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 Arachidonate 5-lipoxygenase (ALOX5) gene encodes 5-Lipoxygenase (5-LO), a key member of the fatty acid oxidase gene family. 5-LO is one of the crucial enzymes in the metabolic pathway of arachidonic acid (AA), an essential fatty acid in humans. It catalyzes the conversion of AA into leukotrienes (LTs), which are important mediators of various inflammatory and allergic diseases. ALOX5 is specifically expressed in bone marrow-derived cells and is significantly upregulated in myeloid leukemia stem cells, playing a pivotal role in the development of myeloid leukemia. Mutations in the promoter region of this gene weaken the response to leukotriene antagonists used for asthma treatment and are also associated with atherosclerosis and some cancers. Multiple splice variants encoding different isoforms have been identified for this gene. This strain is a mouse Alox5 gene deletion model, achieved by using gene editing technology to knock out the homologous gene of human ALOX5 in mice. According to literature reports, these mice exhibit increased total adipose tissue weight, plasma VLDL/LDL cholesterol, and bone mineral density. Their spleens are typically smaller than those of wild-type mice, and they exhibit reduced inflammatory responses and abnormalities in immunophysiology^[1-3]. These homozygous Alox5 KO mice are viable and fertile.

Immunoglobulin G (IgG) is the most abundant type of immunoglobulin in human serum, accounting for about 75% of the total serum immunoglobulins. It also has the longest half-life among serum immunoglobulins. IgG is synthesized in the spleen and lymph nodes and is primarily distributed in serum and tissue fluids. It is a major component of antibodies against bacteria, toxins, and viruses, and plays a crucial role in the body's immune response against infections. IgG is the only immunoglobulin that can cross the placental barrier, playing an important role in neonatal infection protection ^[1]. There are four IgG subtypes in the human body, with the IgG1 subtype accounting for about 66% of the total serum IgG. IgG1 is very important for mediating antibody responses against viral pathogens. It can effectively bind to C1q, triggering complement-dependent cytotoxicity (CDC), and bind to various Fc receptors, inducing antibody-dependent cell-mediated cytotoxicity (ADCC). These are two of the most important functions in immune responses. Therefore, IgG1 has always been the preferred model for antibody therapy and is the most promising subtype in tumor immunotherapy ^[2-3]. Selective IgG Subclass Deficiency is one of the most common immunodeficiency diseases in children. Patients with this disease have reduced total serum IgG levels, or normal total IgG levels but one or more IgG subclasses below normal levels. In most cases, patients with IgG1 deficiency also have deficiencies in other IgG subclasses, often with low serum IgG levels. Those with deficiencies in other IgG categories are prone to developing common variable immunodeficiency (CVID). Patients usually have a lifelong history of susceptibility to pyogenic infections, which can develop into chronic, progressively worsening lung infections, and commonly have deficient antibody responses to diphtheria and tetanus toxins ^[4-5]. The mouse Ighg1 gene is homologous to the human IGHG1, IGHG2, and IGHG3 genes. B6-IgG1 KO mice are constructed by knocking out the Ighg1 gene in mice, creating a model of IgG1 deficiency. This model provides an effective tool for research on diseases related to IgG1 deficiency.

The interleukin-2 receptor subunit gamma (IL2Rg or CD132) gene encodes a protein that is an important signaling component of many interleukin receptors and is a common receptor subunit for several important immune factors, including IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. IL2Rg is a glycoprotein expressed on the surface of most lymphocytes. In mammals, the IL2Rg gene is located on the X chromosome, and mutations in IL2Rg in humans can lead to X-linked severe combined immunodeficiency (X-SCID). B6-Il2rg KO mice were obtained by knocking out the expression of the Il2rg gene in C57BL/6JCya mice, which are severely deficient in B and T cells in peripheral blood and bone marrow and partially deficient in the spleen, while the mice show a severe immunodeficient phenotype with almost complete absence of NK cells in peripheral blood, spleen, and bone marrow. This strain can be used for research in the fields of oncology, immunology, infectious disease, and stem cell biology.

