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Article ; Online: Advances in the pathogenesis of primary and secondary haemophagocytic lymphohistiocytosis: differences and similarities.

Brisse, Ellen / Wouters, Carine H / Matthys, Patrick

2016 Volume 174, Issue 2, Page(s) 203–217

Abstract: 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). ... ...

Abstract	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 CD8(+) 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.
MeSH term(s)	CD8-Positive T-Lymphocytes/pathology ; Diagnosis, Differential ; Humans ; Inflammation ; Lymphohistiocytosis, Hemophagocytic/diagnosis ; Lymphohistiocytosis, Hemophagocytic/etiology ; Lymphohistiocytosis, Hemophagocytic/genetics ; Mutation ; Natural Killer T-Cells/pathology ; Sequence Analysis, DNA
Language	English
Publishing date	2016-07
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	80077-6
ISSN	1365-2141 ; 0007-1048
ISSN (online)	1365-2141
ISSN	0007-1048
DOI	10.1111/bjh.14147
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Article ; Online: Understanding the spectrum of haemophagocytic lymphohistiocytosis: update on diagnostic challenges and therapeutic options.

Brisse, Ellen / Matthys, Patrick / Wouters, Carine H

British journal of haematology

2016 Volume 174, Issue 2, Page(s) 175–187

Abstract: The cytokine storm syndrome 'haemophagocytic lymphohistiocytosis' (HLH) is an under-recognized hyperinflammatory disorder, causing high morbidity and mortality risk in children and adults. It can be subdivided into a primary, genetic form and a secondary, ...

Abstract	The cytokine storm syndrome 'haemophagocytic lymphohistiocytosis' (HLH) is an under-recognized hyperinflammatory disorder, causing high morbidity and mortality risk in children and adults. It can be subdivided into a primary, genetic form and a secondary, acquired form that complicates diverse infections, malignancies and autoimmune or autoinflammatory disorders. Both subtypes present with the same spectrum of non-specific symptoms, making accurate diagnosis and rapid treatment initiation challenging. In the last decade, increased awareness and international collaborative efforts fuelled a marked progress in diagnostic protocols and novel treatment strategies for HLH and new diagnostic guidelines are being tailored to specific secondary HLH subtypes. Therapy is gradually shifting its focus from overall immunosuppression towards targeting specific cytokines, cell types or signalling pathways underlying pathophysiology. Nevertheless, continued research efforts remain indispensable to customize therapy to individual patient needs.
MeSH term(s)	Diagnosis, Differential ; Humans ; Lymphohistiocytosis, Hemophagocytic/classification ; Lymphohistiocytosis, Hemophagocytic/diagnosis ; Lymphohistiocytosis, Hemophagocytic/etiology ; Lymphohistiocytosis, Hemophagocytic/therapy ; Molecular Targeted Therapy
Language	English
Publishing date	2016-07
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	80077-6
ISSN	1365-2141 ; 0007-1048
ISSN (online)	1365-2141
ISSN	0007-1048
DOI	10.1111/bjh.14144
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Article: How Viruses Contribute to the Pathogenesis of Hemophagocytic Lymphohistiocytosis.

Brisse, Ellen / Wouters, Carine H / Andrei, Graciela / Matthys, Patrick

Frontiers in immunology

2017 Volume 8, Page(s) 1102

Abstract: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening, hyperinflammatory syndrome, characterized by the uncontrolled activation of macrophages and T cells, eliciting key symptoms such as persistent fever, hepatosplenomegaly, pancytopenia, ... ...

