillo, T., Bustamante, J. C., Espinosa-Rosales, F. J., & Reyes, S. O. L. (2017) · Frontiers in Pediatrics · doi:10.3389/fped.2017.00075 · Cited by 30 · see citing works
A Case of Macrophage Activation Syndrome Developing in a Patient With Chronic Granulomatous Disease-associated Colitis
Akagi, K., Kawai, T., Watanabe, N., Yokoyama, M., Arai, K., Harayama, S., Oana, S., & Onodera, M. (2013) · Journal of Pediatric Hematology/Oncology · doi:10.1097/mph.0b013e31828e5dae · Cited by 24 · see citing works
OL-EDA-ID Syndrome: a Novel Hypomorphic NEMO Mutation Associated with a Severe Clinical Presentation and Transient HLH
Ricci, S., Romano, F., Nieddu, F., Pïcard, C., & Azzari, C. (2016) · Journal of Clinical Immunology · doi:10.1007/s10875-016-0350-x · Cited by 20 · see citing works
Finding a Balance between Protection and Pathology: The Dual Role of Perforin in Human Disease
Orozco, R. C., & Johnson, A. J. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18081608 · Cited by 20 · see citing works
HLH: genomics illuminates pathophysiological diversity
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An unusual presentation of purine nucleoside phosphorylase deficiency mimicking systemic juvenile idiopathic arthritis complicated by macrophage activation syndrome
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Life-Threatening Primary Varicella Zoster Virus Infection With Hemophagocytic Lymphohistiocytosis-Like Disease in GATA2 Haploinsufficiency Accompanied by Expansion of Double Negative T-Lymphocytes
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Kill or Be Killed
Behrens, E. M., & Cron, R. Q. (2015) · The Journal of Immunology · doi:10.4049/jimmunol.1500774 · Cited by 12 · see citing works
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GATA2 mutation underlies hemophagocytic lymphohistiocytosis in an adult with primary cytomegalovirus infection
Suzuki, T., Takaya, S., Kunimatsu, J., Kutsuna, S., Hayakawa, K., Shibata, H., Yasumi, T., & Ohmagari, N. (2019) · Journal of Infection and Chemotherapy · doi:10.1016/j.jiac.2019.07.002 · Cited by 12 · see citing works
To “Lump” or to “Split” in Macrophage Activation Syndrome and Hemophagocytic Lymphohistiocytosis
Nikiforow, S., & Berliner, N. (2019) · Arthritis & Rheumatology · doi:10.1002/art.41106 · Cited by 11 · see citing works
1431: ADULTS WITH SEPTIC SHOCK AND EXTREME HYPERFERRITINEMIA EXHIBIT PATHOGENIC IMMUNE VARIATION
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Macrophage activation syndrome/haemophagocytic lymphohistiocytosis secondary to Burkholderia cepacia complex septicaemia in an elderly female carrier of X-linked chronic granulomatous disease with extreme lyonisation: ‘cepacia syndrome’ revisited
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Rapid Whole Genome Sequencing and Fulfilling the Promise of Precision Pediatric Critical Care*
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Involvement of the hypothalamic-pituitary-adrenal/gonadal axis and the peripheral nervous system in rheumatoid arthritis: Viewpoint based on a systemic pathogenetic role
Straub, R. H., & Cutolo, M. (2001) · Arthritis & Rheumatism · doi:10.1002/1529-0131(200103)44:3

