title: Subtly impaired humoral immunity predisposes to frequently recurring genital herpes simplex virus type 2 infection and herpetic neuralgia.
abstract: BACKGROUND
  Immunogenetic factors predisposing to recurrent genital herpes remain poorly characterized.
  
  
  METHODS
  In a prospective case-control study, 52 consecutive patients with frequently recurring outbreaks of genital herpes were compared with 80 herpes simplex virus (HSV)-seropositive (types 1 and 2) and 70 HSV-seronegative control subjects. Immunoglobulins (Igs), type-specific anti-HSV-2 IgG and IgG subclass antibodies against glycoprotein G, levels of C3 and C4, and classical pathway hemolytic complement activity were measured, and IgG1 and IgG3 allotyping; C4 immunophenotyping; C4* real-time polymerase chain reaction (PCR) genotyping; and HLA-A*, B*, and DR* typing were performed.
  
  
  RESULTS
  The G3m(g),G1m(a/a(x)) haplotype was more frequent in patients than in HSV-seronegative control subjects (P=.047). Compared with all control subjects, low levels of total IgG1 (odds ratio [OR], 4.9 [95% confidence interval {CI}, 2.0-12.5]; P=.001) and IgG3 (OR 3.6 [95% CI 1.7-7.8]; P=.001), but not of anti-HSV-2 antibodies, were associated with recurrences. Levels of complement were lowest in patients. The C4* null type was negatively associated with neuralgia (OR, 0.2 [95% CI, 0.06-0.81]; P=.022).
  
  
  CONCLUSIONS
  Low levels of antibody-dependent cellular cytotoxicity-mediating IgG1 and IgG3 antibodies, partly dependent of allotype, may predispose to recurrent genital herpes. Antibodies produced by T helper type 1 responses, potentially against an unknown epitope, appear to be relevant in recurrences. In patients, C4* deficiencies are associated with protection from herpetic neuralgias, possibly through reduced inflammation.
authors.affiliation: Department of Medicine, Division of Infectious Diseases, Helsinki University Central Hospital, Hospital District of Helsinki and Uusimaa, Helsinki, Finland. mikko.seppanen@hus.fi
authors.forename: Mikko
authors.initials: M
authors.lastname: Seppanen
authors.forename: Seppo
authors.initials: S
authors.lastname: Meri
authors.forename: Irma-Leena
authors.initials: IL
authors.lastname: Notkola
authors.forename: Ilkka J T
authors.initials: IJ
authors.lastname: Seppala
authors.forename: Eija
authors.initials: E
authors.lastname: Hiltunen-Back
authors.forename: Heikki
authors.initials: H
authors.lastname: Sarvas
authors.forename: Maija
authors.initials: M
authors.lastname: Lappalainen
authors.forename: Hannamari
authors.initials: H
authors.lastname: Valimaa
authors.forename: Anil
authors.initials: A
authors.lastname: Palikhe
authors.forename: Ville V
authors.initials: VV
authors.lastname: Valtonen
authors.forename: Marja-Liisa
authors.initials: ML
authors.lastname: Lokki
mesh_terms: D000328:Adult; D000917:Antibody Formation; D001402:B-Lymphocytes / Q000276:immunology*; D016022:Case-Control Studies; D003181:Complement C4 / Q000032:analysis; D003168:Complement Fixation Tests; D004198:Disease Susceptibility / Q000276:immunology*; D005260:Female; D006558:Herpes Genitalis / Q000453:epidemiology / Q000235:genetics / Q000276:immunology*; D018258:Herpesvirus 2, Human; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D008297:Male; D008875:Middle Aged; D009437:Neuralgia / Q000235:genetics / Q000276:immunology / Q000821:virology*; D012008:Recurrence; D012016:Reference Values
chemical_list: D003181:Complement C4; D007074:Immunoglobulin G