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

• Published in: The Journal of biological chemistry Vol. 299; no. 4; p. 103065
• Main Authors: Doelman, W., Reijnen, R.C., Dijksman, N., Janssen, A.P.A., van Driel, N., ’t Hart, B.A., Philippens, I., Araman, C., Baron, W., van Kasteren, S.I.
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.04.2023; American Society for Biochemistry and Molecular Biology
• Subjects: amyloid; animal model; antigen processing; citrullination; multiple sclerosis; peptide chemical synthesis; ThT; ALN; MOG; IFA; multiple sclerosis; MS; citrullination; EAE; CatG; DCM; LC-MS; amyloid; dPBS; peptide chemical synthesis; Abu; FBS; EBV; antigen processing; animal model; BSM; ThS; CFA
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1016/j.jbc.2023.103065

The peptide spanning residues 35 to 55 of the protein myelin oligodendrocyte glycoprotein (MOG) has been studied extensively 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 citrullination 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 pathogenic mechanism underlying this disease. The immunodominant region of MOG is highly conserved between species, with the only difference between the murine and human protein, 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 citrullinated murine MOG35–55 is fundamentally different for human 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 immunized marmoset monkeys. While the citrullinated murine peptides did not produce a proliferative response, one of the citrullinated human peptides did. We postulate that this unexpected difference is caused by disparate antigen processing. Taken together, our results suggest that further study on the role of citrullination in MOG-induced experimental autoimmune encephalomyelitis is necessary.