Abstract	Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening, hyperinflammatory syndrome, characterized by the uncontrolled activation of macrophages and T cells, eliciting key symptoms such as persistent fever, hepatosplenomegaly, pancytopenia, hemophagocytosis, hyperferritinemia, and coagulopathy. Viral infections are frequently implicated in the onset of active HLH episodes, both in primary, genetic HLH as in the secondary, acquired form. Infections with herpesviruses such as Epstein-Barr virus and cytomegalovirus are the most common. In autoimmune diseases, a link between viral infections and autoreactive immune responses has been recognized for a considerable time. However, the mechanisms by which viruses contribute to HLH pathogenesis remain to be clarified. In this viewpoint, different factors that may come into play are discussed. Viruses, particularly larger DNA viruses such as herpesviruses, are potent modulators of the immune response. By evading immune recognition, interfering with cytokine balances and inhibiting apoptotic pathways, viruses may increase the host's susceptibility to HLH development. In particular cases, a direct connection between the viral infection and inhibition of natural killer cell or T cell cytotoxicity was reported, indicating that viruses may create immunological deficiencies reminiscent of primary HLH.
Language	English
Publishing date	2017-09-07
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2606827-8
ISSN	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2017.01102
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Article ; Online: Hemophagocytic lymphohistiocytosis (HLH): A heterogeneous spectrum of cytokine-driven immune disorders.

Brisse, Ellen / Wouters, Carine H / Matthys, Patrick

Cytokine & growth factor reviews

2015 Volume 26, Issue 3, Page(s) 263–280

Abstract: Hemophagocytic lymphohistiocytosis (HLH) comprises a group of life-threatening immune disorders classified into primary or secondary HLH. The former is caused by mutations in genes involved in granule-mediated cytotoxicity, the latter occurs in a context ...

Abstract	Hemophagocytic lymphohistiocytosis (HLH) comprises a group of life-threatening immune disorders classified into primary or secondary HLH. The former is caused by mutations in genes involved in granule-mediated cytotoxicity, the latter occurs in a context of infections, malignancies or autoimmune/autoinflammatory disorders. Both are characterized by systemic inflammation, severe cytokine storms and immune-mediated organ damage. Despite recent advances, the pathogenesis of HLH remains incompletely understood. Animal models resembling different subtypes of HLH are therefore of great value to study this disease and to uncover novel treatment strategies. In this review, all known animal models of HLH will be discussed, highlighting findings on cell types, cytokines and signaling pathways involved in disease pathogenesis and extrapolating therapeutic implications for the human situation.
MeSH term(s)	Animals ; Cytokines/immunology ; Disease Models, Animal ; Humans ; Lymphohistiocytosis, Hemophagocytic/drug therapy ; Lymphohistiocytosis, Hemophagocytic/immunology
Chemical Substances	Cytokines
Language	English
Publishing date	2015-06
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1330534-7
ISSN	1879-0305 ; 1359-6101
ISSN (online)	1879-0305
ISSN	1359-6101
DOI	10.1016/j.cytogfr.2014.10.001
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Article: Lytic viral replication and immunopathology in a cytomegalovirus-induced mouse model of secondary hemophagocytic lymphohistiocytosis

Brisse, Ellen / Imbrechts, Maya / Mitera, Tania / Vandenhaute, Jessica / Wouters, Carine H / Snoeck, Robert / Andrei, Graciela / Matthys, Patrick

Virology journal. 2017 Dec., v. 14, no. 1

2017

Abstract: BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a rare immunological disorder caused by unbridled activation of T cells and macrophages, culminating in a life-threatening cytokine storm. A genetic and acquired subtype are distinguished, termed ... ...

