The Role of Subclass Switching in the Pathogenesis of Endemic Pemphigus Foliaceus

Abstract

Endemic pemphigus foliaceus, like the sporadic form seen in the developed world, is mediated by IgG antibodies to desmoglein-1. We studied an endemic focus in Limao Verde, Brazil, where disease prevalence is 3.4%. We previously detected IgG antibodies to desmoglein-1 in 97% of patients, but also in 55% of normal subjects in the endemic focus, with progressively lower levels in normal subjects in surrounding areas. An environmental trigger is hypothesized to explain these and other findings. In this study we sought to determine if patients and enzyme-linked-immunosorbent-assay-positive normal subjects in Limao Verde differ in IgG subclass response to desmoglein-1. We developed a sensitive and specific subclass enzyme-linked immunosorbent assay using recombinant desmoglein-1 and standardized the assay to enable comparability between the four subclasses. We found that normal subjects have an IgG1 and IgG4 response, whereas patients have similar levels of IgG1 but a mean 19.3-fold higher IgG4 response. Patients in remission have a weak IgG4 response, and a 74.3-fold higher IgG4 response is associated with active disease. Finally, in five patients in whom we had blood samples from both before and after the onset of clinical disease, a mean 103.08-fold rise in IgG4 was associated with onset of clinical disease, but only a mean 3.45-fold rise in IgG1. These results suggest that the early antibody response in normal subjects living in the endemic area and in patients before the onset of clinical disease is mainly IgG1. Acquisition of an IgG4 response is a key step in the development of clinical disease.

IgG4‐related systemic disease and lymphoplasmacytic aortitis

“…IgG4 is the least abundant of all serum IgG isotypes, comprising only ϳ6% of the total IgG in healthy individuals (37). Serum IgG4 levels have been reported to be elevated in conditions that bear little obvious resemblance to autoimmune pancreatitis and related disorders, such as human filariasis, pemphigus vulgaris, and pemphigus foliaceus (38)(39)(40). IgG4 is effectively a monovalent antibody, which generally binds antigens poorly and does not fix complement (37).…”

Complete FcRn dependence for intravenous Ig therapy in autoimmune skin blistering diseases

“…The concentration of serum rabbit anti-mBP180, human antiDsg1, and human anti-Dsg3 IgG were measured by ELISA (66,74). For rabbit anti-mBP180 ELISA, microtiter plates were coated with purified mBP180 (1 µg/well), incubated with dilutions of serum, developed with HRP-conjugated goat antibodies specific for rabbit IgG F(ab′)2 (Cappel Laboratories), and read at OD492nm using an ELISA plate reader (Bio-Rad Laboratories Inc.).…”

Epitope Spreading of Autoantibody Response to PLA2R Associates with Poor Prognosis in Membranous Nephropathy

“…An ELISA Index value for each antigen was obtained for patients or normal subjects as follows (mean test result-mean domain negative control)/(mean domain positive control-mean domain negative control)3domain correction factor3100. The domain correction factor was determined for each domain as the mean of all the positive controls for that domain on all plates minus the mean of the negative controls, divided by the cut-off for that domain assay as described by Warren et al 38 …”