Immunoglobulin A (IgA) is the second most abundant immunoglobulin in serum, comprising 10–20% of serum immunoglobulins, following IgG. IgA is primarily produced by the mucosal tissues of the digestive, respiratory, and urogenital systems, where mucosal-associated lymphoid tissues generate IgA to counteract pathogen invasion. Additionally, IgA is present in saliva, tears, and breast milk ^[1]. In the human body, IgA can be classified into serum IgA and secretory IgA based on its location. Serum IgA exhibits relatively weak immune functions ^[2], whereas secretory IgA is a critical component of the mucosal defense system. It is widely distributed in breast milk, saliva, and mucosal secretions of the gastrointestinal, respiratory, and urogenital tracts, playing an essential role in inhibiting microbial adhesion to respiratory epithelium and reducing viral replication. IgA possesses antibody activity against certain viruses, bacteria, and general antigens, serving as the first line of defense against pathogen invasion ^[3]. Selective immunoglobulin A (IgA) deficiency is a systemic immunological disorder caused by a primary immunodeficiency characterized by the absence of detectable IgA in the blood and secretions, while other immunoglobulin types remain unaffected. The function of T lymphocytes, phagocytes, and the complement system in these patients is also preserved. Approximately half of the patients with selective IgA deficiency are susceptible to recurrent infections, such as otitis media, sinusitis, bronchitis, and pneumonia ^[4]. Moreover, these patients exhibit a significantly increased prevalence of autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus, and immune thrombocytopenic purpura, as well as allergic conditions such as asthma ^[4-5]. The B6-IgA KO mouse is an IgA-deficient model developed by knocking out the mouse Igha gene, which encodes IgA, in mice. This mouse model provides a valuable tool for studying diseases associated with selective IgA deficiency.

Immunoglobulins recognize foreign antigens and initiate immune responses such as phagocytosis and the complement system. Each immunoglobulin molecule consists of two identical heavy chains and two identical light chains. Immunoglobulin heavy locus, also known as IGH, is a region that contains a gene for the heavy chains of human antibodies (or immunoglobulins), this locus includes V (variable), D (diversity), J (joining), and C (constant) segments. During B cell development, a recombination event at the DNA level joins a single D segment with a J segment; the fused D-J exon of this partially rearranged D-J region is then joined to a V segment. The rearranged V-D-J region containing a fused V-D-J exon is then transcribed and fused at the RNA level to the IGHM constant region; this transcript encodes a mu-heavy chain. Later in development B cells generate V-D-J-Cmu-Cdelta pre-messenger RNA, which is alternatively spliced to encode either a mu or a delta-heavy chain. Mature B cells in the lymph nodes undergo switch recombination so that the fused V-D-J gene segment is brought in proximity to one of the IGHG, IGHA, or IGHE gene segments and each cell expresses either the gamma, alpha, or epsilon heavy chain.^br/ This strain is an Ighj-deletion model, in the homozygous B6-Ighj KO mice, the J-segment of the Ig heavy chain locus is completely deleted, resulting in the inability of the cell to produce a recombinant version of the complete heavy chain variable region. The B cells of B6-Ighj KO mice have undergone dramatic changes in the developmental process and cell number, which can be used as an animal model of B-cell immune deficiency. B6-Ighj KO mice retain other immune cells except for B cells, so the presence of other immune cells can be detected in B6-Ighj KO mice.

