Interferons (IFNs) are potent cytokines that serve as a critical component of the body's first line of defense against viral infections, playing a key role in inflammation and immune control by directly inducing pathogen-inhibiting molecules that suppress viral replication ^[1]. Arthropod-borne viruses (arboviruses) like Dengue virus (DENV), Zika virus (ZIKV), and Yellow Fever virus (YFV) encode proteins that antagonize the IFN response, helping these viruses evade host immunity and maintain sufficient viral loads in the blood (viremia) to sustain the vector-host transmission. Arboviruses pose a significant public health threat, affecting around 3.9 billion people in tropical and subtropical regions. However, most preclinical studies suggest that arboviruses cannot inhibit IFN responses in mice, rendering immunocompetent mice resistant to infection, with low viral loads and limited circulation, thus limiting their use in infection research ^[2-3]. As a result, immunodeficient mouse models with defects in multiple IFN signaling pathways have become essential tools for studying arbovirus pathogenesis and vaccine development ^[2-4]. Studies have demonstrated that wild-type mice of strains like C57BL/6, CD-1, or 129 rarely exhibit clinical symptoms after infection with arboviruses such as ZIKV. However, the virus has been detected in the blood, ovaries, and spleen of ZIKV-infected 129 mice, suggesting that this strain may be more susceptible to arboviruses ^[5-6]. Because the virus can persist in the bloodstream without causing disease or death, the 129 strain can be used to evaluate the teratogenic effects of such viruses. Furthermore, the 129 strain is commonly used in interferon signaling-deficient models related to other viral infections ^[7-8]. The IFNAR1 gene encodes a protein that is an essential component of the type I interferon (IFN) receptor, playing a critical role in the antiviral and immune responses. IFNAR1 is primarily expressed in immune cells, such as lymphocytes and dendritic cells, and various tissues, including the liver, brain, and skin. Defects in IFNAR1, whether due to mutations or regulatory abnormalities, can lead to severe diseases such as systemic lupus erythematosus, where excessive immune activation results in tissue damage, and certain cancers. Other diseases associated with IFNAR1 include hepatitis C, yellow fever, measles, papilloma, and viral infections. The A129 (Ifnar1 KO) mice on a 129 background are a type I (α/β) interferon receptor (Ifnar1) gene knockout model. The absence of the IFNAR1 protein in these mice leads to a lack of type I IFN receptor function, thereby reducing immune response and increasing susceptibility to viral infections. Homozygous A129 (Ifnar1 KO) mice are viable and fertile, but they show increased susceptibility to arbovirus infections.

Interferons (IFNs) are potent cytokines that serve as a critical component of the body's first line of defense against viral infections, playing a key role in inflammation and immune control by directly inducing pathogen-inhibiting molecules that suppress viral replication ^[1]. Arthropod-borne viruses (arboviruses) like Dengue virus (DENV), Zika virus (ZIKV), and Yellow Fever virus (YFV) encode proteins that antagonize the IFN response, helping these viruses evade host immunity and maintain sufficient viral loads in the blood (viremia) to sustain the vector-host transmission. Arboviruses pose a significant public health threat, affecting around 3.9 billion people in tropical and subtropical regions. However, most preclinical studies suggest that arboviruses cannot inhibit IFN responses in mice, rendering immunocompetent mice resistant to infection, with low viral loads and limited circulation, thus limiting their use in infection research ^[2-3]. As a result, immunodeficient mouse models with defects in multiple IFN signaling pathways have become essential tools for studying arbovirus pathogenesis and vaccine development ^[2-4]. Studies have demonstrated that wild-type mice of strains like C57BL/6, CD-1, or 129 rarely exhibit clinical symptoms after infection with arboviruses such as ZIKV. However, the virus has been detected in the blood, ovaries, and spleen of ZIKV-infected 129 mice, suggesting that this strain may be more susceptible to arboviruses ^[5-6]. Because the virus can persist in the bloodstream without causing disease or death, the 129 strain can be used to evaluate the teratogenic effects of such viruses. Furthermore, the 129 strain is commonly used in interferon signaling-deficient models related to other viral infections ^[7-8]. The IFNAR1 gene encodes a key component of the type I IFN receptor, while the IFNGR1 gene encodes the ligand-binding chain (α) of the type II (γ) IFN receptor. AG129 mice, which are knockout models for both the type I (α/β) IFN receptor (Ifnar1) and the type II (γ) IFN receptor (Ifngr1), lack functional IFNAR1 and IFNGR1 proteins, resulting in deficiencies in α/β/γ interferon receptor signaling and heightened susceptibility to viral infections. Homozygous AG129 mice are viable and fertile, and exhibit increased sensitivity to arboviral infections, generating viremia similar to that seen in humans. Compared to IFNα/β/γR KO mice on the C57BL/6 background, the 129-background AG129 mice exhibit more pronounced neurological symptoms after infection ^[6,9].

