X-SCID
Encyclopedia
X-linked severe combined immunodeficiency (X-SCID) is an immunodeficiency
disorder that affects lymphocytes. It is a recessive trait stemming from a defective version of the gene responsible for the functionality of the Interleukin 2
receptor (IL2RG).
, an inflammation of the lung which produces common symptoms such as cough, fever, chills, and shortness of breath. In addition, moniliasis, a type of fungal infection, is a telltale sign of X-SCID. Moniliasis involves moist areas of the body such as skin, the mouth, respiratory tract, and vagina. Symptoms of moniliasis include difficulty in swallowing, pain on swallowing and oral lesions. Recurrent eczema
-like rashes are also a common symptom. X-SCID is usually fatal in the first years of life.
Even though seeing this type in females is extremely rare, the mutation in both genes can cause a female to develop this x-linked disorder.
. The gene IL2RG codes for the common gamma chain
protein, which is a common subunit of the individual receptors for Interleukin 2
, Interleukin 4
, Interleukin 7
, Interleukin 9
, Interleukin 15
and Interleukin 21
. Signalling from these receptors normally promotes growth and differentiation of T-cells, B cells, natural killer cells, glial cells, and cells of the monocyte
lineage, depending on the cell type and receptor activated. This gene is mutated in X-SCID. Its mutation is caused by large, or even single nucleotide, deletions in the IL2RG gene, that disable the common gamma chain
so that it is unable to bind with other receptor subunits and signal cytokine activation. This change prevents the T-lymphocytes from signaling other cells, like B-lymphocytes and natural killer cells. Because these cells never receive these signals, they can never mature and differentiate into full grown immune cells. The gene is located on Xq13, with a DNA length of 4.2 kb. Analysis has shown that the mRNA length is 3.6 kb long. IL2RG has 369 amino acids, and contains eight exons and seven introns.
There are also tests of lymphocyte function. These tests introduce agents to the immune system and observation, one can see how the lymphocytes react. Antibody responses to introduced vaccines and infections are absent, and T-cell responses to mitogens, substances that stimulate lymphocyte transformation, are deficient. Immunoglobulins, substances that aid in fighting off infections, are very low. Also, the thymic shadow is absent on chest X-rays.
Since the mutation in X-SCID is X-linked, there are genetic tests for detecting carriers in XSCID pedigrees. One method is to look for family-specific IL2RG mutations. Finally, if none of those options are available, there is an unusual pattern of nonrandom X-chromosome inactivation on lymphocytes in carriers, thus looking for such inactivation would prove useful.
, an organ in which lymphocytes thrive and later become T-cells. There is a lack of delayed hypersensitivity, sensitivity regulated by T-lymphocytes.
In particular, IL2 promotes lymphocyte growth and differentiation. This process happens after interaction with its receptors (IL2R) which has three subunits, to which only its third, the gamma chain, is of importance. The gamma chain subunit is known as IL2RG, and is necessary of the function of IL2 receptors. Thus, a mutation in IL2RG results in a synergistic effect: a lack in the growth and differentiation in lymphocytes.
Gene therapy is also available to replace the mutant allele. Though, this process can be achieved through various processes, it has been successful in treating X-SCID by insertion of functional, healthy genes with a retrovirus
. This, coupled with the bone marrow stem cells, has been successful in treating individuals with X-SCID. Although over 10 children have now been cured almost completely of X-SCID, four of the children have gone on to develop leukemia probably as a direct result of the therapy.
Immunodeficiency
Immunodeficiency is a state in which the immune system's ability to fight infectious disease is compromised or entirely absent. Immunodeficiency may also decrease cancer immunosurveillance. Most cases of immunodeficiency are acquired but some people are born with defects in their immune system,...
disorder that affects lymphocytes. It is a recessive trait stemming from a defective version of the gene responsible for the functionality of the Interleukin 2
Interleukin 2
Interleukin-2 is an interleukin, a type of cytokine immune system signaling molecule, which is a leukocytotrophic hormone that is instrumental in the body's natural response to microbial infection and in discriminating between foreign and self...
receptor (IL2RG).