Abstract	BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a rare immunological disorder caused by unbridled activation of T cells and macrophages, culminating in a life-threatening cytokine storm. A genetic and acquired subtype are distinguished, termed primary and secondary HLH, respectively. Clinical manifestations of both forms are frequently preceded by a viral infection, predominantly with herpesviruses. The exact role of the viral infection in the development of the hemophagocytic syndrome remains to be further elucidated. METHODS: We utilized a recently developed murine model of cytomegalovirus-associated secondary HLH and dissected the respective contributions of lytic viral replication and immunopathology in its pathogenesis. RESULTS: HLH-like disease only developed in cytomegalovirus-susceptible mouse strains unable to clear the virus, but the severity of symptoms was not correlated to the infectious viral titer. Lytic viral replication and sustained viremia played an essential part in the pathogenesis since abortive viral infection was insufficient to induce a full-blown HLH-like syndrome. Nonetheless, a limited set of symptoms, in particular anemia, thrombocytopenia and elevated levels of soluble CD25, appeared less dependent of the viral replication but rather mediated by the host’s immune response, as corroborated by immunosuppressive treatment of infected mice with dexamethasone. CONCLUSION: Both virus-mediated pathology and immunopathology cooperate in the pathogenesis of full-blown virus-associated secondary HLH and are closely entangled. A certain level of viremia appears necessary to elicit the characteristic HLH-like symptoms in the model.
Keywords	T-lymphocytes ; anemia ; animal models ; cytokines ; dexamethasone ; immune response ; immunopathology ; immunosuppression ; macrophages ; mice ; pathogenesis ; thrombocytopenia ; viral load ; viremia ; virus replication ; viruses
Language	English
Dates of publication	2017-12
Size	p. 240.
Publishing place	BioMed Central
Document type	Article
ISSN	1743-422X
DOI	10.1186/s12985-017-0908-0
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Lytic viral replication and immunopathology in a cytomegalovirus-induced mouse model of secondary hemophagocytic lymphohistiocytosis.

Brisse, Ellen / Imbrechts, Maya / Mitera, Tania / Vandenhaute, Jessica / Wouters, Carine H / Snoeck, Robert / Andrei, Graciela / Matthys, Patrick

Virology journal

2017 Volume 14, Issue 1, Page(s) 240

Abstract: Background: Hemophagocytic lymphohistiocytosis (HLH) is a rare immunological disorder caused by unbridled activation of T cells and macrophages, culminating in a life-threatening cytokine storm. A genetic and acquired subtype are distinguished, termed ... ...

Abstract	Background: Hemophagocytic lymphohistiocytosis (HLH) is a rare immunological disorder caused by unbridled activation of T cells and macrophages, culminating in a life-threatening cytokine storm. A genetic and acquired subtype are distinguished, termed primary and secondary HLH, respectively. Clinical manifestations of both forms are frequently preceded by a viral infection, predominantly with herpesviruses. The exact role of the viral infection in the development of the hemophagocytic syndrome remains to be further elucidated. Methods: We utilized a recently developed murine model of cytomegalovirus-associated secondary HLH and dissected the respective contributions of lytic viral replication and immunopathology in its pathogenesis. Results: HLH-like disease only developed in cytomegalovirus-susceptible mouse strains unable to clear the virus, but the severity of symptoms was not correlated to the infectious viral titer. Lytic viral replication and sustained viremia played an essential part in the pathogenesis since abortive viral infection was insufficient to induce a full-blown HLH-like syndrome. Nonetheless, a limited set of symptoms, in particular anemia, thrombocytopenia and elevated levels of soluble CD25, appeared less dependent of the viral replication but rather mediated by the host's immune response, as corroborated by immunosuppressive treatment of infected mice with dexamethasone. Conclusion: Both virus-mediated pathology and immunopathology cooperate in the pathogenesis of full-blown virus-associated secondary HLH and are closely entangled. A certain level of viremia appears necessary to elicit the characteristic HLH-like symptoms in the model.
MeSH term(s)	Animals ; Antiviral Agents/pharmacology ; Cytosine/analogs & derivatives ; Cytosine/pharmacology ; Dexamethasone/pharmacology ; Disease Models, Animal ; Humans ; Immunosuppressive Agents/pharmacology ; Interleukin-2 Receptor alpha Subunit/drug effects ; Interleukin-2 Receptor alpha Subunit/immunology ; Lymphohistiocytosis, Hemophagocytic/drug therapy ; Lymphohistiocytosis, Hemophagocytic/immunology ; Lymphohistiocytosis, Hemophagocytic/physiopathology ; Lymphohistiocytosis, Hemophagocytic/virology ; Mice ; Mice, Inbred BALB C ; Mice, Knockout ; Muromegalovirus/physiology ; Organophosphonates/pharmacology ; T-Lymphocytes/drug effects ; T-Lymphocytes/immunology ; Toll-Like Receptor 3/agonists ; Toll-Like Receptor 3/physiology ; Toll-Like Receptor 9/agonists ; Toll-Like Receptor 9/physiology ; Virus Diseases/physiopathology ; Virus Replication/drug effects ; Virus Replication/physiology
Chemical Substances	Antiviral Agents ; Immunosuppressive Agents ; Interleukin-2 Receptor alpha Subunit ; Organophosphonates ; Toll-Like Receptor 3 ; Toll-Like Receptor 9 ; Dexamethasone (7S5I7G3JQL) ; Cytosine (8J337D1HZY) ; cidofovir (JIL713Q00N)
Language	English
Publishing date	2017--19
Publishing country	England
Document type	Journal Article
ISSN	1743-422X
ISSN (online)	1743-422X
DOI	10.1186/s12985-017-0908-0
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Article ; Online: IFN-γ stimulates CpG-induced IL-10 production in B cells via p38 and JNK signalling pathways.

