The FAH gene encodes fumarylacetoacetate hydrolase (FAH), an enzyme abundant in the liver and kidneys and involved in the final step of tyrosine degradation. Genetic changes in the FAH gene can lead to various health conditions, with the most relevant disease being Tyrosinemia Type I (HT1). This metabolic disorder, caused by mutations in the FAH gene, leads to the accumulation of toxic substances in the body, resulting in liver and kidney problems as well as other complications. Tyrosinemia Type I (HT1) is an autosomal recessive disorder resulting from the deficiency or dysfunction of FAH. Normally, tyrosine is ultimately metabolized to fumarylacetoacetate and acetoacetate. However, when the FAH gene is deficient, toxic fumarylacetoacetate and maleylacetoacetate accumulate, and secondary toxic metabolites such as succinylacetone are produced, which cause damage to the liver and kidneys. In the early stages, liver damage can lead to liver failure and cirrhosis, while kidney damage may result in rickets and developmental delays ^[1-2]. The IL2RG gene, also known as the CD132 gene, encodes the interleukin-2 receptor gamma chain (IL-2Rγ), which is a critical signaling component of several interleukin receptors and a common receptor subunit for many important immune factors, including IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. These interleukin receptors are located on the surface of immune cells, and when one of these interleukins binds to its receptor, it triggers a cascade of chemical reactions within the cell, promoting cell growth and division. Therefore, the interleukin-2 receptor gamma chain is also referred to as the common gamma chain (γc). Mutations in the IL2RG gene in humans can lead to X-linked severe combined immunodeficiency (X-SCID). This condition is characterized by the lack of T cells and natural killer cells and the dysfunction of B cells, making patients extremely susceptible to recurrent infections and preventing them from surviving beyond infancy ^[3-4]. In mice, knockout of the Il2rg gene leads to severe deficiencies of B cells, T cells, and NK cells in the bone marrow, peripheral blood, and spleen, resulting in a phenotype of severe immunodeficiency ^[4]. The RAG2 gene encodes a protein that, together with the RAG1 protein, forms the RAG complex, which plays a crucial role in V(D)J recombination during the maturation of B and T cells. It not only participates in catalyzing the reaction but also regulates the reaction by controlling access to specific gene loci ^[5]. Lack of functional RAG2 protein can also lead to severe combined immunodeficiency (SCID). The loss of the Rag2 gene in mice results in the absence of V(D)J recombination, which blocks the differentiation, development, and maturation of T and B cells, ultimately causing a severe combined immunodeficiency-like phenotype ^[6]. B6RG-Fah-KO mice are obtained by crossing Fah KO mice (Catalog No.: C001273) with B6RG mice (Rag2 and Il2rg double knockout mice, Catalog No.: C001367). Research shows that B6RG-Fah-KO mice (triple knockout of Fah, Rag, and Il2rg), developed by mating Fah KO mice with Rag2 KO and Il2rg KO mice, can be used to study human hepatocyte regeneration. After transplantation of human hepatocytes, these mice can develop "humanized livers" ^[7], which are of significant importance for research in liver biology, stem cells, infectious diseases, metabolism, and gene therapy.

TNF-like ligand 1A (TL1A), also known as TNF superfamily member 15 (TNFSF15), is a member of the tumor necrosis factor (TNF) family encoded by the TNFSF15 gene in humans. TL1A acts as a ligand for death receptor 3 (DR3) and decoy receptor 3 (DcR3), providing a stimulatory signal for downstream pathways. It regulates the proliferation, activation, and apoptosis of effector cells, as well as cytokine and chemokine production. TL1A is expressed in various immune cells, including monocytes, macrophages, dendritic cells, and T cells, as well as in non-immune cells such as synovial fibroblasts and endothelial cells. It plays a crucial role in modulating immune responses by promoting the differentiation and survival of T cells, particularly Th17 cells involved in inflammatory processes ^[1]. TL1A enhances IL-2 responses in anti-CD3/CD28-stimulated T cells and synergizes with IL-12 and IL-18 to augment IFN-γ release in human T and NK cells, biasing T cell differentiation toward a Th1 phenotype ^[2]. Dysregulation of TL1A expression is implicated in autoimmune diseases, including inflammatory bowel disease (IBD), rheumatoid arthritis (RA), primary biliary cholangitis (PBC), systemic lupus erythematosus (SLE), and ankylosing spondylitis (AS) ^[1]. TL1A has emerged as a promising therapeutic target, with ongoing research focused on developing monoclonal antibodies and other biologics to neutralize TL1A and reduce inflammation in autoimmune disorders. Clinical trial results suggest that TL1A inhibition can be used in the treatment of various autoimmune diseases, particularly IBD ^[3-5]. The RAG2 gene encodes a protein that, together with the RAG1 protein, forms the RAG complex, playing a crucial role in V(D)J recombination during the maturation of B and T cells. During V(D)J recombination, the RAG complex attaches to the recombination signal sequences (RSS) located adjacent to V, D, or J segments in the DNA. The RAG complex cuts the DNA between the signal sequences and the segments, allowing the segments to separate and move to different regions of the genome. This process occurs repeatedly in B and T cells, arranging the V, D, and J segments in various combinations. The resulting protein diversity provides a broader capability to recognize foreign invaders, allowing the body to combat infections effectively. RAG2 is essential in V(D)J recombination, not only catalyzing the reaction but also regulating it by controlling access to specific loci. A lack of functional RAG2 protein can also lead to severe combined immunodeficiency (SCID). In mice, deleting the Rag2 gene results in the absence of V(D)J recombination, blocking the differentiation, development, and maturation of T and B cells, which lose their normal functions, leading to a SCID-like phenotype. The huTL1A/Rag2-KO mouse is an immunodeficient humanized model obtained by mating huTL1A mice (catalog number: C001603) with Rag2-KO mice (catalog number: C001324). This model is suitable for studying a variety of autoimmune diseases such as inflammatory bowel disease (IBD), rheumatoid arthritis (RA), primary biliary cholangitis (PBC), systemic lupus erythematosus (SLE), and ankylosing spondylitis (AS), providing an ideal pre-clinical research platform for the development of drugs such as anti-human TL1A antibodies.