Symptoms
Persons afflicted with X-SCID often have infections very early in life, before three months of age. This is followed by pneumonitisPneumonitis
Pneumonitis or pulmonitis is a general term that refers to inflammation of lung tissue.Pneumonia is pneumonitis combined with consolidation and exudation...
, an inflammation of the lung which produces common symptoms such as cough, fever, chills, and shortness of breath. In addition, moniliasis, a type of fungal infection, is a telltale sign of X-SCID. Moniliasis involves moist areas of the body such as skin, the mouth, respiratory tract, and vagina. Symptoms of moniliasis include difficulty in swallowing, pain on swallowing and oral lesions. Recurrent eczema
Eczema
Eczema is a form of dermatitis, or inflammation of the epidermis . In England, an estimated 5.7 million or about one in every nine people have been diagnosed with the disease by a clinician at some point in their lives.The term eczema is broadly applied to a range of persistent skin conditions...
-like rashes are also a common symptom. X-SCID is usually fatal in the first years of life.
Genetics
X-SCID is X-linked mutation, which means males born from a female carrier (either heterozygous or homozygous), will inherit X-SCID, and thus, express it. Many times, X-linked mutations can be passed by a healthy, unaffected mother. A heterozygous woman carrier will have a 50% chance of transmitting the disease-causing mutation. Females who are heterozygous are carriers, but will not be affected.Even though seeing this type in females is extremely rare, the mutation in both genes can cause a female to develop this x-linked disorder.
Molecular biology
Interleukins are produced by lymphocytes, among other cell types, and are released in response to antigenic and non-antigenic stimuliStimulus (physiology)
In physiology, a stimulus is a detectable change in the internal or external environment. The ability of an organism or organ to respond to external stimuli is called sensitivity....
. The gene IL2RG codes for the common gamma chain
Common gamma chain
The common gamma chain , also known as interleukin-2 receptor subunit gamma or IL-2RG, is a cytokine receptor sub-unit that is common to the receptor complexes for at least six different interleukin receptors: IL-2, IL-4, IL-7, IL-9, IL-15 and interleukin-21 receptor...
protein, which is a common subunit of the individual receptors for Interleukin 2
Interleukin 2
Interleukin-2 is an interleukin, a type of cytokine immune system signaling molecule, which is a leukocytotrophic hormone that is instrumental in the body's natural response to microbial infection and in discriminating between foreign and self...
, Interleukin 4
Interleukin 4
Interleukin-4, abbreviated IL-4, is a cytokine that induces differentiation of naive helper T cells to Th2 cells. Upon activation by IL-4, Th2 cells subsequently produce additional IL-4. The cell that initially produces IL-4, thus inducing Th0 differentiation, has not been identified, but recent...
, Interleukin 7
Interleukin 7
IL-7 a hematopoietic growth factor secreted by stromal cells in the red marrow and thymus. It is also produced by keratinocytes, dendritic cells, hepatocytes, neurons, and epithelial cells but is not produced by lymphocytes.- Genetics :...
, Interleukin 9
Interleukin 9
Interleukin 9, also known as IL9, is a cytokine belonging to the group of interleukins.-Further reading:...
, Interleukin 15
Interleukin 15
Interleukin 15 is a cytokine with structural similarity to IL-2. Like IL-2, IL-15 binds to and signals through the IL-2/IL-15 beta chain and the common gamma chain . IL-15 is secreted by mononuclear phagocytes following infection by virus...
and Interleukin 21
Interleukin 21
Interleukin-21 is a protein that in humans is encoded by the IL21 gene.Interleukin 21 is a cytokine that has potent regulatory effects on cells of the immune system, including natural killer cells and cytotoxic T cells that can destroy virally infected or cancerous cells...