The IL18BP (Interleukin 18 Binding Protein) gene encodes a secreted, high-affinity, naturally occurring antagonist of the proinflammatory cytokine Interleukin-18 (IL-18), functioning by binding IL-18 to prevent it from interacting with its receptor, thereby inhibiting IL-18-induced immune responses, such as interferon-gamma (IFN-γ) production ^[1]. The gene's protein, IL-18BP, is constitutively expressed and secreted primarily by mononuclear cells (such as monocytes/macrophages and T-cells) and is widely expressed at the RNA level in numerous tissues, including the spleen, lung, placenta, and small intestine ^[2]. Its expression can be enhanced by IFN-γ in a negative feedback loop to regulate inflammation ^[3]. Dysregulation or an imbalance in the ratio of IL-18 to IL-18BP is associated with a range of inflammatory and autoimmune conditions, including Crohn's disease, rheumatoid arthritis, systemic lupus erythematosus (SLE), systemic juvenile idiopathic arthritis (SJIA), fulminant viral hepatitis, and adult-onset Still's disease. The B6-huIL18BP mouse is a humanized model constructed through gene-editing technology, in which the sequences from the ATG start codon to the TAA stop codon of the endogenous mouse Il18bp gene are replaced with the sequences from the ATG start codon to the TAA stop codon of the human IL18BP gene. This model can be used for research on tumor mechanisms and tumor immunotherapy, inflammatory and autoimmune conditions, as well as for the development of IL18BP-targeted drugs.

Cluster of Differentiation 3 (CD3) is a protein complex that acts as a co-receptor for T cells and is involved in the activation of cytotoxic T cells (CTLs) and helper T cells (THs). CD3 consists of five polypeptide chains: γ, δ, ε, ζ, and η, all of which are transmembrane proteins. The transmembrane regions of CD3 molecules connect with the transmembrane regions of TCR's two polypeptide chains through salt bridges, forming the TCR-CD3 complex, which is essential for T cell antigen recognition ^[1-2]. After TCR recognizes an antigen, the activation signal is transduced by CD3 into the T cell. CD3 is highly specific at all developmental stages of T cells, thus it is considered a T cell-specific immunohistochemical marker. Additionally, CD3 is present in almost all T cell lymphomas and leukemias and can be used to distinguish between morphologically similar B cell and bone marrow tumors. Due to its significant role in T cell activation and antigen recognition, CD3 is an important drug target in immunosuppressive therapy for type 1 diabetes and other autoimmune diseases ^[3]. The EPCAM gene encodes a transmembrane glycoprotein, Epithelial Cell Adhesion Molecule (EPCAM), also known as CD326 or Trop-1, which mediates calcium-independent homotypic cell adhesion and participates in fundamental processes including cell adhesion, migration, proliferation, and signal transduction, thereby maintaining epithelial tissue integrity ^[4]. While normally expressed on the surface of epithelial cells in organs such as the gastrointestinal tract, lungs, and skin, EPCAM is frequently overexpressed in various cancers, including colorectal, breast, and pancreatic carcinomas, but is largely absent or weakly expressed in healthy squamous epithelia ^[4]. Structurally, EPCAM comprises an extracellular domain (EpEX) mediating intercellular adhesion, a transmembrane domain, and