Imbrechts, Maya / De Samblancx, Karen / Fierens, Karlien / Brisse, Ellen / Vandenhaute, Jessica / Mitera, Tania / Libert, Claude / Smets, Ide / Goris, An / Wouters, Carine / Matthys, Patrick

European journal of immunology

2018 Volume 48, Issue 9, Page(s) 1506–1521

Abstract: The production of IL-10, a potent immunosuppressive cytokine, must be strictly regulated to ensure a balanced immune response. IFN-γ, a key cytokine in multiple immune processes and pathologies, is known as an inhibitor of IL-10 production by monocytes ... ...

Abstract	The production of IL-10, a potent immunosuppressive cytokine, must be strictly regulated to ensure a balanced immune response. IFN-γ, a key cytokine in multiple immune processes and pathologies, is known as an inhibitor of IL-10 production by monocytes and macrophages, but also has some regulatory functions. In the present study, we explored the role of IFN-γ on Toll-like receptor (TLR)-induced IL-10 production in murine peritoneal and spleen cells and in human peripheral blood mononuclear cells. IFN-γ inhibited IL-10 production induced by TLR2, TLR3, TLR4 and TLR7/8 agonists, but stimulated IL-10 production when cells were triggered with CpG oligodeoxynucleotides, a specific TLR9 agonist. The stimulatory effect of IFN-γ on TLR9-induced IL-10 was restricted to B cells. In line with the increased IL-10, B cells stimulated with CpG and IFN-γ profoundly inhibited CD4 T cell proliferation. Further research into the mechanisms involved, revealed that the mitogen-activated protein kinases p38 and JNK are essential players in this stimulatory effect, and that the phosphatase MKP1 - an inhibitor of p38 and JNK activity - is downregulated after combined stimulation with IFN-γ and CpG. Our data may represent a novel immunoregulatory role of IFN-γ in B cells after triggering of TLR9, by stimulating IL-10 production.
MeSH term(s)	Animals ; B-Lymphocytes/immunology ; CD4-Positive T-Lymphocytes/immunology ; Cell Proliferation/genetics ; Cells, Cultured ; CpG Islands/genetics ; Dual Specificity Phosphatase 1/biosynthesis ; Humans ; Interferon-gamma/genetics ; Interferon-gamma/metabolism ; Interleukin-10/biosynthesis ; JNK Mitogen-Activated Protein Kinases/metabolism ; Lymphocyte Activation/genetics ; MAP Kinase Signaling System/genetics ; Macrophages/immunology ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mice, Knockout ; Receptor, Interferon alpha-beta/genetics ; Signal Transduction/immunology ; Toll-Like Receptor 9/metabolism ; p38 Mitogen-Activated Protein Kinases/metabolism
Chemical Substances	IFNG protein, mouse ; IL10 protein, mouse ; Ifnar1 protein, mouse ; Tlr9 protein, mouse ; Toll-Like Receptor 9 ; Interleukin-10 (130068-27-8) ; Receptor, Interferon alpha-beta (156986-95-7) ; Interferon-gamma (82115-62-6) ; JNK Mitogen-Activated Protein Kinases (EC 2.7.11.24) ; p38 Mitogen-Activated Protein Kinases (EC 2.7.11.24) ; Dual Specificity Phosphatase 1 (EC 3.1.3.48) ; Dusp1 protein, mouse (EC 3.1.3.48)
Language	English
Publishing date	2018-08-01
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	120108-6
ISSN	1521-4141 ; 0014-2980
ISSN (online)	1521-4141
ISSN	0014-2980
DOI	10.1002/eji.201847578
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Zs.A 489: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Rapid genotyping of Achromobacter xylosoxidans, Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa and Stenotrophomonas maltophilia isolates using melting curve analysis of RAPD-generated DNA fragments (McRAPD).

