Skin recruitment of monomyeloid precursors involves human herpesvirus-6 reactivation in drug allergy

Allergy. 2013;68(5):681-9. doi: 10.1111/all.12138. Epub 2013 Apr 10.


Background: In drug-induced hypersensitivity syndrome (DIHS), latent human herpesvirus (HHV)-6 is frequently reactivated in association with flaring of symptoms such as fever and hepatitis. We recently demonstrated an emergence of monomyeloid precursors expressing HHV-6 antigen in the circulation during this clinical course.

Methods: To clarify the mechanism of HHV-6 reactivation, we immunologically investigated peripheral blood mononuclear cells (PBMCs), skin-infiltrating cells, and lymphocytes expanded from skin lesions of patients with DIHS.

Results: The circulating monomyeloid precursors in the patients with DIHS were mostly CD11b(+) CD13(+) CD14(-) CD16(high) and showed substantial expression of skin-associated molecules, such as CCR4. CD13(+) CD14(-) cells were also found in the DIHS skin lesions, suggesting skin recruitment of this cell population. We detected high levels of high-mobility group box (HMGB)-1 in blood and skin lesions in the active phase of patients with DIHS and showed that recombinant HMGB-1 had functional chemoattractant activity for monocytes/monomyeloid precursors in vitro. HHV-6 infection of the skin-resident CD4(+) T cells was confirmed by the presence of its genome and antigen. This infection was likely to be mediated by monomyeloid precursors recruited to the skin, because normal CD4(+) T cells gained HHV-6 antigen after in vitro coculture with highly virus-loaded monomyeloid precursors from the patients.

Conclusions: Our results suggest that monomyeloid precursors harboring HHV-6 are navigated by HMGB-1 released from damaged skin and probably cause HHV-6 transmission to skin-infiltrating CD4(+) T cells, which is an indispensable event for HHV-6 replication. These findings implicate the skin as a cryptic and primary site for initiating HHV-6 reactivation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / virology
  • Drug Eruptions
  • Drug Hypersensitivity / etiology*
  • Female
  • HMGB1 Protein / blood
  • Herpesvirus 6, Human / physiology*
  • Humans
  • Male
  • Middle Aged
  • Myeloid Progenitor Cells / immunology*
  • Myeloid Progenitor Cells / metabolism
  • Myeloid Progenitor Cells / ultrastructure
  • Myeloid Progenitor Cells / virology*
  • Phenotype
  • Roseolovirus Infections / transmission
  • Skin / immunology*
  • Skin / pathology*
  • Virus Activation*


  • HMGB1 Protein