2024
Adv Sci (Weinh). 2024 Jun;11(23):e2401513. doi: 10.1002/advs.202401513. Epub 2024 Apr 11.
Human MHC Class II and Invariant Chain Knock-in MiceMimic Rheumatoid Arthritis with Allele Restriction inImmune Response and Arthritis Association
Medical Inflammation Research, Division of Immunology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, 17177, Sweden. Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Fraunhofer Cluster of Excellence for Immune-Mediated Diseases CIMD, Theodor-Stern-Kai 7, 60596, Frankfurt am Main, Germany. Medical Inflammation Research, MediCity Research Laboratory, University of Turku, Turku, FI-20520, Finland. Department of Pediatrics, Institute of Clinical Sciences and Department of Rheumatology and Inflammation Research, Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, 41345, Sweden. Division of Rheumatology, University Hospital Frankfurt, Goethe University, 60590, Frankfurt am Main, Germany.
Service type: Knock-in mice
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.
Keywords: CIA; DTH; MHC class II; autoimmune diseases; humanized mice; rheumatoid arthritis.
