Citrullinated human and murine MOG35-55 display distinct biophysical and biochemical behavior

Doelman, W.; Reijnen, R.C.; Dijksman, N.; Janssen, A.P.A.; Driel, N. van; Hart, B.A.; Philippens, I.; Araman, C.; Baron, W.; Kasteren, S.I. van

doi:doi:10.1016/j.jbc.2023.103065

The peptide spanning residues 35 to 55 of the protein myelin oligodendrocyte glycoprotein (MOG) has been studied exten-sively in its role as a key autoantigen in the neuroinflammatory autoimmune disease multiple sclerosis. Rodents and nonhuman primate species immunized with this peptide develop a neuroinflammatory condition called experimental autoimmune encephalomyelitis, often used as a model for multiple sclerosis. Over the last decade, the role of citrullina-tion of this antigen in the disease onset and progression has come under increased scrutiny. We recently reported on the ability of these citrullinated MOG35-55 peptides to aggregate in an amyloid-like fashion, suggesting a new potential patho-genic mechanism underlying this disease. The immunodo-minant region of MOG is highly conserved between species, with the only difference between the murine and human pro-tein, a polymorphism on position 42, which is serine in mice and proline for humans. Here, we show that the...Show moreThe peptide spanning residues 35 to 55 of the protein myelin oligodendrocyte glycoprotein (MOG) has been studied exten-sively in its role as a key autoantigen in the neuroinflammatory autoimmune disease multiple sclerosis. Rodents and nonhuman primate species immunized with this peptide develop a neuroinflammatory condition called experimental autoimmune encephalomyelitis, often used as a model for multiple sclerosis. Over the last decade, the role of citrullina-tion of this antigen in the disease onset and progression has come under increased scrutiny. We recently reported on the ability of these citrullinated MOG35-55 peptides to aggregate in an amyloid-like fashion, suggesting a new potential patho-genic mechanism underlying this disease. The immunodo-minant region of MOG is highly conserved between species, with the only difference between the murine and human pro-tein, a polymorphism on position 42, which is serine in mice and proline for humans. Here, we show that the biophysical and biochemical behavior we previously observed for citrulli-nated murine MOG35-55 is fundamentally different for hu-man and mouse MOG35-55. The citrullinated human peptides do not show amyloid-like behavior under the conditions where the murine peptides do. Moreover, we tested the ability of these peptides to stimulate lymphocytes derived from MOG immu-nized marmoset monkeys. While the citrullinated murine peptides did not produce a proliferative response, one of the citrullinated human peptides did. We postulate that this un-expected difference is caused by disparate antigen processing. Taken together, our results suggest that further study on the role of citrullination in MOG-induced experimental autoim-mune encephalomyelitis is necessary.Show less

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Citrullinated human and murine MOG35-55 display distinct biophysical and biochemical behavior