Inherited defects causing hemophagocytic lymphohistiocytic syndrome

Ann N Y Acad Sci. 2011 Dec;1246:64-76. doi: 10.1111/j.1749-6632.2011.06307.x.


Hemophagocytic lymphohistiocytosis (HLH) manifests as the uncontrolled activation of T lymphocytes and macrophages infiltrating multiple organs. Molecular studies of individuals with HLH have demonstrated in most of these conditions a critical role of granule-dependent cytotoxic activity in the regulation of lymphocyte homeostasis, and have allowed the characterization of key effectors regulating cytotoxic granule release. The cytolytic process may now be considered a multistep process, including cell activation; the polarization of cytotoxic granules toward the conjugated target cell; the tethering, priming, and fusion of the cytotoxic granules with the plasma membrane; and the release of their contents (perforin and granzymes) into the intercellular cleft, leading to target cell death. Cytolytic cells have a second effector function involving the production of cytokines, principally γ-interferon, which is secreted independently of the exocytosis cytotoxic granule pathway. An analysis of the mechanisms underlying HLH has identified γ-interferon as a key cytokine inducing uncontrolled macrophage activation, and thus represents a potential therapeutic target.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cytoplasmic Granules / immunology
  • Cytoplasmic Granules / metabolism
  • Disease Models, Animal
  • Humans
  • Interferon-gamma / genetics
  • Interferon-gamma / metabolism
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • LIM Domain Proteins / genetics
  • LIM Domain Proteins / metabolism
  • LIM-Homeodomain Proteins / genetics
  • LIM-Homeodomain Proteins / metabolism
  • Lymphohistiocytosis, Hemophagocytic / genetics*
  • Lymphohistiocytosis, Hemophagocytic / immunology*
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Munc18 Proteins / genetics
  • Munc18 Proteins / metabolism
  • Muscle Proteins / genetics
  • Muscle Proteins / metabolism
  • Perforin / genetics
  • Perforin / metabolism
  • Qa-SNARE Proteins / genetics
  • Qa-SNARE Proteins / metabolism
  • T-Lymphocytes, Cytotoxic / immunology
  • Transcription Factors / genetics
  • Transcription Factors / metabolism


  • FHL2 protein, human
  • FHL3 protein, human
  • FHL5 protein, human
  • Intracellular Signaling Peptides and Proteins
  • LIM Domain Proteins
  • LIM-Homeodomain Proteins
  • Membrane Proteins
  • Munc18 Proteins
  • Muscle Proteins
  • Qa-SNARE Proteins
  • STX11 protein, human
  • STXBP2 protein, human
  • Transcription Factors
  • UNC13D protein, human
  • Perforin
  • Interferon-gamma