Human MHC Class II and Invariant Chain Knock-in Mice Mimic Rheumatoid Arthritis with Allele Restriction in Immune Response and Arthritis Association.
Adv Sci (Weinh)
; 11(23): e2401513, 2024 Jun.
Article
em En
| MEDLINE
| ID: mdl-38602454
ABSTRACT
Transgenic mice expressing human major histocompatibility complex class II (MHCII) risk alleles are widely used in autoimmune disease research, but limitations arise due to non-physiologic expression. To address this, physiologically relevant mouse models are established via knock-in technology to explore the role of MHCII in diseases like rheumatoid arthritis. The gene sequences encoding the ectodomains are replaced with the human DRB1*0401 and 0402 alleles, DRA, and CD74 (invariant chain) in C57BL/6N mice. The collagen type II (Col2a1) gene is modified to mimic human COL2. Importantly, DRB1*0401 knock-in mice display physiologic expression of human MHCII also on thymic epithelial cells, in contrast to DRB1*0401 transgenic mice. Humanization of the invariant chain enhances MHCII expression on thymic epithelial cells, increases mature B cell numbers in spleen, and improves antigen presentation. To validate its functionality, the collagen-induced arthritis (CIA) model is used, where DRB1*0401 expression led to a higher susceptibility to arthritis, as compared with mice expressing DRB1*0402. In addition, the humanized T cell epitope on COL2 allows autoreactive T cell-mediated arthritis development. In conclusion, the humanized knock-in mouse faithfully expresses MHCII, confirming the DRB1*0401 alleles role in rheumatoid arthritis and being also useful for studying MHCII-associated diseases.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Artrite Reumatoide
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Camundongos Transgênicos
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Antígenos de Diferenciação de Linfócitos B
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Antígenos de Histocompatibilidade Classe II
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Modelos Animais de Doenças
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Alelos
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Técnicas de Introdução de Genes
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Camundongos Endogâmicos C57BL
Limite:
Animals
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Humans
Idioma:
En
Revista:
Adv Sci (Weinh)
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
Suécia