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Genetics and Pathogenesis of Hemophagocytic Lymphohistiocytosis

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Histiocytic Disorders

Abstract

Haemophagocytic lymphohistiocytosis (HLH) is a syndrome characterized by excessive T cell activation and severe hyperinflammation. It can be subdivided into primary, inherited, forms and secondary forms as a complication of various infections, malignancies and autoinflammatory/autoimmune disorders. In the last decade, it has been shown that most of the primary forms of HLH result from genetic defects that impair the cytotoxic function of natural killer cells and cytotoxic T cells (mutations in the perforin gene or in genes whose products are essential for the exocytosis of the cytotoxic granule contents). Studies of cytotoxicity-deficient mice have helped to define primary HLH as a syndrome in which T cell over-activation by a viral infection leads to excessive, uncontrolled macrophage activation and inflammation-associated cytopenia. The recent identification of late-onset HLH, sometimes associated with hypomorphic and/or monoallelic mutations in genes encoding effectors of the lymphocyte cytotoxicity, has changed our view of HLH’s pathophysiology, in which the disease develops after the progressive accumulation of genetic and environmental factors exceeds a critical threshold.

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Abbreviations

APC:

Antigen-presenting cell

BEACH:

Beige and Chediak-Higashi

CHS:

Chediak-Higashi syndrome

CTL:

Cytotoxic T lymphocytes

CVID:

Common variable immune deficiency

EBV:

Epstein-Barr virus

FHL:

Familial lymphohistiocytosis

GS:

Griscelli syndrome

HLH:

Hemophagocytic lymphohistiocytosis

HPS2:

Hermansky-Pudlak syndrome type 2

IL-:

Interleukin-

INF:

Interferon

IS:

Immunological synapse

JIA:

Juvenile idiopathic arthritis

LRBA:

Lipopolysaccharide-responsive and beige-like anchor protein

LYST:

Lysosomal trafficking regulator

MAS:

Macrophage activation syndrome

MIM:

Mendelian inheritance in man

MTOC:

Microtubule-organizing centre

NK:

Natural killer

PH:

Pleckstrin homology domain

PID:

Primary immunodeficiency

SNARE:

Soluble N-ethylmaleimide-sensitive factor attachment protein receptor

TNF:

Tumour necrosis factor

t-SNARE:

Target-SNARE

XLP:

X-linked lymphoproliferative disease

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Authors and Affiliations

  1. INSERM UMR1163, F-75015, Paris, France

    Geneviève de Saint Basile MD, PhD, Despina Moshous MD, PhD & Alain Fischer MD, PhD

  2. Paris Descartes University-Sorbonne Paris Cité, Imagine Institute, F-75015, Paris, France

    Geneviève de Saint Basile MD, PhD, Despina Moshous MD, PhD & Alain Fischer MD, PhD

  3. Centre d’Etudes des Déficits Immunitaires, Assistance Publique-Hôpitaux de Paris, Hôpital Necker, Paris, France

    Geneviève de Saint Basile MD, PhD

  4. Paediatric Immunology and Hematology Department, Necker Children’s Hospital, AP-HP, Paris, France

    Despina Moshous MD, PhD & Alain Fischer MD, PhD

  5. Collège de France, F-75005, Paris, France

    Alain Fischer MD, PhD

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  1. Geneviève de Saint Basile MD, PhD
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  2. Despina Moshous MD, PhD
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  3. Alain Fischer MD, PhD
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Correspondence to Geneviève de Saint Basile MD, PhD .

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  1. University of Toronto, The Hospital for Sick Children, Toronto, Ontario, Canada

    Oussama Abla

  2. Pediatric Hematology and Oncology, University Medical Center Hamburg Eppendorf, Hamburg, Germany

    Gritta Janka

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de Saint Basile, G., Moshous, D., Fischer, A. (2018). Genetics and Pathogenesis of Hemophagocytic Lymphohistiocytosis. In: Abla, O., Janka, G. (eds) Histiocytic Disorders. Springer, Cham. https://doi.org/10.1007/978-3-319-59632-7_11

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  • DOI: https://doi.org/10.1007/978-3-319-59632-7_11

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