Citrullinated human and murine MOG35-55 display distinct biophysical and biochemical behavior
W Doelman1, R C Reijnen1, N Dijksman2
1Department of Bio-Organic Synthesis, Leiden Institute of Chemistry, Leiden, the Netherlands.
Abstract:
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.
Insights
Citrullination of myelin oligodendrocyte glycoprotein (MOG) peptides impacts experimental autoimmune encephalomyelitis differently in humans versus mice. Human MOG peptides, unlike murine ones, did not aggregate but stimulated marmoset lymphocytes, suggesting varied antigen processing in multiple sclerosis models.
Area of Science:
- Neuroimmunology
- Protein Biochemistry
- Autoimmune Diseases
Background:
- The myelin oligodendrocyte glycoprotein (MOG) peptide 35-55 is a key autoantigen in multiple sclerosis (MS).
- Experimental autoimmune encephalomyelitis (EAE) in rodents and nonhuman primates models MS, often induced by MOG35-55 immunization.
- Citrullination of MOG35-55 has emerged as a potential factor in MS pathogenesis, with previous studies suggesting amyloid-like aggregation of murine peptides.
Purpose of the Study:
- To investigate the species-specific differences in the biophysical and biochemical behavior of citrullinated MOG35-55 peptides.
- To compare the immunogenicity of citrullinated human and murine MOG35-55 peptides in stimulating lymphocytes from MOG-immunized nonhuman primates.
Main Methods:
- Biophysical and biochemical characterization of citrullinated human and murine MOG35-55 peptides.
- Assessment of amyloid-like aggregation properties under specific conditions.
- Lymphocyte proliferation assays using cells from MOG-immunized marmoset monkeys.
Main Results:
- Citrullinated human MOG35-55 peptides did not exhibit amyloid-like aggregation, contrasting with previously observed behavior of citrullinated murine MOG35-55 peptides.
- Lymphocyte stimulation assays revealed that citrullinated murine MOG35-55 peptides failed to induce a proliferative response.
- One specific citrullinated human MOG35-55 peptide successfully stimulated lymphocytes from MOG-immunized marmosets.
Conclusions:
- The biophysical behavior and immunogenicity of citrullinated MOG35-55 peptides differ significantly between human and murine sequences.
- Disparate antigen processing is postulated as the underlying reason for the observed differences in lymphocyte stimulation.
- Further research into the role of citrullination in MOG-induced EAE is warranted, considering these species-specific variations.
