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Autoantibodies from pemphigus patients cause skin blistering by inhibition of Rho GTPases
Author(s) -
Spindler Volker,
Bruggeman Paola,
Sitaru Cassian,
Zillikens Detlef,
Drenckhahn Detlev,
Waschke Jens
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a877-a
Subject(s) - autoantibody , pemphigus vulgaris , gtpase , pemphigus foliaceus , pemphigus , acantholysis , desmoglein 3 , immunology , desmoglein , epidermis (zoology) , antibody , medicine , chemistry , microbiology and biotechnology , biology , anatomy
The autoimmune blistering skin diseases pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are mediated by autoantibodies (IgG) against the desmosomal cadherins desmoglein 1 (Dsg 1) and Dsg 3. Recently we demonstrated that PF IgG do not reduce Dsg 1‐mediated adhesion by steric hindrance but rather required cell‐dependent mechanisms (J. Clin. Invest. 2005, Oct 6 Epub). Here we provide evidence that PV‐IgG (directed to Dsg 1 and Dsg 3) and PF‐IgG (directed to Dsg 1) induce skin blistering by inhibition of Rho family GTPases. PV‐IgG and PF‐IgG caused epidermal blistering in biopsies of human skin and intercellular gap formation in cultured keratinocytes. Moreover, autoantibodies reduced Dsg 1‐mediated binding assessed by laser tweezers and inactivated cellular Rho family GTPases. Both PV‐IgG and PF‐IgG induced inactivation of Rho A whereas PV‐IgG additionally inhibited Rac 1 and Cdc42. Concomitant activation of these GTPases by E. coli cytotoxic necrotizing factor 1 (CNF‐1) outbalanced autoantibody‐induced Rho‐GTPase inactivation and largely abolished antibody‐induced effects on human epidermis and cultured keratinocytes. These data indicate that inactivation of Rho‐GTPases is important for pemphigus pathogenesis. DFG SFB487