Deschaght, Pieter / Van Simaey, Leen / Decat, Ellen / Van Mechelen, Els / Brisse, Sylvain / Vaneechoutte, Mario

Research in microbiology

2011 Volume 162, Issue 4, Page(s) 386–392

Abstract: Typing of bacteria is important for monitoring newly emerging pathogens and for examining local outbreaks. We evaluated the randomly amplified polymorphic DNA technique in combination with melting curve analysis (McRAPD) of the amplified DNA fragments to ...

Abstract	Typing of bacteria is important for monitoring newly emerging pathogens and for examining local outbreaks. We evaluated the randomly amplified polymorphic DNA technique in combination with melting curve analysis (McRAPD) of the amplified DNA fragments to genotype isolates from five Gram-negative species, i.e. Achromobacter xylosoxidans, Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa and Stenotrophomonas maltophilia. By determining the melting temperature peaks of the amplified DNA fragments, we were able to distinguish the different genotypes of isolates, as they had been assessed by other genotyping techniques, i.e. agarose gel electrophoresis of RAPD fragments, multilocus sequence typing and/or AFLP™. According to our results, McRAPD may offer the possibility of genotyping a limited number of bacterial isolates, e.g. in case of suspicion of hospital outbreak, via a less costly, more rapid, less laborious and more user-friendly technique than RAPD followed by electrophoresis.
MeSH term(s)	Achromobacter denitrificans/classification ; Achromobacter denitrificans/genetics ; Achromobacter denitrificans/isolation & purification ; Acinetobacter baumannii/classification ; Acinetobacter baumannii/genetics ; Acinetobacter baumannii/isolation & purification ; Bacterial Typing Techniques/methods ; DNA, Bacterial/genetics ; Genotype ; Gram-Negative Bacterial Infections/microbiology ; Humans ; Klebsiella pneumoniae/classification ; Klebsiella pneumoniae/genetics ; Klebsiella pneumoniae/isolation & purification ; Pseudomonas aeruginosa/classification ; Pseudomonas aeruginosa/genetics ; Pseudomonas aeruginosa/isolation & purification ; Random Amplified Polymorphic DNA Technique/methods ; Stenotrophomonas maltophilia/classification ; Stenotrophomonas maltophilia/genetics ; Stenotrophomonas maltophilia/isolation & purification ; Transition Temperature
Chemical Substances	DNA, Bacterial
Language	English
Publishing date	2011-05
Publishing country	France
Document type	Evaluation Studies ; Journal Article
ZDB-ID	1004220-9
ISSN	1769-7123 ; 0923-2508
ISSN (online)	1769-7123
ISSN	0923-2508
DOI	10.1016/j.resmic.2011.02.002
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Zs.A 890: Show issues

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Article ; Online: IDO1 Deficiency Does Not Affect Disease in Mouse Models of Systemic Juvenile Idiopathic Arthritis and Secondary Hemophagocytic Lymphohistiocytosis.

