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.
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 arthritis-associated DR4 subtype (DRB1*0404) only at three residues (DR beta 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. The DG-(190-204) 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 DG-(190-204), which carries a positive charge at the P4 position, was due to the negatively charged residues of the P4 pocket (DR beta 70 and 71). DR beta 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.
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
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Wucherpfennig
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Yu
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Bhol
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Argyris
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Karr
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Ahmed
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Strominger
D000595:Amino Acid Sequence; D017951:Antigen Presentation; D001324:Autoantigens / Q000276:immunology*; D015551:Autoimmunity; D001665:Binding Sites / Q000235:genetics; D015820:Cadherins / Q000276:immunology*; D002999:Clone Cells; D051184:Desmoglein 3; D008040:Genetic Linkage; D006684:HLA-DR Antigens / Q000235:genetics / Q000276:immunology*; D059811:HLA-DRB1 Chains; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010392:Pemphigus / Q000209:etiology / Q000235:genetics / Q000276:immunology*; D010446:Peptide Fragments / Q000276:immunology; D011110:Polymorphism, Genetic; D017386:Sequence Homology, Amino Acid; D013601:T-Lymphocytes / Q000276:immunology
D001324:Autoantigens; D015820:Cadherins; C071894:DSG3 protein, human; D051184:Desmoglein 3; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; C553506:HLA-DRB1*04:02 antigen; D010446:Peptide Fragments; D016753:Interleukin-10; D015847:Interleukin-4