Structural basis for major histocompatibility complex (MHC)-linked susceptibility to autoimmunity: charged residues of a single MHC binding pocket confer selective presentation of self-peptides in pemphigus vulgaris.

Abstract

Human T-cell-mediated autoimmune diseases are genetically linked to particular alleles of MHC class II genes. Susceptibility to pemphigus vulgaris (PV), an autoimmune disease of the skin, is linked to a rare subtype of HLA-DR4 (DRB1*0402, 1 of 22 known DR4 subtypes). The PV-linked DR4 subtype differs from a rheumatoid arthritisassociated DR4 subtype (DRB1*0404) only at three residues (DR,3 67, 70, and 71). The disease is caused by autoantibodies against desmoglein 3 (DG), and T cells are thought to trigger the autoantibody production against this keratinocyte adhesion molecule. Based on the DRB1*0402 binding motif, seven candidate peptides of the DG autoantigen were identified. T cells from four PV patients with active disease responded to one of these DG peptides (residues 190-204); two patients also responded to DG-(206-220). T-cell clones specific for DG-(190-204) secreted high levels of interleukins 4 and 10, indicating that they may be important in triggering the production of DG-specific autoantibodies. peptide was presented by the disease-linked DRB1*0402 molecule but not by other DR4 subtypes. Site-directed mutagenesis of DRB1*0402 demonstrated that selective presentation of , which carries a positive charge at the P4 position, was due to the negatively charged residues of the P4 pocket (DR,8 70 and 71). DR8 71 has a negative charge in DRB1*0402 but a positive charge in other DR4 subtypes, including the DR4 subtypes linked to rheumatoid arthritis. The charge of the P4 pocket in the DR4 peptide binding site therefore appears to be a critical determinant of MHC-linked susceptibility to PV and rheumatoid arthritis.

Dichotomy of Autoreactive Th1 and Th2 Cell Responses to Desmoglein 3 in Patients with Pemphigus Vulgaris (PV) and Healthy Carriers of PV-Associated HLA Class II Alleles

“…Dsg3-reactive T cell clones from a Dsg3-reactive healthy donor were restricted by HLA-DRB1*1102 that shares the negatively charged residues, asparagic acid and glutamic acid, at positions DR␤70 and ␤71 with the PVassociated allele, HLA-DRB1*0402, and by HLA-DQB1*0301 that shares asparagic acid at position B57 with the PV-associated HLA-DQB1*0503 (14,23). The importance of these distinct peptide binding motifs of the aforementioned HLA class II alleles is supported by the identification of Dsg3 peptides, such as peptide DG 190 -204 , that carry a positive charge at the P4 pocket that may be critical for binding to the negatively charged P4 pockets of DRB1*0402 (DR␤70 and -71) and DQB1*0503 (DQ␤57) (17,25). The ongoing identification of immunodominant T cell epitopes of Dsg3 will help to address the question of whether some Dsg3 peptides promiscuously bind to both DRB1*0402 and DQB1*0503.…”

“…Autoreactive T cells recognized epitopes of the ECD of Dsg3 and were restricted by HLA-DRB1*0402 and HLA class II alleles that were identical or homologous (with regard to peptide binding motifs) to HLA-DRB1*0402 or HLA-DQB1*0503. A previous study suggested that autoreactive T cells of PV patients recognized distinct Dsg3 peptides with conserved anchor motifs required for binding to HLA-DRB1*0402 (17).…”

Epistasis between DSG1 and HLA class II genes in pemphigus foliaceus

“…3,4 How HLA class II genes and the C/C(809) genotype interact to mediate PF susceptibility might be explained by the fact that MHC class II molecules and autoantigens intervene in the biological pathway leading to the autoimmune processes and tolerance breakage of autoreactive lymphocytes, since MHC gene products present antigens to immune T cells. 25 The C/T polymorphism at position 809 is a silent mutation and therefore, does not directly modify a putative T-cell epitope on the corresponding region of DSG1. However, preliminary results showing an alternative splicing of the 3Ј extremity of the intron 6 of the DSG1 gene, located 50-bp upstream to the SNP(809), allow to consider the role of the SNP(809) on the regulation of this alternative splicing.…”

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

“…The present study demonstrates that all of the identified Dsg3 epitopes share common anchor residues at relative positions 1, 4, and 6. These amino acid motifs were previously identified by Wucherpfennig and coworkers (19,33) to be potential HLA class II binding sites. Based on putative binding motifs of DRB1*0402 (which is prevalent in PV) (34), Wucherpfennig and colleagues (19,33) proposed seven candidate T cell epitopes of Dsg3 that share amino acid residues at p1, 4, and 6 anchor positions (Table III).…”