Put, Karen / Brisse, Ellen / Avau, Anneleen / Imbrechts, Maya / Mitera, Tania / Janssens, Rik / Proost, Paul / Fallarino, Francesca / Wouters, Carine H / Matthys, Patrick

PloS one

2016 Volume 11, Issue 2, Page(s) e0150075

Abstract: Objectives: Indoleamine 2,3-dioxygenase-1 (IDO1) is an immune-modulatory enzyme that catalyzes the degradation of tryptophan (Trp) to kynurenine (Kyn) and is strongly induced by interferon (IFN)-γ. We previously reported highly increased levels of IFN-γ ...

Abstract	Objectives: Indoleamine 2,3-dioxygenase-1 (IDO1) is an immune-modulatory enzyme that catalyzes the degradation of tryptophan (Trp) to kynurenine (Kyn) and is strongly induced by interferon (IFN)-γ. We previously reported highly increased levels of IFN-γ and corresponding IDO activity in patients with hemophagocytic lymphohistiocytosis (HLH), a hyper-inflammatory syndrome. On the other hand, IFN-γ and IDO were low in patients with systemic juvenile idiopathic arthritis (sJIA), an autoinflammatory syndrome. As HLH can occur as a complication of sJIA, the opposing levels of both IFN-γ and IDO are remarkable. In animal models for sJIA and HLH, the role of IFN-γ differs from being protective to pathogenic. In this study, we aimed to unravel the role of IDO1 in the pathogenesis of sJIA and HLH. Methods: Wild-type and IDO1-knockout (IDO1-KO) mice were used in 3 models of sJIA or HLH: complete Freund's adjuvant (CFA)-injected mice developed an sJIA-like syndrome and secondary HLH (sHLH) was evoked by either repeated injection of unmethylated CpG oligonucleotide or by primary infection with mouse cytomegalovirus (MCMV). An anti-CD3-induced cytokine release syndrome was used as a non-sJIA/HLH control model. Results: No differences were found in clinical, laboratory and hematological features of sJIA/HLH between wild-type and IDO1-KO mice. As IDO modulates the immune response via induction of regulatory T cells and inhibition of T cell proliferation, we investigated both features in a T cell-triggered cytokine release syndrome. Again, no differences were observed in serum cytokine levels, percentages of regulatory T cells, nor of proliferating or apoptotic thymocytes and lymph node cells. Conclusions: Our data demonstrate that IDO1 deficiency does not affect inflammation in sJIA, sHLH and a T cell-triggered cytokine release model. We hypothesize that other tryptophan-catabolizing enzymes like IDO2 and tryptophan 2,3-dioxygenase (TDO) might compensate for the lack of IDO1.
MeSH term(s)	Animals ; Apoptosis/immunology ; Arthritis, Experimental/genetics ; Arthritis, Experimental/immunology ; Arthritis, Juvenile/genetics ; Arthritis, Juvenile/pathology ; Cell Proliferation ; Cytokines/blood ; Cytomegalovirus/immunology ; Cytomegalovirus Infections/immunology ; Cytomegalovirus Infections/pathology ; Freund's Adjuvant/immunology ; Indoleamine-Pyrrole 2,3,-Dioxygenase/genetics ; Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism ; Inflammation/immunology ; Interferon-gamma/genetics ; Interferon-gamma/immunology ; Interferon-gamma/metabolism ; Lymphohistiocytosis, Hemophagocytic/genetics ; Lymphohistiocytosis, Hemophagocytic/pathology ; Macrophage Activation Syndrome/genetics ; Macrophage Activation Syndrome/pathology ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mice, Knockout ; T-Lymphocytes/immunology ; Tryptophan Oxygenase/metabolism
Chemical Substances	Cytokines ; IDO1 protein, mouse ; IDO2 protein, mouse ; Indoleamine-Pyrrole 2,3,-Dioxygenase ; Interferon-gamma (82115-62-6) ; Freund's Adjuvant (9007-81-2) ; Tryptophan Oxygenase (EC 1.13.11.11)
Language	English
Publishing date	2016-02-25
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0150075
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Article ; Online: Mouse Cytomegalovirus Infection in BALB/c Mice Resembles Virus-Associated Secondary Hemophagocytic Lymphohistiocytosis and Shows a Pathogenesis Distinct from Primary Hemophagocytic Lymphohistiocytosis.

