title: Induction of keratinocyte IL-8 expression and secretion by IgG autoantibodies as a novel mechanism of epidermal neutrophil recruitment in a pemphigus variant.
abstract: A subset of pemphigus herpetiformis, a rare pemphigus variant, is characterized histopathologically by subcorneal acantholysis and neutrophilic infiltration. The mechanism of neutrophil infiltration is unknown, but chemokines such as IL-8 may play a role. We investigated the possible role of IL-8 in two such cases. Direct and indirect immunofluorescence studies demonstrated in vivo-bound and circulating IgG epithelial cell surface-binding autoantibodies, both predominated by IgG4 subclass. ELISA and immunoblotting studies revealed that the patients' IgG autoantibodies recognized recombinant desmoglein 1 but not desmoglein 3. Preadsorption of the patients' sera with recombinant desmoglein 1 completely removed the epidermal cell surface immunostaining. Significantly, immunohistochemistry demonstrated intense expression of IL-8, co-localized with in vivo-bound IgG, in the upper epidermis, where the acantholysis took place. Affinity-purified sera IgG from these two patients, a normal individual, and a pemphigus vulgaris patient containing desmoglein 1 autoantibodies, were incubated with normal human keratinocytes in vitro. Cells treated with these patients' IgG secreted a seven-to-nine-fold increase of IL-8 (30-37 pg/ml) compared with the controls (2-4 pg/ml) and expressed a higher intensity of cytoplasmic IL-8 staining. These data demonstrate a novel functional role for IL-8 in the pathogenesis of the neutrophil-dominant subset of pemphigus herpetiformis. The autoantibody-induced epidermal cell IL-8 expression may represent a novel mechanism of epidermal neutrophil recruitment.
authors.affiliation: North-western University Medical School, Chicago, IL, USA.
authors.forename: E A
authors.initials: EA
authors.lastname: O'Toole
authors.forename: L L
authors.initials: LL
authors.lastname: Mak
authors.forename: J
authors.initials: J
authors.lastname: Guitart
authors.forename: D T
authors.initials: DT
authors.lastname: Woodley
authors.forename: T
authors.initials: T
authors.lastname: Hashimoto
authors.forename: M
authors.initials: M
authors.lastname: Amagai
authors.forename: L S
authors.initials: LS
authors.lastname: Chan
mesh_terms: D000328:Adult; D000368:Aged; D000918:Antibody Specificity; D001323:Autoantibodies / Q000097:blood / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000276:immunology; D051183:Desmoglein 1; D051184:Desmoglein 3; D051182:Desmogleins; D051180:Desmoplakins; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood / Q000378:metabolism*; D016209:Interleukin-8 / Q000378:metabolism*; D015603:Keratinocytes / Q000276:immunology*; D008297:Male; D009504:Neutrophils / Q000276:immunology / Q000473:pathology; D010392:Pemphigus / Q000209:etiology / Q000276:immunology* / Q000473:pathology; D012867:Skin / Q000276:immunology / Q000473:pathology
chemical_list: D001323:Autoantibodies; D003598:Cytoskeletal Proteins; C495297:DSG1 protein, human; D051183:Desmoglein 1; D051184:Desmoglein 3; D051182:Desmogleins; D051180:Desmoplakins; D007074:Immunoglobulin G; D016209:Interleukin-8