Do you recall the famous "Bubble Boy"? Poor David suffered from Severe Combined Immunodeficiency (SCID), which made him incapable of combatting any bacteria or viruses, forcing him to spend his entire life in a sterile environment. Shortly after his birth, doctors placed him into a sterile bubble, hence the term "Bubble Boy" for people with similar conditions. Today, let's delve deeper into immunodeficiency disorders.
The immune system serves as an organism’s disease defense system that consists of immune organs, immune cells, and immune active substances. These elements work together to enable the immune system to effectively defend against invading pathogens. Under normal circumstances, the immune system can detect various types of pathogens and/or harmful substances and can differentiate these substances from the organism’s own healthy cells and tissues. However, genetic abnormalities can lead to dysregulation of the immune system, resulting in the development of immune system diseases such as Primary Immunodeficiency Diseases (PIDs) and autoimmune diseases, causing abnormalities in the immune system or loss of immune functions. Several of these genetic autoimmune disorders are rare diseases, but these remain worthy of attention for preclinical research towards interventions.
Figure 1. Primary Immunodeficiency Diseases (PIDs) in the Context of the Classic Immune Response 
Common Variable Immunodeficiency (CVID) is a primary immunodeficiency disease (PID) characterized by low levels of protective antibodies, an increased risk of infections, and – most notably – by a reduction in immunoglobulins (Ig). Symptoms include heightened sensitivity to foreign invaders, chronic lung diseases, as well as gastrointestinal inflammation and infections. CVID is a lifelong condition associated with defects in immune cells, and the causative genes include ICOS, TACI, and other genes encoding T cell surface proteins and cytokine receptors .
The inducible T cell co-stimulator (ICOS) factor encoded by the ICOS gene is exclusively expressed on activated T cells. It plays a vital role in intercellular signaling, cell proliferation, germinal center formation, immunoglobulin isotype switching, and memory B cell development. Homozygous loss-of-function mutations in the ICOS gene within T cells can lead to the development of CVID . In mice, knockout of Icos results in a phenotype similar to human CVID, including abnormalities in immunoglobulin isotype switching, immunoglobulin levels, T cell-dependent B cell responses, interferon and interleukin levels, lymph node size, and germinal center formation [4-5]. These mice are widely used in research related to CVID and studies of the immune system, especially those involving immunoglobulin isotype switching and germinal center formation.
Figure 2. Impaired Primary Antibody Response to T Cell-Dependent Antigens and Germinal Center Formation in Icos-Knockout (Icos-KO) Mice 
Immune Deficiency 15A (IMD15A) and Immune Deficiency 15B (IMD15B) are both primary immunodeficiency diseases (PIDs) caused by mutations in the IKBKB gene. IMD15A is caused by heterozygous mutations in IKBKB and typically manifests later in life, characterized by recurrent respiratory infections and lymphocytopenia. IMD15B, on the other hand, is caused by homozygous mutations in IKBKB and typically presents in infancy. Patients with IMD15B often have low or absent immunoglobulins, and their immune cell differentiation and activation functions are impaired , leading to life-threatening bacterial, fungal, and viral infections. Currently, there is no effective treatment for either condition, and management primarily involves infection prevention, treatment, and bolstering the maintenance of the immune system.
IKBKB gene encodes the β subunit of IκB kinase (IKK) complex, known as IKK-β, which plays an inhibitory role in NF-κB signaling pathway. The NF-κB pathway is involved in various biological processes, including immune responses, inflammatory reactions, cell apoptosis, tumor development, regulation of cytokines, cell adhesion molecules, immune modulators, growth factors, transcription factors, and growth-regulatory factors. Mutations in IKBKB result in antigen receptor-related activation of T and B cells.
In mice, the loss of Ikbkb gene leads to a more severe phenotype, resulting in embryonic lethality characterized by severe hepatocellular degeneration and increased apoptosis . B cell-specific deletion of Ikbkb affects B cell development, leading to a reduced number of mature B cells . Similarly, T cell-specific deletion of Ikbkb results in a significant reduction in peripheral CD4+ and CD8+ T cells, along with lower IgE levels and delayed T cell-dependent antibody responses . Moreover, myeloid-specific Ikbkb knockout impairs neutrophil and macrophage chemotaxis and neutrophil recruitment .