Brisse, Ellen / Imbrechts, Maya / Put, Karen / Avau, Anneleen / Mitera, Tania / Berghmans, Nele / Rutgeerts, Omer / Waer, Mark / Ninivaggi, Marisa / Kelchtermans, Hilde / Boon, Louis / Snoeck, Robert / Wouters, Carine H / Andrei, Graciela / Matthys, Patrick

Journal of immunology (Baltimore, Md. : 1950)

2016 Volume 196, Issue 7, Page(s) 3124–3134

Abstract: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening immunological disorder that is characterized by systemic inflammation, widespread organ damage, and hypercytokinemia. Primary HLH is caused by mutations in granule-mediated cytotoxicity, ... ...

Abstract	Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening immunological disorder that is characterized by systemic inflammation, widespread organ damage, and hypercytokinemia. Primary HLH is caused by mutations in granule-mediated cytotoxicity, whereas secondary HLH occurs, without a known genetic background, in a context of infections, malignancies, or autoimmune and autoinflammatory disorders. Clinical manifestations of both HLH subtypes are often precipitated by a viral infection, predominantly with Herpesviridae. Exploiting this knowledge, we established an animal model of virus-associated secondary HLH by infecting immunocompetent wild-type mice with the β-herpesvirus murine CMV. C57BL/6 mice developed a mild inflammatory phenotype, whereas BALB/c mice displayed the clinicopathologic features of HLH, as set forth in the Histiocyte Society diagnostic guidelines: fever, cytopenia, hemophagocytosis, hyperferritinemia, and elevated serum levels of soluble CD25. BALB/c mice also developed lymphadenopathy, liver dysfunction, and decreased NK cell numbers. Lymphoid and myeloid cells were in a hyperactivated state. Nonetheless, depletion of CD8(+) T cells could not inhibit or cure the HLH-like syndrome, highlighting a first dissimilarity from mouse models of primary HLH. Immune cell hyperactivation in BALB/c mice was accompanied by a cytokine storm. Notably, plasma levels of IFN-γ, a key pathogenic cytokine in models of primary HLH, were the highest. Nevertheless, murine CMV-infected IFN-γ-deficient mice still developed the aforementioned HLH-like symptoms. In fact, IFN-γ-deficient mice displayed a more complete spectrum of HLH, including splenomegaly, coagulopathy, and decreased NK cell cytotoxicity, indicating a regulatory role for IFN-γ in the pathogenesis of virus-associated secondary HLH as opposed to its central pathogenic role in primary HLH.
MeSH term(s)	Animals ; Biomarkers ; Cytokines/genetics ; Cytokines/metabolism ; Cytotoxicity, Immunologic ; Disease Models, Animal ; Herpesviridae Infections/complications ; Herpesviridae Infections/virology ; Histiocytes/immunology ; Histiocytes/metabolism ; Interferon-gamma/deficiency ; Interferon-gamma/genetics ; Interferon-gamma/metabolism ; Killer Cells, Natural/immunology ; Killer Cells, Natural/metabolism ; Liver/immunology ; Liver/metabolism ; Liver/pathology ; Liver/virology ; Lymphohistiocytosis, Hemophagocytic/diagnosis ; Lymphohistiocytosis, Hemophagocytic/etiology ; Lymphohistiocytosis, Hemophagocytic/metabolism ; Mice ; Mice, Inbred BALB C ; Mice, Knockout ; Muromegalovirus/physiology ; T-Lymphocyte Subsets/immunology ; T-Lymphocyte Subsets/metabolism
Chemical Substances	Biomarkers ; Cytokines ; Interferon-gamma (82115-62-6)
Language	English
Publishing date	2016-04-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.1501035
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Ud II Zs.37: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
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