Genetics and Pathogenesis of Hemophagocytic Lymphohistiocytosis

  • Geneviève de Saint BasileEmail author
  • Despina Moshous
  • Alain Fischer


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.


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

List of Abbreviations


Antigen-presenting cell


Beige and Chediak-Higashi


Chediak-Higashi syndrome


Cytotoxic T lymphocytes


Common variable immune deficiency


Epstein-Barr virus


Familial lymphohistiocytosis


Griscelli syndrome


Hemophagocytic lymphohistiocytosis


Hermansky-Pudlak syndrome type 2






Immunological synapse


Juvenile idiopathic arthritis


Lipopolysaccharide-responsive and beige-like anchor protein


Lysosomal trafficking regulator


Macrophage activation syndrome


Mendelian inheritance in man


Microtubule-organizing centre


Natural killer


Pleckstrin homology domain


Primary immunodeficiency


Soluble N-ethylmaleimide-sensitive factor attachment protein receptor


Tumour necrosis factor




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
    Email author
  • 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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