a short intracellular domain (EpICD). Upon proteolytic cleavage by ADAM17 and γ-secretase, EpICD translocates to the nucleus, activating oncogenic pathways such as Wnt/β-catenin, ERK, and FAK-AKT, which promotes epithelial-mesenchymal transition (EMT), tumor progression, and metastasis ^[5]. Notably, EPCAM serves as a marker for circulating tumor cells (CTCs) and cancer stem cells, and its downregulation during EMT can complicate advanced cancer detection ^[5-6]. Furthermore, dysregulated EPCAM expression is associated with congenital tufting enteropathy (CTE), a severe intestinal epithelial dysfunction ^[5]. Given its involvement in tumor metastasis through interaction with HGFR (c-Met), targeting EPCAM with strategies like the neutralizing antibody EpAb2-6 in combination with HGFR inhibitors has shown promising preclinical efficacy ^[7]. The B6-hCD3/hEPCAM mouse is obtained by crossbreeding B6-hCD3 mice (Catalog No.: C001325) with B6-hEPCAM mice. It can be used for the development of CD3/EPCAM-targeted drugs, as well as for research in tumor immunotherapy and autoimmune disease-related drugs.

Complement component C3 plays a central role in activating the complement system and is the most abundant complement protein in human plasma, primarily synthesized in the liver. As part of the innate immune system, the complement system is activated during tissue damage and pathogen invasion, playing a crucial role in the inflammatory response, host homeostasis, and pathogen defense. The complement cascade is activated through the classical pathway, alternative pathway, and lectin pathway, all of which generate C3 convertase, which cleaves C3 into C3a and C3b. C3a is a potent anaphylatoxin with pro-inflammatory activity, while C3b is a regulator that induces C5 cleavage, thereby participating in the dissolution and clearance of immune complexes. Mutations in this gene are associated with atypical hemolytic uremic syndrome (aHUS) and age-related macular degeneration (AMD). Deficiencies in C3 and C3-derived peptides can lead to autoimmune diseases (such as rheumatoid arthritis, systemic lupus erythematosus, and vasculitis) and make individuals susceptible to recurrent respiratory infections and infections caused by encapsulated organisms. Conversely, excessive activation of C3 and related complement components is associated with kidney diseases (immune complex glomerulonephritis, hemolytic uremic syndrome, lupus nephritis, membranous nephropathy, and immune-mediated nephropathy) ^[1-2]. Specifically, the C3*R102G mutation involves a substitution of the amino acid arginine (R) with glycine (G) at position 102 of the mature C3 protein, often leading to a gain-of-function that results in the protein being more susceptible to cleavage and thus causing uncontrolled complement activation ^[3]. The B6-huC3*R102G mouse is a humanized disease model constructed by gene-editing technology. The sequences from upstream of exon 1 to the TGA stop codon of mouse C3 were replaced with the sequences from upstream of exon 1 to downstream of exon 41 of human C3. The p.R102G (CGC to GGC) mutation was introduced into human C3 exon 3. This model is suitable for the mechanistic study of immune-related diseases caused by uncontrolled activation of the complement system (such as age-related macular degeneration (AMD), etc.) and the development of therapies targeting C3 R102G.

