Recombination activating gene 1 also known as RAG-1 is a protein that in humans is encoded by the RAG1 gene. [5]
The RAG1 and RAG2 genes are largely conserved in humans. 55.99% and 55.98% of the encoded amino acids contain no reported variants, respectively. [6]
The protein encoded by this gene is involved in antibody and T-cell receptor V(D)J recombination. RAG-1 is involved in recognition of the DNA substrate, but stable binding and cleavage activity also requires RAG-2. The RAG-1/2 complex recognizes recombination signal sequences (RSSs) that flank the V, D and J regions in the genes that encode the heavy and light chains of antibodies and components of T-cell receptors. The complex binds to the RSSs and nicks the DNA. This leads to the removal of the intervening DNA and the eventual ligation of the V, D and J sequences. [7] Defects in this gene can cause several different diseases. [5]
Because of these effects, Rag1 deletion is used in mouse models of disease to impair T cell and B cell development, and functionally deletes mature T and B cells from the immune system. [8]
In humans, RAG deficiency was first recognised as a form of immune dysregulation known as Omenn syndrome. RAG deficiency is considered an autosomal recessive disease. The disorder is generally identified in infants. Complete loss-of-function in RAG1/2, the main components responsible for V(D)J recombination activity, produces severe immunodeficiency in humans. Hypomorphic RAG variants can retain partial recombination activity [9] and result in a distinct phenotype of combined immunodeficiency with granuloma and/or autoimmunity (CID-G/A), [10] [11] [12] as well as other milder forms, such as antibody deficiency, [13] Idiopathic CD4+ T lymphopenia [14] or vasculitis. [15] RAG deficiency can be measured by in vitro quantification of recombination activity. [16] [17] [18] 71 RAG1 and 39 RAG2 variants have been functionally assayed to date (2019) (less than 10% of the potential point mutations that may cause disease). However, top candidate variants have been ranked by their predicted clinical relevance. [6]
Immunoglobulin D (IgD) is an antibody isotype that makes up about 1% of proteins in the plasma membranes of immature B-lymphocytes where it is usually co-expressed with another cell surface antibody called IgM. IgD is also produced in a secreted form that is found in very small amounts in blood serum, representing 0.25% of immunoglobulins in serum. The relative molecular mass and half-life of secreted IgD is 185 kDa and 2.8 days, respectively. Secreted IgD is produced as a monomeric antibody with two heavy chains of the delta (δ) class, and two Ig light chains.
Immunodeficiency, also known as immunocompromisation, is a state in which the immune system's ability to fight infectious diseases and cancer is compromised or entirely absent. Most cases are acquired ("secondary") due to extrinsic factors that affect the patient's immune system. Examples of these extrinsic factors include HIV infection and environmental factors, such as nutrition. Immunocompromisation may also be due to genetic diseases/flaws such as SCID.
Omenn syndrome is an autosomal recessive severe combined immunodeficiency. It is associated with hypomorphic missense mutations in immunologically relevant genes of T-cells such as recombination activating genes, Interleukin-7 receptor-α (IL7Rα), DCLRE1C-Artemis, RMRP-CHH, DNA-Ligase IV, common gamma chain, WHN-FOXN1, ZAP-70 and complete DiGeorge syndrome. It is fatal without treatment.
Activation-induced cytidine deaminase, also known as AICDA, AID and single-stranded DNA cytosine deaminase, is a 24 kDa enzyme which in humans is encoded by the AICDA gene. It creates mutations in DNA by deamination of cytosine base, which turns it into uracil. In other words, it changes a C:G base pair into a U:G mismatch. The cell's DNA replication machinery recognizes the U as a T, and hence C:G is converted to a T:A base pair. During germinal center development of B lymphocytes, AID also generates other types of mutations, such as C:G to A:T. The mechanism by which these other mutations are created is not well understood. It is a member of the APOBEC family.
In immunology, central tolerance is the process of eliminating any developing T or B lymphocytes that are autoreactive, i.e. reactive to the body itself. Through elimination of autoreactive lymphocytes, tolerance ensures that the immune system does not attack self peptides. Lymphocyte maturation occurs in primary lymphoid organs such as the bone marrow and the thymus. In mammals, B cells mature in the bone marrow and T cells mature in the thymus.
V(D)J recombination is the mechanism of somatic recombination that occurs only in developing lymphocytes during the early stages of T and B cell maturation. It results in the highly diverse repertoire of antibodies/immunoglobulins and T cell receptors (TCRs) found in B cells and T cells, respectively. The process is a defining feature of the adaptive immune system.
X-linked severe combined immunodeficiency (X-SCID) is an immunodeficiency disorder in which the body produces very few T cells and NK cells.
