Disruption of MyD88 signaling suppresses hemophagocytic lymphohistiocytosis in mice

Blood. 2011 Jun 16;117(24):6582-8. doi: 10.1182/blood-2011-01-329607. Epub 2011 May 6.


Hemophagocytic lymphohistiocytosis (HLH) is a rare inflammatory disorder with a poor prognosis for affected individuals. To find a means of suppressing the clinical phenotype, we investigated the cellular and molecular mechanisms leading to HLH in Unc13d(jinx/jinx) mice, in which cytolytic function of NK and CD8(+) T cells is impaired. Unc13d(jinx/jinx) mutants infected with lymphochoriomeningitis virus (LCMV) present typical clinical features of HLH, including splenomegaly, elevated serum IFNγ, and anemia. Proteins mediating cell-cell contact, cytokine signaling or Toll-like receptor (TLR) signaling were analyzed. We show that neither the integrin CD18, which is involved in adhesion between antigen-presenting cells and effector T cells, nor tumor necrosis factor (TNF) made nonredundant contributions to the disease phenotype. Disruption of IFNγ signaling reduced immune cell activation in Unc13d(jinx/jinx) mice, but also resulted in uncontrolled viral proliferation and exaggerated release of inflammatory cytokines. Abrogating the function of myeloid differentiation primary response gene 88 (MyD88) in Unc13d(jinx/jinx) mice suppressed immune cell activation and controlled cytokine production in an IL-1 receptor 1 (IL-1R1)-independent way. Our findings implicate MyD88 as the key initiator of myeloid and lymphoid proliferation in HLH, and suggest that blockade of this signaling molecule may reduce immunopathology in patients.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cytoprotection / genetics
  • Down-Regulation / genetics
  • Down-Regulation / physiology
  • Genetic Predisposition to Disease
  • Genetic Therapy / methods
  • Immune Tolerance / genetics
  • Immune Tolerance / physiology
  • Lymphohistiocytosis, Hemophagocytic / genetics*
  • Lymphohistiocytosis, Hemophagocytic / metabolism
  • Lymphohistiocytosis, Hemophagocytic / therapy
  • Membrane Proteins / genetics
  • Membrane Proteins / physiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mutagenesis, Site-Directed
  • Myeloid Differentiation Factor 88 / genetics
  • Myeloid Differentiation Factor 88 / metabolism
  • Myeloid Differentiation Factor 88 / physiology*
  • Signal Transduction / genetics
  • Signal Transduction / physiology


  • Membrane Proteins
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • Unc13d protein, mouse