Gluten-specific antibodies of celiac disease gut plasma cells recognize long proteolytic fragments that typically harbor T-cell epitopes

被引:20
作者
Dorum, Siri [1 ,2 ,3 ]
Steinsbo, Oyvind [1 ,2 ,3 ]
Bergseng, Elin [1 ,2 ,3 ]
Arntzen, Magnus O. [5 ]
de Souza, Gustavo A. [1 ,2 ,3 ,4 ]
Sollid, Ludvig M. [1 ,2 ,3 ]
机构
[1] Univ Oslo, Ctr Immune Regulat, N-0424 Oslo, Norway
[2] Univ Oslo, Dept Immunol, N-0424 Oslo, Norway
[3] Oslo Univ Hosp, Rikshosp, N-0424 Oslo, Norway
[4] Oslo Univ Hosp, Prote Core Facil, Rikshosp, N-0424 Oslo, Norway
[5] Norwegian Univ Life Sci, NMBU, Dept Chem Biotechnol & Food Sci, N-1432 As, Norway
关键词
TISSUE TRANSGLUTAMINASE; GLIADIN; IGA; IDENTIFICATION; DEAMIDATION; MONOVALENT; MUCOSA;
D O I
10.1038/srep25565
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
This study aimed to identify proteolytic fragments of gluten proteins recognized by recombinant IgG1 monoclonal antibodies generated from single IgA plasma cells of celiac disease lesions. Peptides bound by monoclonal antibodies in complex gut-enzyme digests of gluten treated with the deamidating enzyme transglutaminase 2, were identified by mass spectrometry after antibody pull-down with protein G beads. The antibody bound peptides were long deamidated peptide fragments that contained the substrate recognition sequence of transglutaminase 2. Characteristically, the fragments contained epitopes with the sequence QPEQPFP and variants thereof in multiple copies, and they typically also harbored many different gluten T-cell epitopes. In the pull-down setting where antibodies were immobilized on a solid phase, peptide fragments with multivalent display of epitopes were targeted. This scenario resembles the situation of the B-cell receptor on the surface of B cells. Conceivably, B cells of celiac disease patients select gluten epitopes that are repeated multiple times in long peptide fragments generated by gut digestive enzymes. As the fragments also contain many different T-cell epitopes, this will lead to generation of strong antibody responses by effective presentation of several distinct T-cell epitopes and establishment of T-cell help to B cells.
引用
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页数:12
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