Selective immunoglobulin A (IgA) deficiency (SIgAD) is a kind of immunodeficiency, a type of hypogammaglobulinemia. People with this deficiency lack immunoglobulin A (IgA), a type of antibody that protects against infections of the mucous membranes lining the mouth, airways, and digestive tract. It is defined as an undetectable serum IgA level in the presence of normal serum levels of IgG and IgM, in persons older than 4 years. It is the most common of the primary antibody deficiencies. Most such persons remain healthy throughout their lives and are never diagnosed.
Complement C2 is a protein that in humans is encoded by the C2 gene. The protein encoded by this gene is part of the classical pathway of the complement system, acting as a multi-domain serine protease. Deficiency of C2 has been associated with certain autoimmune diseases.
Bruton's tyrosine kinase, also known as tyrosine-protein kinase BTK, is a tyrosine kinase that is encoded by the BTK gene in humans. BTK plays a crucial role in B cell development.
Hyper IgM syndrome is a rare primary immune deficiency disorders characterized by low or absent levels of serum IgG, IgA, IgE and normal or increased levels of serum IgM.
Primary immunodeficiencies are disorders in which part of the body's immune system is missing or does not function normally. To be considered a primary immunodeficiency (PID), the immune deficiency must be inborn, not caused by secondary factors such as other disease, drug treatment, or environmental exposure to toxins. Most primary immunodeficiencies are genetic disorders; the majority are diagnosed in children under the age of one, although milder forms may not be recognized until adulthood. While there are over 430 recognized inborn errors of immunity (IEIs) as of 2019, the vast majority of which are PIDs, most are very rare. About 1 in 500 people in the United States are born with a primary immunodeficiency. Immune deficiencies can result in persistent or recurring infections, auto-inflammatory disorders, tumors, and disorders of various organs. There are currently limited treatments available for these conditions; most are specific to a particular type of PID. Research is currently evaluating the use of stem cell transplants (HSCT) and experimental gene therapies as avenues for treatment in limited subsets of PIDs.
The recombination-activating genes (RAGs) encode parts of a protein complex that plays important roles in the rearrangement and recombination of the genes encoding immunoglobulin and T cell receptor molecules. There are two recombination-activating genes RAG1 and RAG2, whose cellular expression is restricted to lymphocytes during their developmental stages. The enzymes encoded by these genes, RAG-1 and RAG-2, are essential to the generation of mature B cells and T cells, two types of lymphocyte that are crucial components of the adaptive immune system.
Recombination activating gene 2protein is a lymphocyte-specific protein encoded by RAG2 gene on human chromosome 11. Together with RAG1 protein, RAG2 forms a V(D)J recombinase, a protein complex required for the process of V(D)J recombination during which the variable regions of immunoglobulin and T cell receptor genes are assembled in developing B and T lymphocytes. Therefore, RAG2 is essential for generation of mature B and T lymphocytes.
Interleukin-2 receptor alpha chain is a protein involved in assembly of high-affinity Interleukin-2 receptor, consisting of alpha (IL2RA), beta (IL2RB) and the common gamma chain (IL2RG). As the name indicates, this receptor interacts with pleiotropic cytokine called Interleukin-2, which effect is mainly important for immune homeostasis.
Humoral immune deficiencies are conditions which cause impairment of humoral immunity, which can lead to immunodeficiency. It can be mediated by insufficient number or function of B cells, the plasma cells they differentiate into, or the antibody secreted by the plasma cells. The most common such immunodeficiency is inherited selective IgA deficiency, occurring between 1 in 100 and 1 in 1000 persons, depending on population. They are associated with increased vulnerability to infection, but can be difficult to detect in the absence of infection.
Recombination signal sequences are conserved sequences of noncoding DNA that are recognized by the RAG1/RAG2 enzyme complex during V(D)J recombination in immature B cells and T cells. Recombination signal sequences guide the enzyme complex to the V, D, and J gene segments that will undergo recombination during the formation of the heavy and light-chain variable regions in T-cell receptors and immunoglobulin molecules.
Tetratricopeptide repeat domain 7A (TTC7A) is a protein that in humans is encoded by the TTC7A gene.
Deficiency of Adenosine deaminase 2 (DADA2) is a monogenic disease associated with systemic inflammation and vasculopathy that affects a wide variety of organs in different patients. As a result, it is hard to characterize a patient with this disorder. Manifestations of the disease include but are not limited to recurrent fever, livedoid rash, various cytopenias, stroke, immunodeficiency, and bone marrow failure. Symptoms often onset during early childhood, but some cases have been discovered as late as 65 years old.
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