title: Skin recruitment of monomyeloid precursors involves human herpesvirus-6 reactivation in drug allergy.
abstract: 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.
authors.affiliation: Department of Dermatology, Hamamatsu University School of Medicine, Hamamatsu. hihashiz0001@mac.com
authors.forename: H
authors.initials: H
authors.lastname: Hashizume
authors.forename: T
authors.initials: T
authors.lastname: Fujiyama
authors.forename: J
authors.initials: J
authors.lastname: Kanebayashi
authors.forename: Y
authors.initials: Y
authors.lastname: Kito
authors.forename: M
authors.initials: M
authors.lastname: Hata
authors.forename: H
authors.initials: H
authors.lastname: Yagi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D003875:Drug Eruptions; D004342:Drug Hypersensitivity / Q000209:etiology*; D005260:Female; D024243:HMGB1 Protein / Q000097:blood; D015654:Herpesvirus 6, Human / Q000502:physiology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D023461:Myeloid Progenitor Cells / Q000276:immunology* / Q000378:metabolism / Q000648:ultrastructure / Q000821:virology*; D010641:Phenotype; D019349:Roseolovirus Infections / Q000635:transmission; D012867:Skin / Q000276:immunology* / Q000473:pathology*; D014775:Virus Activation
chemical_list: D024243:HMGB1 Protein