CORRELATION OF PEPTIDE SPECIFICITY AND IGG SUBCLASS WITH PATHOGENIC AND NONPATHOGENIC AUTOANTIBODIES IN PEMPHIGUS-VULGARIS - A MODEL FOR AUTOIMMUNITY

Pemphigus vulgaris (PV) is a rare, potentially fatal, autoimmune disea se that affects the skin and mucous membranes. The PV antigen (PVA) ha s been characterized as desmoglein 3. PV patients carry HLA-DR4- or HL A-DR6-bearing extended haplotypes. We recently demonstrated that patie nts with active disease have high titers of PV autoantibodies of the I gG1 and IgG4 subclasses. Patients in remission, healthy unaffected rel atives, and some MHC-matched normal individuals have low levels of PV autoantibodies, which are IgG1 only. Furthermore, intraperitoneal inje ction of IgG from patients with active disease caused clinical disease in mice, but IgG from patients in remission, healthy relatives, or MH C-matched normal individuals did not. We prepared 12 peptides of 30 am ino acids each (peptides Bos 1-12) spanning the extracellular domain o f PVA. Patients with active disease recognize peptides Bos 1 and Bos 6 with high titers of IgG1 and IgG4 autoantibodies. Patients in remissi on have IgG1 autoantibodies to peptide Bos 1 only, in statistically si gnificantly lower titers (P < 0.01). They no longer have IgG4 subclass autoantibodies to peptide Bos 6. Healthy relatives and normal unrelat ed individuals have low levels of only IgG1 autoantibodies that recogn ize only Bos 1. In vitro studies indicate that Bos 6-specific IgG and, to a lesser extent, Bos 1-specific IgG can cause acantholysis. Our da ta suggest that Bos 6-specific IgG4 is probably the main acantholytic autoantibody, while Bos 1-specific IgG4 may act as a facilitator or en hancer of the process. In this study we illustrate some of the paradig ms that demonstrate the interactions between the MHC, subclass of auto antibodies, and peptide specificities of the autoantibodies in the aut oimmune process. Thus, PV provides an important model to study the pat hogenesis of autoimmunity.