Frontotemporal Dementia (FTD) is the second most prevalent form of early-onset dementia, following Alzheimer’s disease (AD). This condition is distinguished by the selective degeneration of the frontal and temporal lobes, resulting in personality and behavioral changes, language impairments, and executive dysfunction. Approximately 40%-50% of FTD cases have a familial component, with known causative genes including MAPT, FUS, and TARDBP. Of these, MAPT is the earliest discovered and most frequently implicated in FTD. Mutations in the MAPT gene are detectable in roughly 30% of familial FTD cases ^[1]. The tau protein, a microtubule-associated protein encoded by MAPT, is primarily localized to neuronal axons and plays a critical role in microtubule stability and assembly. By binding to microtubules, the tau protein helps to maintain neuronal cell shape. Mutations in MAPT can promote tau aggregation, leading to pathological tau protein accumulation and death of glutamatergic cortical neurons ^[2]. Additionally, certain MAPT mutations can affect pre-mRNA exon splicing, altering the ratio of 3R to 4R tau protein isoforms and increasing the relative production of 4R-tau protein, which is more prone to fibril formation ^[3-4]. Therapies targeting the MAPT gene primarily consist of small-molecule drugs and monoclonal antibodies, with indications including AD and FTD. Transgenic mice are frequently used in the drug development process, and the utilization of humanized animal models can facilitate the translation of promising treatments into clinical trials ^[5-9]. The tumor necrosis factor-alpha (TNF/TNF-α) gene encodes a pro-inflammatory cytokine belonging to the TNF superfamily. It is primarily produced by macrophages/monocytes during acute inflammation. TNF-α regulates immune cell function by binding to its receptors TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR, participating in normal inflammatory and immune responses. TNF-α is involved in various biological processes, including cell proliferation, differentiation, apoptosis, lipid metabolism, and coagulation. This factor is associated with several diseases, such as autoimmune conditions, insulin resistance, psoriasis, rheumatoid arthritis, ankylosing spondylitis, tuberculosis, autosomal dominant polycystic kidney disease, and cancer. Mutations in the TNF-α gene impact susceptibility to cerebral malaria, septic shock, and Alzheimer’s disease ^[10-11]. In mice, defects in this gene are associated with impaired responses to bacterial infections, defects in the organization of follicular dendritic cell networks and germinal centers, and a lack of primary B cell follicles. The B6;D1-htau/hTNF mouse is a dual-gene humanized model generated by crossing B6-htau mice (Catalog No.: C001410) with DBA/1-hTNF mice (Catalog No.: C001587). This model can be used for the study of neurodegenerative diseases such as frontotemporal lobar dementia (FTD) and Alzheimer's disease (AD) and autoimmune diseases such as rheumatoid arthritis (RA), as well as for the research and development, screening, and pre-clinical evaluation of Tau/TNF-targeted drugs.

Interleukin-13, encoded by the IL13 gene, is a key type 2 immune response cytokine, predominantly expressed by activated Th2 helper T cells, type 2 innate lymphoid cells (ILC2s), and mast cells, and central to type 2 immune responses elicited by allergens or other stimuli ^[1]. The IL-13 protein, a ~13 kDa molecule with a four-helix bundle structure, mediates its biological effects by binding to the cell surface receptor IL-13Rα1 and recruiting the IL-4Rα chain to form a functional receptor complex, thereby activating the downstream JAK/STAT6 signaling pathway ^[2]. Key functions of IL-13 include promoting B cell maturation and plasma cell differentiation, inducing IgE isotype switching, and suppressing the pro-inflammatory activity of macrophages, leading to reduced production of pro-inflammatory cytokines and chemokines ^[3]. Furthermore, IL-13 induces goblet cell hyperplasia, promotes mucus secretion, and contributes to airway remodeling and fibrosis ^[4]. Numerous studies have established the critical role of IL-13 in the pathogenesis of various diseases, including asthma, allergic rhinitis, atopic dermatitis, and eosinophilic esophagitis ^[1-4]. Consequently, targeting IL-13 and its signaling pathways has become a significant