. Signalling from these receptors normally promotes growth and differentiation of T-cells, B cells, natural killer cells, glial cells, and cells of the monocyte
Monocyte
Monocytes are a type of white blood cell and are part of the innate immune system of vertebrates including all mammals , birds, reptiles, and fish. Monocytes play multiple roles in immune function...
lineage, depending on the cell type and receptor activated. This gene is mutated in X-SCID. Its mutation is caused by large, or even single nucleotide, deletions in the IL2RG gene, that disable the common gamma chain
Common gamma chain
The common gamma chain , also known as interleukin-2 receptor subunit gamma or IL-2RG, is a cytokine receptor sub-unit that is common to the receptor complexes for at least six different interleukin receptors: IL-2, IL-4, IL-7, IL-9, IL-15 and interleukin-21 receptor...
so that it is unable to bind with other receptor subunits and signal cytokine activation. This change prevents the T-lymphocytes from signaling other cells, like B-lymphocytes and natural killer cells. Because these cells never receive these signals, they can never mature and differentiate into full grown immune cells. The gene is located on Xq13, with a DNA length of 4.2 kb. Analysis has shown that the mRNA length is 3.6 kb long. IL2RG has 369 amino acids, and contains eight exons and seven introns.
Diagnosis
Diagnosis of X-SCID is possible through observation and investigation of the immune system. A healthy immune system should contain large amounts of lymphocytes, but individuals with X-SCID will contain unusually small amounts of T-cells, non-functional B-cells, and no natural killer cells.There are also tests of lymphocyte function. These tests introduce agents to the immune system and observation, one can see how the lymphocytes react. Antibody responses to introduced vaccines and infections are absent, and T-cell responses to mitogens, substances that stimulate lymphocyte transformation, are deficient. Immunoglobulins, substances that aid in fighting off infections, are very low. Also, the thymic shadow is absent on chest X-rays.
Since the mutation in X-SCID is X-linked, there are genetic tests for detecting carriers in XSCID pedigrees. One method is to look for family-specific IL2RG mutations. Finally, if none of those options are available, there is an unusual pattern of nonrandom X-chromosome inactivation on lymphocytes in carriers, thus looking for such inactivation would prove useful.
Pathophysiology
X-SCID is characterized by an abnormally low number of lymphocytes and susceptibility to various infections. Susceptibility is in part due to the atrophy of the thymusThymus
The thymus is a specialized organ of the immune system. The thymus produces and "educates" T-lymphocytes , which are critical cells of the adaptive immune system....
, an organ in which lymphocytes thrive and later become T-cells. There is a lack of delayed hypersensitivity, sensitivity regulated by T-lymphocytes.
In particular, IL2 promotes lymphocyte growth and differentiation. This process happens after interaction with its receptors (IL2R) which has three subunits, to which only its third, the gamma chain, is of importance. The gamma chain subunit is known as IL2RG, and is necessary of the function of IL2 receptors. Thus, a mutation in IL2RG results in a synergistic effect: a lack in the growth and differentiation in lymphocytes.
Treatment
Bone marrow transplantation is standard procedure for immune reconstitution. Though the BMT process is ‘common’, it requires immunodeficiency specialists for maximum potential. Infants, in which there is no donor, can undergo BMT, only if the marrow is first depleted of its mature T-cells. The T-cells must be depleted in order to remove mismatched T-cells which would cause a reaction in the infant.Gene therapy is also available to replace the mutant allele. Though, this process can be achieved through various processes, it has been successful in treating X-SCID by insertion of functional, healthy genes with a retrovirus
Retrovirus
A retrovirus is an RNA virus that is duplicated in a host cell using the reverse transcriptase enzyme to produce DNA from its RNA genome. The DNA is then incorporated into the host's genome by an integrase enzyme. The virus thereafter replicates as part of the host cell's DNA...
. This, coupled with the bone marrow stem cells, has been successful in treating individuals with X-SCID. Although over 10 children have now been cured almost completely of X-SCID, four of the children have gone on to develop leukemia probably as a direct result of the therapy.