Defining the pathogenic involvement of desmoglein 4 in pemphigus and staphylococcal scalded skin syndrome

Abstract

Desmogleins (Dsgs), cadherin-type cell adhesion molecules, are targeted in skin-blistering diseases such as pemphigus and staphylococcal scalded skin syndrome (SSSS). The role of Dsg4, a new isoform, was investigated in these diseases. Dsg4 was recognized by 30 (77%) of 39 pemphigus sera containing anti-Dsg1 IgG but not by 16 pemphigus sera containing no anti-Dsg1 IgG or by 34 normal control sera. The Dsg4 immunoreactivity of these sera was abolished by removal of anti-Dsg1 IgG. Conversely, the removal of anti-Dsg4 IgG from pemphigus sera reduced the immunoreactivity against Dsg1 only 13.8% ± 8.8% (n = 23) and did not affect its ability to induce blisters in neonatal mice. IgG that was affinity-purified on Dsg4 recognized Dsg1 but failed to induce blisters, while IgG purified on Dsg1 from the same pemphigus foliaceus sera induced blisters. Thus, pemphigus sera show Dsg4 reactivity due to cross-reactivity of a subset of anti-Dsg1 IgG, and the Dsg4/Dsg1-cross-reacting IgG has no demonstrable pathogenic effect. In addition, Dsg4 was not cleaved by exfoliative toxins that induce blisters in SSSS. These findings suggest that Dsg4 may play a role other than adhesion and that the cross-reactivity of desmoglein autoantibodies should be factored into the framework of future studies of autoimmune mechanisms in pemphigus.

Removal of amino-terminal extracellular domains of desmoglein 1 by staphylococcal exfoliative toxin is sufficient to initiate epidermal blister formation

“…Recombinant, secreted-form extracellular domains of mouse Dsg1a, Dsg1b, Dsg1g, and Dsg4, fused with E-and His-tags on their carboxyl terminus, were produced using the baculovirus expression system as described previously [13][14][15]. Culture supernatants of High Five TM insect cells (Invitrogen Corp., Carlsbad, CA) containing recombinant mouse Dsg were collected and stored at À70 8C after removal of cell debris by centrifugation.…”

Epitope Spreading Is Rarely Found in Pemphigus Vulgaris by Large-Scale Longitudinal Study Using Desmoglein 2–Based Swapped Molecules

“…Dsg3 is the autoantigen in mucocutaneous-type PV and mucosal dominant-type PV (Amagai et al, 1991(Amagai et al, , 1994Koch et al, 1997;Mahoney et al, 1999). Pemphigus sera occasionally contain Dsg4/Dsg1 cross-reacting IgG autoantibodies (Kljuic et al, 2003;Whittock and Bower, 2003;Nagasaka et al, 2004). No reactivity against Dsg2 was found in PF or PV sera (Ota et al, 2003).…”

Involvement of TH1/TH2 Cytokines in the Pathogenesis of Autoimmune Skin Disease—Pemphigus Vulgaris

“…The antigen recognized by the autoantibodies in patients with Pemphigus vulgaris was cloned by Amagai et al showed that the Pemphigus vulgaris antigen is desmoglein 3(Dsg3) and serum from patients with pemphigus foliaceus contains antibodies that bind to desmoglein 1(Dsg1), members of the desmoglein family (Amagai et al, 1991). The pathogenic role of autoantibodies against Dsg1 and Dsg3 has been clearly established, despite the identification of potential additional autoantigens such as α-9-acetylcholine receptor , pemphaxin , and, recently, Dsg4 (Kljuic et al, 2003;Nagasaka et al, 2004).…”