SurveyHemophagocytic lymphohistiocytosis (HLH): A heterogeneous spectrum of cytokine-driven immune disorders
Introduction
Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening disorder that was first described by Scott and Robb-Smith in 1939 [1]. It is characterized by severe systemic inflammation caused by uncontrolled proliferation and activation of lymphocytes and macrophages, secreting large amounts of cytokines, creating a so-called cytokine storm. The hallmark of HLH is the emergence of hemophagocytosis, a process in which histiocytes actively engulf blood cells and their precursors. Table 1 provides a comprehensive overview of symptoms that are most commonly observed in HLH [2], [3], [4], together with their application in the current diagnostic criteria [5].
Several subtypes of HLH are distinguished on the basis of current knowledge concerning their etiology and pathogenesis, and are classified as either primary or secondary HLH (Table 2). Primary HLH is an autosomal recessive, monogenic disorder, caused by loss-of-function mutations in genes involved in the cytotoxic function of natural killer (NK) cells and CD8+ T cells. The affected proteins and their role in granule exocytosis are depicted in Fig. 1. Secondary HLH is defined by a similar clinical syndrome but is assumed to lack a known genetic basis. This form of HLH is thought to occur in the context of an underlying immunological condition, such as malignancy or an autoimmune or autoinflammatory disorder. Secondary HLH associated with the latter two is also referred to as ‘macrophage activation syndrome’ (MAS). Clinical manifestations in both primary and secondary HLH are often precipitated by an infectious trigger, including viral, bacterial, fungal and protozoan infections, and can possibly be facilitated by immune-modulating therapies [2], [3], [6], [7], [8]. Taken together, HLH comprises a heterogeneous spectrum of etiologically different disorders (Fig. 2), which impedes early recognition of the syndrome, proper diagnosis and timely treatment of the diverse patients [3], [8], [9], [10].
Despite recent advances, the pathogenic mechanisms behind the different subtypes of HLH remain incompletely understood, which hampers the development of effective therapies for all patients. Therapeutic regimens are often empirically based, and patient responses are highly variable. Mortality rates can raise up to 70% in certain subtypes [11]. This accentuates the need for ongoing research. Specific animal models resembling different subtypes of HLH are of great value to study the pathogenesis of this perplexing disease and to uncover novel treatment options. In this paper all known animal models, covering the full spectrum of primary as well as secondary HLH, will be comprehensively reviewed. A summary of all models can be found in Table 3. Findings on cell types, cytokines and signaling pathways playing a role in pathogenesis will be discussed, together with their potential relevance and therapeutic implications for the human situation.
Section snippets
Animal models for primary HLH
The ongoing identification of mutations in different genes playing a role in granule-mediated cytotoxicity in primary HLH patients has driven the development of animal models specific for this subtype of HLH. Mice have been genetically engineered so as to mirror the mutations found in patients, in order to decipher the importance of these genes in disease pathogenesis. Most of these mutant mice do not spontaneously develop HLH but are predisposed to progress to an HLH-like syndrome after an
Spectrum of primary HLH phenotypes: comparative analysis of animal models
A comparative analysis of the different animal models for primary HLH reveals a wide spectrum of disease severity. Not all models reflect the full-blown disease seen in patients. Models of XLP, in particular, fail to clarify how HLH can emerge in XLP1 or XLP2. One hypothesis relates the variable predisposition to HLH in different patients, and in different animal models, to differences in the cytotoxic function. The residual cytotoxic function of a patient with primary HLH is determined by the
Animal models for secondary HLH
The clinical and laboratory manifestations of secondary HLH are identical to that of primary HLH, but no homozygous defects in the cytotoxic function are detectable. Nevertheless, decreased numbers of NK cells, low NK cell activity or reduced perforin expression in cytotoxic cells can be found in patients with secondary HLH [74], [75], [76]. Patients with MAS in particular may even possess heterozygous mutations in genes involved in the cytolytic pathway, blurring the thin line between primary
Therapies in animal models of HLH: implications for the treatment of patients?
Currently, treatment of HLH is predominantly based on the therapeutic guidelines of the HLH-2004 protocol, which prescribes chemo-immunotherapy such as etoposide, dexamethasone, cyclosporine A, intrathecal methotrexate and corticosteroids together with appropriate supportive care. Hematopoietic stem cell transplantation is advised for patients with primary HLH or recurrent disease [5]. However, these approaches are not equally effective in all patients, often resulting in empirical therapy for
Final considerations
The development of very diverse animal models for primary and secondary HLH have greatly enhanced our understanding of these complex syndromes. As discussed in this review, inflammatory cytokines are significantly increased in the large majority of animal models that investigated them, endorsing the importance of a cytokine storm in disease pathogenesis. IFN-γ has been studied in most models and was reported to be consistently increased in all but one model. This is indicative of a major role
Acknowledgements
The authors thank Prof. Alfons Billiau and Dr. Anneleen Avau for critical revision of the manuscript. This work was supported by grants from the Agency for Innovation by Science and Technology (IWT), the Regional Government of Flanders (GOA program), the Fund for Scientific Research Flanders (FWO-Vlaanderen) and the Interuniversity Attraction Poles (IAP). E.B. received a fellowship from the IWT. The authors declare no competing financial interests.
Ellen Brisse obtained her master's degree in Bioscience Engineering and is currently working as a PhD student at the Laboratory of Immunobiology of the Rega Institute (University of Leuven, Belgium). As a fellow of the Agency for Innovation by Science and Technology (IWT), she is investigating the role of pro-inflammatory cytokines, specific cell types and viral infection in mouse models of herpesvirus-associated hemophagocytic lymphohistiocytosis and macrophage activation syndrome complicating
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Ellen Brisse obtained her master's degree in Bioscience Engineering and is currently working as a PhD student at the Laboratory of Immunobiology of the Rega Institute (University of Leuven, Belgium). As a fellow of the Agency for Innovation by Science and Technology (IWT), she is investigating the role of pro-inflammatory cytokines, specific cell types and viral infection in mouse models of herpesvirus-associated hemophagocytic lymphohistiocytosis and macrophage activation syndrome complicating rheumatic diseases.
Carine H. Wouters is a professor at the Faculty of Medicine at the University of Leuven and a pediatric rheumatologist, affiliated to the University Hospital of Leuven and Hôpital Necker-Enfants Malades in Paris. She participates in multiple international projects to develop guidelines for diagnoses and treatments of juvenile arthritis and macrophage activation syndrome, including clinical trials with anti-cytokine therapies.
Patrick Matthys is professor in Immunology at the University of Leuven and a research director at the Rega Institute. He earned his PhD in 1993 with experimental work demonstrating the key role of IFN-γ in cytokine release syndromes and in eliciting tumor-associated cachexia. Matthys now continues conducting research at the Rega Institute, focusing on the pathogenesis of autoimmune diseases, in particular autoimmune arthritis, and autoinflammatory syndromes, i.e. systemic juvenile idiopathic arthritis and macrophage activation syndrome. The complex role of IFN-γ in the pathogenesis of these diseases remains a preferred subject of his investigations, together with in-depth analysis of interactions with other cytokines, chemokines and inflammatory mediators.
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- 3
These authors contributed equally to this work.