A self-peptide with large anchor residues binds IAd and induces Th2-like autoimmune gastritis (99.45)

A mouse model of autoimmune gastritis with Th2-like phenotype in which BALB/c mice expressing a transgenic αβ TCR spontaneously develop the disease was developed in our laboratory. The TCR recognizes a 12-mer peptide from the alpha subunit of gastric parietal cell H/K ATPase presented in the context of IAd. The disease is characterized by slow and incomplete penetrance, anti-gastric mucosal cell antibodies, inflammatory eosinophilic infiltrates, parietal cell destruction and elevated Th2 cytokines. To investigate the contribution of MHC/peptide interactions to the initiation and maintenance of AIG, we generated a soluble recombinant version of the IAd/H/K ATPase889-900 complex for biophysical and crystallographic analyses. The 2.5 Å X-ray structure of the complex reveals rare features not seen in other IAd/peptide complexes: cysteine in P1, an imino acid in P6, and a large acidic residue in P9. This first structure of IAd in complex with an autoimmunogenic peptide reveals a previously unrecognized peptide binding motif for IAd with large anchor residues and with GLU in P9 encapsulated by a web of polar contacts that may contribute to stabilization of the complex and to maintenance of antigen presentation in disease. This research was supported by the Intramural Research Program of the NIH, NIAID.