The IL23A gene encodes the p19 subunit, a component of interleukin-23 (IL-23), which forms a heterodimer with the p40 subunit (encoded by IL12B) to generate the functional IL-23 cytokine ^[1]. Primarily expressed by activated dendritic cells, macrophages, and monocytes, IL-23 signals through the IL-23 receptor (IL-23R) complex, activating the JAK-STAT pathway to promote Th17 cell differentiation and maintain IL-17 production. This process drives inflammatory responses and mucosal immunity against extracellular pathogens ^[1-2]. Genetic polymorphisms within IL23A are strongly associated with autoimmune and inflammatory diseases, including psoriasis, Crohn's disease, and inflammatory bowel disease, due to dysregulated Th17 activity and chronic inflammation ^[1-2]. Monoclonal antibodies targeting IL-23, such as risankizumab and guselkumab, selectively block the p19 subunit, demonstrating therapeutic efficacy in psoriasis and inflammatory bowel diseases by suppressing pathogenic IL-17/Th17 pathways ^[3]. Also, monoclonal antibodies targeting IL-12B, such as ustekinumab, are clinically utilized for the treatment of moderate to severe psoriasis and Crohn's disease ^[4]. While IL-23 plays a role in protective immunity, its overactivation contributes to tissue damage in autoimmune settings, highlighting its dual function in immune regulation and disease pathogenesis ^[1-5]. TNF-like ligand 1A (TL1A), also known as TNF superfamily member 15 (TNFSF15), is a member of the tumor necrosis factor (TNF) family encoded by the TNFSF15 gene in humans. TL1A acts as a ligand for death receptor 3 (DR3) and decoy receptor 3 (DcR3), providing a stimulatory signal for downstream pathways. It regulates the proliferation, activation, and apoptosis of effector cells, as well as cytokine and chemokine production. TL1A is expressed in various immune cells, including monocytes, macrophages, dendritic cells, and T cells, as well as in non-immune cells such as synovial fibroblasts and endothelial cells. It plays a crucial role in modulating immune responses by promoting the differentiation and survival of T cells, particularly Th17 cells involved in inflammatory processes ^[6]. TL1A enhances IL-2 responses in anti-CD3/CD28-stimulated T cells and synergizes with IL-12 and IL-18 to augment IFN-γ release in human T and NK cells, biasing T cell differentiation toward a Th1 phenotype ^[7]. Dysregulation of TL1A expression is implicated in autoimmune diseases, including inflammatory bowel disease (IBD), rheumatoid arthritis (RA), primary biliary cholangitis (PBC), systemic lupus erythematosus (SLE), and ankylosing spondylitis (AS) ^[6]. TL1A has emerged as a promising therapeutic target, with ongoing research focused on developing monoclonal antibodies and other biologics to neutralize TL1A and reduce inflammation in autoimmune disorders. Clinical trial results suggest that TL1A inhibition can be used in the treatment of various autoimmune diseases, particularly IBD ^[8-10]. The RAG2 gene encodes a protein that, together with the RAG1 protein, forms the RAG complex, playing a crucial role in V(D)J recombination during the maturation of B and T cells. During V(D)J recombination, the RAG complex attaches to the recombination signal sequences (RSS) located adjacent to V, D, or J segments in the DNA. The RAG complex cuts the DNA between the signal sequences and the segments, allowing the segments to separate and move to different regions of the genome. This process occurs repeatedly in B and T cells, arranging the V, D, and J segments in various combinations. The resulting protein diversity provides a broader capability to recognize foreign invaders, allowing the body to combat infections effectively. RAG2 is essential in V(D)J recombination, not only catalyzing the reaction but also regulating it by controlling access to specific loci. A lack of functional RAG2 protein can also lead to severe combined immunodeficiency (SCID). In mice, deleting the Rag2 gene results in the absence of V(D)J recombination, blocking the differentiation, development, and maturation of T and B cells, which lose their normal functions, leading to a SCID-like phenotype. The huTL1A/huIL23A/huIL12B/Rag2-KO mouse is a model generated by crossing huTL1A/huIL23A/huIL12B mice (Catalog No.: C001796) with Rag2-KO mice (Catalog No.: C001324). This model serves as a valuable tool for studying immune-related diseases, including immune response regulation and autoimmune disorders. It provides a robust preclinical research platform for the screening, development, and safety evaluation of drugs targeting IL23A, IL12B, and TL1A.