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Cytokine storm
Fajgenbaum, D. C., & June, C. H. (2020) · New England Journal of Medicine · doi:10.1056/nejmra2026131 · Cited by 3,196 · see citing works
Cytokine Storm in COVID-19—Immunopathological Mechanisms, Clinical Considerations, and Therapeutic Approaches: The REPROGRAM Consortium Position Paper
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Cytokine Storm Syndrome
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SARS-CoV-2 Infection–Associated Hemophagocytic Lymphohistiocytosis
Prilutskiy, A., Kritselis, M. A., Shevtsov, A., Yambayev, I., Vadlamudi, C., Zhao, Q., Kataria, Y., Sarosiek, S., Lerner, A., Sloan, J. M., et al. (2020) · American Journal of Clinical Pathology · doi:10.1093/ajcp/aqaa124 · Cited by 130 · see citing works
Immune cartography of macrophage activation syndrome in the COVID-19 era
McGonagle, D., Ramanan, A. V., & Bridgewood, C. (2021) · Nature Reviews Rheumatology · doi:10.1038/s41584-020-00571-1 · Cited by 117 · see citing works
The cytokine storms of COVID-19, H1N1 influenza, CRS and MAS compared. Can one sized treatment fit all?
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Severe COVID-19: what have we learned with the immunopathogenesis?
Corrêa, B. B., Rodrigues, M. B., Cortez, A. F., Vieira, M., & Pinheiro, M. M. (2020) · Revista Brasileira de Reumatologia · doi:10.1186/s42358-020-00151-7 · Cited by 78 · see citing works
Retinal manifestations in patients with SARS-CoV-2 infection and pathogenetic implications: a systematic review
Sen, S., Kannan, N. B., Kumar, J., Rajan, R. P., Kumar, K., Baliga, G., Reddy, H., Upadhyay, A., & Ramasamy, K. (2021) · International Ophthalmology · doi:10.1007/s10792-021-01996-7 · Cited by 75 · see citing works
Hemophagocytic Lymphohistiocytosis Gene Variants in Multisystem Inflammatory Syndrome in Children
Vagrecha, A., Zhang, M., Acharya, S. S., Lozinsky, S., Singer, A. M., Levine, C., Al‐Ghafry, M., Levy, C. F., & Cron, R. Q. (2022) · Biology · doi:10.3390/biology11030417 · Cited by 45 · see citing works
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Innate and adaptive immune abnormalities underlying autoimmune diseases: the genetic connections
Chi, X., Huang, M., Tu, H., Zhang, B., Lin, X., Xu, H., Dong, C., & Hu, X. (2023) · Science China Life Sciences · doi:10.1007/s11427-021-2187-3 · Cited by 45 · see citing works
Pathogenesis and Treatment of Refractory Disease Courses in Systemic Juvenile Idiopathic Arthritis
Erkens, R. G. A., Esteban, Y., Towe, C. T., Schulert, G. S., & Vastert, S. J. (2021) · Rheumatic Disease Clinics of North America · doi:10.1016/j.rdc.2021.06.003 · Cited by 45 · see citing works
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The role of antirheumatics in patients with COVID-19
Nissen, C. B., Sciascia, S., ANDRADE, D. C. O. D., Atsumi, T., Bruce, I. N., Cron, R. Q., Hendricks, O., Roccatello, D., Stach, K., Trunfio, M., et al. (2021) · The Lancet Rheumatology · doi:10.1016/s2665-9913(21)00062-x · Cited by 42 · see citing works
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Macrophage Activation Syndrome
Nigrovic, P. A. (2024) · Arthritis & Rheumatology · doi:10.1002/art.43052 · Cited by 40 · see citing works
Diagnosis and Management of Adult Malignancy-Associated Hemophagocytic Lymphohistiocytosis
Lee, J. C., & Logan, A. C. (2023) · Cancers · doi:10.3390/cancers15061839 · Cited by 39 · see citing works
NLRP3 Inflammasome Involvement in Heart, Liver, and Lung Diseases—A Lesson from Cytokine Storm Syndrome
Napodano, C., Carnazzo, V., Basile, V., Pocino, K., Stefanile, A., Gallucci, S., Natali, P., Basile, U., & Marino, M. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms242316556 · Cited by 35 · see citing works
Heterogeneity of macrophage activation syndrome and treatment progression
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Host genetics of pediatric SARS-CoV-2 COVID-19 and multisystem inflammatory syndrome in children
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The Multifaceted Immunology of Cytokine Storm Syndrome
Lee, P. Y., & Cron, R. Q. (2023) · The Journal of Immunology · doi:10.4049/jimmunol.2200808 · Cited by 32 · see citing works
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Severe adult hemophagocytic lymphohistiocytosis (HLHa) correlates with HLH-related gene variants
Bloch‐Queyrat, C., Jaïs, J., Gil, M., Boubaya, M., Lepelletier, Y., Bader‐Meunier, B., Mahlaoui, N., Garcelon, N., Lambotte, O., Launay, D., et al. (2023) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2023.07.023 · Cited by 30 · see citing works
Digenic Inheritance: Evidence and Gaps in Hemophagocytic Lymphohistiocytosis
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Coronavirus infection: An immunologists' perspective
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Elevated free interleukin-18 associated with severity and mortality in prospective cohort study of 206 hospitalised COVID-19 patients
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Perforin, COVID‐19 and a possible pathogenic auto‐inflammatory feedback loop
Cunningham, L., Kimber, I., Basketter, D. A., Peter Simmonds, K., McSweeney, S. M., Tziotzios, C., & McFadden, J. P. (2021) · Scandinavian Journal of Immunology · doi:10.1111/sji.13102 · Cited by 27 · see citing works
Managing rheumatic diseases during COVID-19
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Inflammasomes—New Contributors to Blood Diseases
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Authors: Schulert, G. S., & Cron, R. Q.
Affiliations: Cincinnati Children's Hospital Medical Center (US)
Children's of Alabama (US)
Corresponding author: Cron, Randy Q.
ORCID: Schulert, Grant S.
Cron, Randy Q.
Venue: Genes & Immunity
Publisher: Springer Science and Business Media LLC
Published: 2020-04-15
Volume: 21
Issue: 3
Pages: 169-181
ISSN: 1466-4879 (ISSN-L)
1476-5470
DOI: 10.1038/s41435-020-0098-4
OpenAlex: W3015523006
Cited by: 91
References: 124
Citations by year: 2026: 11 · 2025: 6 · 2024: 16 · 2023: 16 · 2022: 15 · 2021: 17 · 2020: 10
FWCI: 2.27
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Genes and Immunity (publishedVersion)
PubMed (publishedVersion)
Funders: Histiocytosis Association (pilot grant)
Cincinnati Children's Research Foundation (N/A)
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: macrophage activation syndrome, secondary hemophagocytic lymphohistiocytosis, familial hemophagocytic lymphohistiocytosis, natural killer cells, heterozygous mutation, hypomorphic allele, chronic inflammation, rheumatic diseases, virus control, NLRC4, inflammasome, NEMO, LIPA, cytokine storm, genetic risk stratification
MeSH terms: Heterozygote, Humans, Killer Cells, Natural, Mutation, Virus Diseases, CD8-Positive T-Lymphocytes, Genetic Predisposition to Disease, Lymphohistiocytosis, Hemophagocytic, Perforin, Macrophage Activation Syndrome, Inflammasomes

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The genetics of macrophage activation syndrome

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