Figure 3. T Cell-Specific Ikbkb (Ikk2) Conditional Knockout (cKO) Mice Lack Regulatory and Memory T Cells 
The CHUK gene encodes IκB kinase complex alpha subunit (IKK-α). Mutations in this gene can lead to two severe developmental disorders: Fetal Encasement Syndrome (FES) and Bartsocas-Papas Syndrome Type 2 (BPS2).
FES is characterized by severe fetal malformations, including craniofacial abnormalities, elliptical deformities, and limbs that are poorly developed, wrapped in abnormal, translucent, membranous skin that lacks elasticity. BPS2 is characterized by skin webbing of one or more joints, cleft lip and/or palate, finger deformities, and genital malformations.
Studies have shown that Chuk knockout (KO) mice exhibit a perinatal lethal phenotype and a bottle-like body shape. Their limbs and tail are wrapped in thick, sticky epidermal tissue. Additionally, these mice may display skeletal abnormalities, developmental eye and conjunctival abnormalities, and embryonic vascular development abnormalities, similar to the phenotype seen in human FES disease [11-13]. Furthermore, these mice also exhibit immunodeficiency, including abnormalities in B cell number and function .
Figure 4. Severe Embryonic and Skeletal Developmental Defects in Chuk-Knockout (Chuk-KO) Mice 
Gene-edited mouse models play a crucial role in studying the mechanisms of rare diseases and evaluating drug development. Cyagen has thousands of self-developed gene-edited mouse strains, including various gene knockout and conditional knockout rare disease mouse models, covering genes such as ICOS, AIRE, ITK, and IKBKB. Additionally, we offer specialized customized services tailored to your research needs, accelerating your research projects.
|Common Variable Immunodeficiency (CVID)||ICOS||KO, cKO|
|Immune Deficiency 15A/B (IMD15A/B)||IKBKB||KO, cKO|
|Fetal Encasement Syndrome (FES)||CHUK||KO, cKO|
The Rare Disease Data Center (RDDC) is hosted and developed by the Rare Disease Gene Therapy Alliance under the leadership of Artificial Intelligence Innovation Center at the Tsinghua University and Pearl River Delta Research Institute. With the biological and genetic technology support provided by Cyagen, it has undergone upgrades from version 1.0 to 2.0. This database offers information on various rare diseases and aims to better serve researchers' needs for data querying and data mining.
After login, users can swiftly progress from target gene discovery to querying the phenotypes and functions of these target genes. Additionally, they can also select the most relevant animal models based on the phenotypes associated with the target genes. This streamlined process enables researchers to rapidly formulate research strategies and embark on scientific investigations and drug discovery efforts targeting disease-causing genes.
C-NKG mice are a severe immunodeficient strain developed by Cyagen through knockout of the Il2rg gene on the NOD-Scid background strain. These models are currently recognized as an ideal model for research in areas such as cancer, immune function, autoimmune diseases, immunotherapy, infectious disease/vaccines, graft versus host disease (GvHD), safety assessment, and stem cell biology. Additionally, Cyagen can provide services tailored to your project requirements, including human immune system reconstitution and xenotransplantation of human tumor cell lines.
|C-NKG (In-house Developed Severe Immunodeficient Mice)||N/A||N/A||N/A||Suppressed||Defective||Defective||C-NKG mice are one of the mouse strains with a high degree of immunodeficiency. They exhibit high compatibility for xenotransplantation, making them suitable for most human tumor cell/tissue grafts. These mice have a high tumor formation rate and a rapid tumor growth rate. They are well-suited for irradiation at doses below 2Gy and do not spontaneously develop lymphomas. Furthermore, C-NKG mice have a normal lifespan.|
|BALB/c (Nude Mice)||N/A||Normal||Normal||Normal||Normal||Normal||These mice are hairless and exhibit congenital thymic defects. They have lower compatibility for xenotransplantation, and are suitable for only a subset of human tumor cell/tissue grafts.|
|NOD-Scid||N/A||N/A||Low activity||Suppressed||Defective||Defective||These mice have a higher degree of immunodeficiency compared to BALB/c nude mice and are well-suited for xenotransplantation of human tumor cell/tissue grafts. They can tolerate irradiation at doses below 2Gy, but they are prone to developing spontaneous lymphomas, which limits their lifespan to approximately 8 months.|
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National Center for Biotechnology Information. (n.d.). Severe combined immunodeficiency due to IKK2 deficiency.
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