Human MHC Class II and Invariant Chain Knock-in Mice Mimic Rheumatoid Arthritis with Allele Restriction in Immune Response and Arthritis Association.
Laura Romero-CastilloTaotao LiNhu-Nguyen DoOuti SareilaBingze XuViktoria HenningsZhongwei XuCarolin SvenssonAna Oliveira-CoelhoZeynep SenerVilma UrbonaviciuteOlov EkwallHarald BurkhardtRickard HolmdahlPublished in: Advanced science (Weinheim, Baden-Wurttemberg, Germany) (2024)
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.
Keyphrases
- rheumatoid arthritis
- endothelial cells
- poor prognosis
- immune response
- induced pluripotent stem cells
- disease activity
- pluripotent stem cells
- magnetic resonance
- multiple sclerosis
- binding protein
- computed tomography
- high glucose
- systemic lupus erythematosus
- gene expression
- magnetic resonance imaging
- case report
- adipose tissue
- metabolic syndrome
- wild type
- genome wide
- toll like receptor
- ankylosing spondylitis
- oxidative stress
- inflammatory response
- copy number
- tissue engineering
- idiopathic pulmonary fibrosis
- stress induced