1. Human MHC Class II and Invariant Chain Knock-in Mice Mimic Rheumatoid Arthritis with Allele Restriction in Immune Response and Arthritis Association.
- Author
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Romero-Castillo L, Li T, Do NN, Sareila O, Xu B, Hennings V, Xu Z, Svensson C, Oliveira-Coelho A, Sener Z, Urbonaviciute V, Ekwall O, Burkhardt H, and Holmdahl R
- Subjects
- Animals, Mice, Humans, Arthritis, Experimental genetics, Arthritis, Experimental immunology, HLA-DRB1 Chains genetics, HLA-DRB1 Chains immunology, Collagen Type II genetics, Collagen Type II immunology, Arthritis, Rheumatoid genetics, Arthritis, Rheumatoid immunology, Antigens, Differentiation, B-Lymphocyte genetics, Antigens, Differentiation, B-Lymphocyte immunology, Disease Models, Animal, Mice, Inbred C57BL, Mice, Transgenic, Gene Knock-In Techniques methods, Histocompatibility Antigens Class II genetics, Histocompatibility Antigens Class II immunology, Alleles
- 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*04:01 and 04:02 alleles, DRA, and CD74 (invariant chain) in C57BL/6N mice. The collagen type II (Col2a1) gene is modified to mimic human COL2. Importantly, DRB1*04:01 knock-in mice display physiologic expression of human MHCII also on thymic epithelial cells, in contrast to DRB1*04:01 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*04:01 expression led to a higher susceptibility to arthritis, as compared with mice expressing DRB1*04:02. 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*04:01 alleles role in rheumatoid arthritis and being also useful for studying MHCII-associated diseases., (© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)
- Published
- 2024
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