therapeutic strategy for these conditions; for example, the monoclonal antibody Dupilumab, which simultaneously blocks IL-4 and IL-13 signaling, has demonstrated substantial efficacy in treating diverse type 2 inflammation-related diseases ^[5]. Thus, IL-13 represents a promising therapeutic target for allergic and inflammatory disorders. Thymic stromal lymphopoietin (TSLP), an interleukin-7 (IL-7) family cytokine, is encoded by the TSLP gene and is predominantly produced by epithelial cells. Its expression is notably upregulated by environmental cues, including allergens and proteases, positioning it as a sentinel at the interface of environmental exposure and immune activation ^[6-7]. Secreted by a range of cell types, such as epithelial cells, keratinocytes, mast cells, and dendritic cells, TSLP is critical in the initiation of immune responses, primarily through the activation of dendritic cells and subsequent polarization of T helper type 2 (Th2) cell differentiation. This process has broad implications for diverse immune cell populations and B cell functions relevant to allergic inflammation ^[7]. Transcriptional regulation of TSLP gene expression is tightly controlled by factors including NF-κB and AP-1, with genetic polymorphisms within the TSLP locus being strongly implicated in asthma susceptibility ^[6-8]. Dysregulated TSLP signaling is now recognized as a pivotal factor in the pathogenesis of atopic disorders, encompassing conditions such as atopic dermatitis, asthma, allergic rhinitis, and eosinophilic esophagitis ^[6-9]. For example, tezepelumab, a monoclonal antibody that blocks the TSLP signaling pathway, has demonstrated significant efficacy in clinical trials for patients with severe asthma, reducing acute exacerbations and improving lung function ^[9]. Consequently, TSLP is under intense investigation as a therapeutic target, with current strategies focusing on disrupting its signaling pathways to modulate allergic and inflammatory diseases. The B6-huIL13/huTSLP mouse is a double-gene humanized model obtained by mating B6-huIL13 mice (catalog number: C001634) with B6-huTSLP mice (catalog number: C001809). This model can be used for mechanism research and development of treatment methods for allergic diseases, inflammation, and autoimmune diseases, as well as for the development of IL13/TSLP-targeted drugs.

Thymic stromal lymphopoietin (TSLP), an interleukin-7 (IL-7) family cytokine, is encoded by the TSLP gene and is predominantly produced by epithelial cells. Its expression is notably upregulated by environmental cues, including allergens and proteases, positioning it as a sentinel at the interface of environmental exposure and immune activation ^[1-2]. Secreted by a range of cell types, such as epithelial cells, keratinocytes, mast cells, and dendritic cells, TSLP is critical in the initiation of immune responses, primarily through the activation of dendritic cells and subsequent polarization of T helper type 2 (Th2) cell differentiation. This process has broad implications for diverse immune cell populations and B cell functions relevant to allergic inflammation ^[2]. Transcriptional regulation of TSLP gene expression is tightly controlled by factors including NF-κB and AP-1, with genetic polymorphisms within the TSLP locus being strongly implicated in asthma susceptibility ^[1-3]. Dysregulated TSLP signaling is now recognized as a pivotal factor in the pathogenesis of atopic disorders, encompassing conditions such as atopic dermatitis, asthma, allergic rhinitis, and eosinophilic esophagitis ^[1-4]. For example, tezepelumab, a monoclonal antibody that blocks the TSLP signaling pathway, has demonstrated significant efficacy in clinical trials for patients with severe asthma, reducing acute exacerbations and improving lung function ^[4]. Consequently, TSLP is under intense investigation as a therapeutic target, with current strategies focusing on disrupting its signaling pathways to modulate allergic and inflammatory diseases. The B6-hTSLP mouse is a humanized model constructed using gene editing technology, where the mouse Tslp endogenous domain was replaced with the human TSLP domain . The murine signal peptide was preserved. This model can be used for studying the pathological mechanisms and therapeutic approaches of allergic and inflammatory diseases and for the development of TSLP-targeted drugs.

