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Investigation of immune complexes formed by mitochondrial antigens containing a new lipoylated site in sera of primary biliary cholangitis patients

Authors :
Minoru Nakamura
Naoya Kishikawa
Kaname Ohyama
Mikiro Nakashima
Kazuhiro Tsukamoto
Atsushi Kawakami
Mami Tamai
Naotaka Kuroda
Nozomi Aibara
Hideki Nakamura
Source :
Clin Exp Immunol
Publication Year :
2021
Publisher :
Oxford University Press (OUP), 2021.

Abstract

Summary Primary biliary cholangitis (PBC) is characterized by the presence of serum anti-mitochondrial autoantibodies (AMAs). To date, four antigens among the 2-oxo-acid dehydrogenase complex family, which commonly have lipoyl domains as an epitope, have been identified as AMA-corresponding antigens (AMA-antigens). It has recently been reported that AMAs react more strongly with certain chemically modified mimics than with the native lipoyl domains in AMA-antigens. Moreover, high concentrations of circulating immune complexes (ICs) in PBC patients have been reported. However, the existence of ICs formed by AMAs and their antigens has not been reported to date. We hypothesized that AMAs and their antigens formed ICs in PBC sera, and analyzed sera of PBC and four autoimmune diseases (Sjögren's syndrome, systemic lupus erythematosus, systemic scleroderma, and rheumatoid arthritis) using immune complexome analysis, in which ICs are separated from serum and are identified by nano-liquid chromatography-tandem mass spectrometry. To correctly assign MS/MS spectra to peptide sequences, we used a protein-search algorithm that including lipoylation and certain xenobiotic modifications. We found three AMA-antigens, the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2), the E2 subunit of the 2-oxo-glutarate dehydrogenase complex (OGDC-E2) and dihydrolipoamide dehydrogenase binding protein (E3BP), by detecting peptides containing lipoylation and xenobiotic modifications from PBC sera. Although the lipoylated sites of these peptides were different from the well-known sites, abnormal lipoylation and xenobiotic modification may lead to production of AMAs and the formation ICs. Further investigation of the lipoylated sites, xenobiotic modifications, and IC formation will lead to deepen our understanding of PBC pathogenesis.

Details

ISSN :
13652249 and 00099104
Volume :
204
Database :
OpenAIRE
Journal :
Clinical and Experimental Immunology
Accession number :
edsair.doi.dedup.....aebfae6af8f8de8d8b38900e58ec3394