Diminished class II-associated Ii peptide binding to the juvenile dermatomyositis HLA-DQ alpha 1*0501/DQ beta 1*0301 molecule.

HLA class II molecules bind and present peptide Ags to T cells, binding specific sets of peptides due to polymorphism in the peptide binding groove. Class II proteins associate with the invariant chain (Ii chain) and its derived class II-associated Ii peptide (CLIP). Ii chain association is important for normal trafficking of class II proteins to the peptide loading vesicles and for blocking premature access of peptides to HLA class II molecules during maturation. We have previously shown that juvenile dermatomyositis is associated with the HLA-DQA10501 allele. There is limited information available about the interaction of any DQ molecule with the Ii chain and little information about binding of individual peptides to HLA-DQalpha10501/DQbeta10301. We sequenced peptides eluted from the juvenile dermatomyositis-associated class II allele HLA-DQalpha10501/DQbeta10301. Surprisingly, we found no Ii chain or CLIP. Further examination of peptide binding to the HLA-DQalpha10501/DQbeta10301 molecule demonstrated poor CLIP binding. However, newly synthesized HLA-DQalpha10501/DQbeta10301 molecules do associate with intact Ii chain. Molecular modeling suggests that CLIP binds differently to HLA-DQalpha10501/DQbeta10301 than to DR molecules. The lack of CLIP association suggests that HLA-DQalpha10501/DQbeta1*0301 has access to peptides earlier in the processing pathway and so might encounter novel peptides that induce autoimmunity.