Investigating celiac disease using recombinant soluble MHC class II molecules
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AbstractCeliac disease (CD) is a chronic intestinal inflammation showing a strong association to HLA-DQ2.5. This thesis focused on the use of soluble MHC class II tetramers to examine the underlying mechanism for this selective CD association and also to develop a potential diagnostic tool based on the detection of gluten specific T cells.
DQ2.5 is associated with atypically high amounts of Ii-chain derived CLIP peptides. This phenotype was assigned to an abnormally low interaction with the peptide editing molecule HLA-DM, and high kinetic stability of CLIP peptides to DQ2.5. HLA-DQ2.2 is a highly similar molecule, but does not show strong CD association. Interestingly, this molecule displayed a CLIP low phenotype due to a drastically reduced kinetic stability for CLIP. This was assigned to a polymorphic residue causing the gain/loss of a hydrogen bond involved in peptide binding.
In addition, the application of a short bread challenge allowed for the detection of gluten reactive T cells in peripheral blood of CD patients using flow cytometry and MHC tetramers. This opens for the use of MHC tetramers as a diagnostic tool for diseases where the antigen and MHC restriction elements are known.
LIST OF PAPERS
Paper I Fallang L-E., Roh S., Holm A., Bergseng E., Yoon T., Fleckenstein B., Bandyopadhyay A., Mellins E.D., Sollid L.M. Complexes of two cohorts of CLIP peptides and HLA-DQ2 of the autoimmune DR3-DQ2 haplotype are poor substrates for HLA-DM. J Immunol. 2008; 181(8):5451-61.
Paper II Fallang L-E., Bergseng E., Hotta K., Berg-Larsen A., Kim C-Y., Sollid L.M. HLA-DQ2 disease association depends on a polymorphic residue hydrogen bonding to peptide main chain. Manuscript submitted.
Paper III Raki M., Fallang L-E., Brottveit M., Bergseng E., Quarsten H., Lundin K.E., Sollid L.M. Tetramer visualization of gut-homing gluten-specific T cells in the peripheral blood of celiac disease patients. Proc Natl Acad Sci U S A. 2007; 104(8):2831-6.