Genetics and Pathogenesis of Hemophagocytic Lymphohistiocytosis

  • Geneviève de Saint Basile
  • Despina Moshous
  • Alain Fischer
Chapter

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.

Keywords

Cytotoxicity T cell activation EBV Perforin SAP XIAP Granule exocytosis Hypopigmentation NLRC4 Inflammation Inflammatory cytokine Primary HLH MAS 

List of 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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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Geneviève de Saint Basile
    • 1
    • 2
    • 3
  • Despina Moshous
    • 1
    • 2
    • 4
  • Alain Fischer
    • 1
    • 2
    • 4
    • 5
  1. 1.INSERM UMR1163ParisFrance
  2. 2.Paris Descartes University-Sorbonne Paris Cité, Imagine InstituteParisFrance
  3. 3.Centre d’Etudes des Déficits ImmunitairesAssistance Publique-Hôpitaux de Paris, Hôpital NeckerParisFrance
  4. 4.Paediatric Immunology and Hematology DepartmentNecker Children’s Hospital, AP-HPParisFrance
  5. 5.Collège de FranceParisFrance

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