Antibodies, or immunoglobulins (Igs), are crucial components of the immune system, specifically recognizing and neutralizing foreign pathogens. They bind selectively to antigens, triggering an immune response. Upon antigen entry, B cells differentiate into plasma cells, which subsequently synthesize and secrete antibodies. Beyond neutralization, antibodies engage Fc receptors on T cells, macrophages, mast cells, and complement components, thereby facilitating antigen clearance through antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), or modulating the activation of classical pathways ^[1-2]. The immunoglobulin (Ig) structure comprises two identical light chains (L) and two identical heavy chains (H), forming a classical Y-shaped structure stabilized by interchain disulfide bonds, noncovalent interactions, and hinge regions ^[2-3]. Each heavy and light chain contains a variable region and a constant region; the variable regions are essential for recognizing and binding specific antigens. Antibody diversity arises largely from sequence variations within these variable regions, enabling B cells to detect a vast array of antigens. In mammals, immunoglobulins contain both kappa (κ) and lambda (λ) light chains. Although there are no significant functional differences between these two light chain types, individual B cells express only one type. The ratio of κ- to λ-expressing B cells varies by species: in humans, this ratio is approximately 2:1, whereas in mice, it is about 20:1, with the majority of mouse B cells expressing only κ light chains ^[4]. The gene segments encoding antibody structures (Ig motifs) are spatially separated in embryonic cells, predominantly comprising variable (V) and constant (C) regions. The highly variable V region includes variable (V), diversity (D), and joining (J) genes, which undergo random DNA rearrangements to connect with the relatively conserved C region, thereby encoding diverse antibody types ^[5]. Notably, antibody light chains lack D genes and are composed solely of V, J, and C gene fragments. The B6-Igl KO mouse is a knockout model targeting the gene segment encoding the λ light chain. Through gene editing, the sequences encoding the V, J, and C regions of the mouse λ light chain (Igl) locus are completely ablated, resulting in the absence of B cells expressing immunoglobulin light chain λ. Consequently, B6-Igl KO mice serve as a valuable tool for investigating B cell development and function, generating κ light chain-only mouse antibodies, elucidating the role of the λ light chain in specific immune responses or autoimmune diseases, and exploring antibody diversity, immune regulatory mechanisms, and potential therapeutic strategies ^[6].

T cell receptors (TCRs) recognize foreign antigens which have been processed as small peptides and bound to major histocompatibility complex (MHC) molecules at the surface of antigen-presenting cells (APC). Each T cell receptor is a dimer consisting of one alpha and one beta chain or one delta and one gamma chain. In a single cell, the T cell receptor loci are rearranged and expressed in the order delta, gamma, beta, and alpha. If both delta and gamma rearrangements produce functional chains, the cell expresses delta and gamma. If not, the cell proceeds to rearrange the beta and alpha loci. The TCRA gene encodes part of the alpha-beta T cell receptor complex, which in turn is involved in T cell-mediated cytotoxicity against tumor cell targets and detection of tumor cells. This strain is a Tcra gene deletion model in which homozygous B6-Tcra KO mice with αβ T-cell receptor deficiency have thymuses lacking CD4+CD8- and CD4-CD8+ cells, and approximately 1.5% of thymocytes express γδ T-cell receptors. homozygous B6-Tcra KO mice are developmentally normal and fertile, but mortality increases after 6 months, and few mice survive beyond one year.

The IL2RG gene encodes the interleukin-2 receptor gamma chain (IL-2Rγ), also known as the common gamma chain (γc). This receptor subunit is shared by several immune factors, including IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. When these cytokines bind to their receptors, they promote cell growth and division. Mutations in the IL2RG gene can lead to X-linked severe combined immunodeficiency (X-SCID), a condition characterized by a lack of T cells and natural killer cells, and non-functional B cells. As a result, patients with X-SCID are highly susceptible to recurrent infections and are unable to survive beyond infancy ^[1-2]. In mice, knockout of the Il2rg gene leads to severe depletion of B cells, T cells, and NK cells ^[2]. The RAG2 gene encodes a protein that forms the RAG complex with the RAG1 protein. This complex plays a crucial role in V(D)J recombination during B and T cell maturation. The RAG complex attaches to a section of DNA called a recombination signal sequence (RSS), next to a V, D, or J segment, and makes small cuts in the DNA so that the segment can be separated and moved. This process is repeated multiple times in different areas within B cells and T cells so that the V, D, and J segments are arranged in various combinations, providing greater recognition of foreign invaders ^[3]. A lack of functional RAG2 protein can lead to SCID. In mice, deletion of the Rag2 gene leads to loss of V(D)J recombination, resulting in blocked differentiation, development, and maturation of T cells and B cells ^[4]. BRG mice are models with the double knockout of Il2rg and Rag2 genes. This model presents more severe depletion of B cells, T cells, and NK cells as well as other severe combined immunodeficiency phenotypes than mice with knockout of either the Il2rg or Rag2 genes alone ^[5]. BRG mice can be used for research in various fields of oncology and immunology.