T Cell Recognition of Desmoglein 3 Peptides in Patients with Pemphigus Vulgaris and Healthy Individuals

Abstract

Pemphigus vulgaris is a severe autoimmune disease caused by autoantibodies against the cutaneous adhesion molecule, desmoglein 3 (Dsg3). The aim of this study was to characterize the specificity of autoreactive Th cells, which presumably regulate Dsg3-specific autoantibody production. Ninety-seven Th1 and Th2 clones isolated from 16 pemphigus patients and 12 HLA-matched healthy donors recognized the Dsg3 peptides, DG3(78-94), DG3(96-112), DG3(189-205), DG3(205-221), and DG3(250-266). Peptide DG3(96-112), and to a lesser extent DG3(250-266), was recognized by the majority of T cells from patients and healthy donors in association with HLA-DRB1*0402 and DQB1*0503 which were prevalent in the pemphigus patients and Dsg3-responsive healthy donors. Analyzing the Vβ-chain of the TCR of the DG3(96-112)-specific T cells showed no restricted TCR usage. Peptides DG3(342-358) and DG3(376-392) were exclusively recognized by T cell clones (n = 13) from patients while DG3(483-499) was only recognized by T cell clones (n = 3) from a healthy donor. All Dsg3 peptides contained conserved amino acids at relative positions 1, 4, and 6; amino acids with a positive charge at position 4 presumably represent anchor motifs for DRB1*0402. These findings demonstrate that T cell recognition of distinct Dsg3 peptides is restricted by distinct HLA class II molecules and is independent from the development of pemphigus vulgaris.

Inhibition of the Transcription Factor Foxp3 Converts Desmoglein 3-Specific Type 1 Regulatory T Cells into Th2-Like Cells

“…Involvement of Th cells in the pathogenesis of PV has been suggested by several studies: both Dsg3-reactive Th1 and Th2 cells were identified by our group and others (11,12) and appear to recognize epitopes of the extracellular domain of Dsg3 (13). A critical role for autoreactive T cells in the induction and regulation of Dsg3 autoantibody production has been suggested in a recent study by Nishifuji et al (14).…”

“…The recombinant protein PVhis, a fusion protein consisting of the entire extracellular domain of Dsg3 linked to an E-tag and histidine-tag, was used as a source of human Dsg3 and expressed in a baculovirus system with SF21 insect cells as described previously (12,13). For the production of Dsg3 protein, 3 ϫ 10 8 High-Five insect cells were inoculated with PVhis baculovirus at a multiplicity of infection of 10.…”

Type I Regulatory T Cells Specific for Desmoglein 3 Are More Frequently Detected in Healthy Individuals than in Patients with Pemphigus Vulgaris

“…Both Dsg3-reactive Th1 and Th2 cells were identified by our group and others (4, reviewed in Ref. 5) and appear to recognize epitopes of the extracellular domain of Dsg3 in association with HLA-DRB1*0402 and HLA-DQB1*0503 (6). A critical role for autoreactive T cells in the induction and regulation of Dsg3 autoantibody production has been suggested by a recent study by Nishifuji et al (reviewed in Ref.…”

“…Active immune regulation may thus be operative in Dsg3-responsive healthy individuals. It is presumed that this is not the consequence of deletion or immune deviation of autoreactive T cells because autoreactive Th cells specific for identical Dsg3 epitopes were detected both in patients and healthy donors (6).…”

Autoreactive T and B Cells from Bullous Pemphigoid (BP) Patients Recognize Epitopes Clustered in Distinct Regions of BP180 and BP230

“…Noteworthy, recent studies in pemphigus vulgaris, an unrelated autoimmune bullous skin disorder, showed that autoaggressive T cells specific for desmoglein 3 preferentially targeted regions located in the NH 2 -terminal domains EC1 and EC2 (38) that were also preferentially recognized by IgG autoantibodies (39). In a HLA class II-transgenic mouse model of myasthenia gravis, autoreactive T cells responded to three cytoplasmic peptide sequences of the human acetylcholine receptor, which were also targeted by the pathogenic autoantibodies (40).…”