Complement factor B (CFB) is a circulating serine protease that plays a central role in the alternative pathway of the complement system, a critical component of innate immunity. Encoded by the CFB gene, this protein is primarily synthesized by hepatocytes, adipocytes, and monocytes, reflecting its systemic and local involvement in immune surveillance and inflammation ^[1]. Upon activation by factor D, CFB forms the active enzyme factor Bb, which, in complex with complement component C3b, constitutes the alternative pathway C3 convertase (C3bBb). This convertase catalyzes the cleavage of C3 into the anaphylatoxin C3a and the opsonin C3b, leading to the amplification of the complement cascade and the subsequent elimination of pathogens and damaged cells ^[2]. Dysregulation of CFB activity, often stemming from genetic polymorphisms within the CFB locus, has been implicated in the pathogenesis of several human diseases, including age-related macular degeneration (AMD), atypical hemolytic uremic syndrome (aHUS), and systemic lupus erythematosus (SLE), underscoring the delicate balance required for proper complement regulation and immune homeostasis ^[3-4]. These associations highlight CFB as a key mediator of both protective and pathological immune responses. The MASP2 gene encodes MASP-2, a serum serine protease that serves as a key mediator in complement system activation. MASP-2 initiates the lectin pathway by forming complexes with pattern recognition molecules such as mannose-binding lectin (MBL) and ficolins. Upon pathogen recognition by MBL, MASP-2 is activated and subsequently cleaves complement components C4 and C2, leading to the generation of C3 convertase and triggering downstream complement activation. Beyond its role in the complement cascade, MASP-2 also contributes to the coagulation pathway by cleaving prothrombin to generate thrombin, thereby linking innate immunity and hemostasis ^[5]. Emerging evidence highlights the clinical significance of MASP2 gene polymorphisms, which are associated with altered susceptibility to infectious diseases and immune-related disorders. Reduced plasma levels of MASP-2 have been linked to increased vulnerability to HIV infection, while elevated MASP-2 activity may exacerbate inflammatory responses ^[6]. Given its pivotal role in immune regulation, MASP-2 has emerged as a promising therapeutic target. Inhibition of MASP-2 is currently under investigation as a potential strategy for treating a range of conditions, including IgA nephropathy (IgAN) ^[7], atypical hemolytic uremic syndrome (aHUS), and transplant-associated thrombotic microangiopathy (TA-TMA) ^[8]. The B6-huCFB/hMASP2 mouse is a dual-gene humanized model obtained by mating B6-huCFB mice (catalog number: C001710) with B6-hMASP2 mice (catalog number: C001592). This model can be used for research on the pathological mechanisms and treatment methods of autoimmune diseases and infectious diseases, as well as the development of CFB/MASP2-targeted drugs.

Interleukin-13, encoded by the IL13 gene, is a key type 2 immune response cytokine, predominantly expressed by activated Th2 helper T cells, type 2 innate lymphoid cells (ILC2s), and mast cells, and central to type 2 immune responses elicited by allergens or other stimuli ^[1]. The IL-13 protein, a ~13 kDa molecule with a four-helix bundle structure, mediates its biological effects by binding to the cell surface receptor IL-13Rα1 and recruiting the IL-4Rα chain to form a functional receptor complex, thereby activating the downstream JAK/STAT6 signaling pathway ^[2]. Key functions of IL-13 include promoting B cell maturation and plasma cell differentiation, inducing IgE isotype switching, and suppressing the pro-inflammatory activity of macrophages, leading to reduced production of pro-inflammatory cytokines and chemokines ^[3]. Furthermore, IL-13 induces goblet cell hyperplasia, promotes mucus secretion, and contributes to airway remodeling and fibrosis ^[4]. Numerous studies have established the critical role of IL-13 in the pathogenesis of various diseases, including asthma, allergic rhinitis, atopic dermatitis, and eosinophilic esophagitis ^[1-4]. Consequently, targeting IL-13 and its signaling pathways has become a significant therapeutic strategy for these conditions; for example, the monoclonal antibody Dupilumab, which simultaneously blocks IL-4 and IL-13 signaling, has demonstrated substantial efficacy in treating diverse type 2 inflammation-related diseases ^[5]. Thus, IL-13 represents a promising therapeutic target for allergic and inflammatory disorders. The BALB/c-hIL13 mouse is a humanized model constructed using gene editing technology to replace the sequence of the mouse Il13 gene in situ with the corresponding sequence from the human IL13 gene. This model can be used for studying the pathological mechanisms and therapeutic approaches of allergic and inflammatory diseases, and for the development of IL13-targeted drugs.