Enrichment of total serum IgG4 in patients with pemphigus

Pemphigus is a potentially fatal antibody-mediated, tissue-specific autoimmune disease caused by autoantibodies against desmoglein (Dsg) cell adhesion proteins.1 In pemphigus foliaceus (PF), autoantibodies against Dsg1 cause superficial blisters in the skin. In pemphigus vulgaris (PV), Dsg3 autoantibodies cause deeper suprabasal blisters in the mucous membrane epithelia. Some patients with PV develop Dsg1 in addition to Dsg3 autoantibodies, which correlate with the presence of suprabasal blisters in both mucosa and skin. The clinical and histological site of blister formation in patients with PF and PV can be explained by the expression patterns of the different Dsg isoforms in mucosa and skin.2 The pathogenicity of Dsg3- and Dsg1-specific PV and PF IgG has been experimentally validated, indicating that anti-Dsg IgG is both necessary and sufficient for blister formation, and that serum autoantibody enzyme-linked immunosorbent assay (ELISA) titres correlate with disease activity.3–7 Although the Fc region of pemphigus autoantibodies is not required for blister formation in experimental pemphigus models,8–11 anti-Dsg antibodies have been shown to preferentially associate with the IgG4 subclass. In both PV and PF, patients with active disease demonstrate Dsg-reactive IgG4 and IgG1, while patients in remission and some healthy relatives of patients with pemphigus can demonstrate only anti-Dsg IgG1.12–15 IgG2 and IgG3 anti-Dsg autoantibodies have not been associated with disease.16,17 Longitudinal studies of patients with an endemic form of PF indicate that a preferential rise in the ratio of IgG4 to IgG1 Dsg-reactive antibodies accompanies the onset of disease activity. Additionally, an IgG4-specific Dsg ELISA was shown to have greater sensitivity and specificity than a total IgG Dsg ELISA in detecting active disease in endemic PF, suggesting a more significant clinical association of pathogenic antibodies with IgG4 rather than with other IgG subclasses in this patient population.18 Collectively, these studies indicate that the acquisition of an anti-Dsg IgG4 response is a characteristic serological finding in patients with active pemphigus. Although Dsg-specific IgG4 has been described in patients with pemphigus, particularly those with endemic PF, to our knowledge no studies have investigated levels of total serum IgG4 in pemphigus. A hyper-IgG4 state is uncommon in humans, having been described only in people receiving repetitive cutaneous immunization with monoclonal or oligoclonal antigens, such as beekeepers and individuals undergoing allergic desensitization therapy.19 We postulated that skin blisters could act as a form of chronic autovaccination to Dsg antigens in pemphigus, leading to an anti-Dsg IgG4 response that could potentially elevate the total serum IgG4 relative to other IgG subclasses. We therefore examined whether total serum IgG4 is enriched in patients with pemphigus. To determine what percentage of total IgG is Dsg-specific, we quantitated Dsg-specific IgG1 and IgG4 in patients with pemphigus. Finally, we evaluated whether IgG4 depletion abrogates the pathogenicity of PV sera.