Myelin oligodendrocyte glycoprotein‐35–55 peptide induces severe chronic experimental autoimmune encephalomyelitis in HLA‐DR2‐transgenic mice

Abstract

The use of HLA class II-transgenic (Tg) mice has facilitated identification of antigenic T cell epitopes that may contribute to inflammation in T cell-mediated diseases such as rheumatoid arthritis and multiple sclerosis (MS). In this study, we compared the encephalitogenic activity of three DR2-restricted myelin determinants [mouse (m) myelin oligodendrocyte glycoprotein (MOG)-35-55, human (h)MOG-35-55 and myelin basic protein (MBP)-87-99] in Tg mice expressing the MS-associated DR2 allele, DRB1*1501. We found that mMOG-35-55 peptide was strongly immunogenic and induced moderately severe chronic experimental autoimmune encephalomyelitis (EAE) with white matter lesions after a single injection in Freund's complete adjuvant followed by pertussis toxin. hMOG-35-55 peptide, which differs from mMOG-35-55 peptide by a proline for serine substitution at position 42, was also immunogenic, but not encephalitogenic, and was only partially cross-reactive with mMOG-35-55. In contrast, MBP-87-99, which can induce EAE in double-Tg mice expressing both HLA-DR2 and a human MBP-specific TCR, was completely non-encephalitogenic in HLA-DR2-Tg mice lacking the human TCR transgene. These findings demonstrate potent encephalitogenic activity of the mMOG-35-55 peptide in association with HLA-DR2, thus providing a strong rationale for further study of hMOG-35-55 peptide as a potential pathogenic determinant in humans.

Epitope specificity determines pathogenicity and detectability in ANCA-associated vasculitis

“…DR2 Tg mice (12,29) were immunized subcutaneously with 3 × 100 μg of peptide antigen (OVA323-339 [n = 4] or MPO442-460 [n = 10]) first in FCA then FIA on days 0, 7, and 14. Mice were culled on day 28.…”

The HLA-DRB1*15

“…Mouse MHC class II 2/2 , HLA-DRB1*15:01 Tg mice, and mouse MHC class II 2/2 , HLA-DRB1*01:01 Tg mice were generated by intercrossing mouse MHC class II 2/2 , HLA DRB1*15:01 Tg mice 50 with mouse MHC class II +/+ , HLA DRB1*01:01 Tg mice. 51 The expression of mouse MHC class II was screened using Alexa Fluor 488 and 0101 Tg .FcgRIIb2/2 , respectively) immunized with a3 136-146 .…”

Myelin-derived and putative molecular mimic peptides share structural properties in aqueous and membrane-like environments

“…4a) is a widely recognized inducer of encephalitogenic reactions, and it is routinely used to induce mouse EAE models [55,56]. The mMOG35-55 epitope is highly immunogenic and induces EAE, while the corresponding peptide from human MOG is less active in causing EAE [57]. This is surprising, since only one residue distinguishes mMOG35-55 and hMOG35-55 from each other.…”

“…a Location of the segment 35-55 in the MOG Ig domain crystal structure [58]. Shown (as sticks) are also the glycosylation site Asn31 [101] and the Ser42 residue (at the hairpin of the MOG35-55 epitope), which when mutated to Pro, as in human MOG, produces a less encephalitogenic response [57]. b SRCD spectra of the human (top) and mouse (bottom) MOG35-55 peptides in the absence and presence of lipid vesicles.…”