Severe combined immunodeficiency
Encyclopedia
Severe combined immunodeficiency (SCID), (also known as "Alymphocytosis," "Glanzmann–Riniker syndrome," "Severe mixed immunodeficiency syndrome," and "Thymic alymphoplasia") is a genetic disorder in which both "arms" (B cell
s and T cell
s) of the adaptive immune system
are impaired due to a defect in one of several possible genes. SCID is a severe form of heritable immunodeficiency
. It is also known as the "bubble boy
" disease because its victims are extremely vulnerable to infectious diseases and some of them, such as David Vetter
, become famous for living in a sterile environment.
SCID is the result of an immune system so highly compromised that it is considered almost absent.
Chronic diarrhea, ear infections, recurrent Pneumocystis jirovecii
pneumonia, and profuse oral candidiasis
commonly occur. These babies, if untreated, usually die within 1 year due to severe, recurrent infections unless they have undergone successful Hematopoietic stem cell transplantation.
Recent studies indicate that one in every 2,500 children in the Navajo
population inherit severe combined immunodeficiency. This condition is a significant cause of illness and death among Navajo children. Ongoing research reveals a similar genetic pattern among the related Apache
people.
Despite these pilot programs, standard testing for SCID is not currently available in newborns due to the diversity of the genetic defect. Some SCID can be detected by sequencing fetal DNA if a known history of the disease exists. Otherwise, SCID is not diagnosed until about six months of age, usually indicated by recurrent infections. The delay in detection is because newborns carry their mother's antibodies
for the first few weeks of life and SCID babies look normal.
ation, which has been successful using either a matched related or unrelated donor, or a half-matched donor, who would be either parent. The half-matched type of transplant is called haploidentical and was perfected by Memorial Sloan Kettering Cancer Center in New York and also Duke University Medical Center which currently does the highest number of these transplants of any center in the world. David Vetter
, the original "bubble boy", had one of the first transplantations but eventually died because of an unscreened virus, Epstein-Barr (tests were not available at the time), in his newly transplanted bone marrow from his sister. Today, transplants done in the first three months of life have a high success rate. Physicians have also had some success with in utero transplants done before the child is born and also by using cord blood which is rich in stem cells.
More recently gene therapy
has been attempted as an alternative to the bone marrow transplant. Transduction
of the missing gene to hematopoietic stem cells using viral
vector
s is being tested in ADA SCID and X-linked SCID. In 1990, four-year-old Ashanthi DeSilva became the first patient to undergo successful gene therapy. Researchers collected samples of Ashanthi's blood, isolated some of her white blood cells, and used a virus to insert a healthy adenosine deaminase (ADA) gene into them. These cells were then injected back into her body, and began to express a normal enzyme. This, augmented by weekly injections of ADA, corrected her deficiency.
In 2000, a gene therapy "success" resulted in SCID patients with a functional immune system. These trials were stopped when it was discovered that two of ten patients in one trial had developed leukemia
resulting from the insertion of the gene-carrying retrovirus near an oncogene
. In 2007, four of the ten patients have developed leukemias. Work is now focusing on correcting the gene without triggering an oncogene. No leukemia cases have yet been seen in trials of ADA-SCID, which does not involve the gamma c gene that may be oncogenic when expressed by a retrovirus
.
Trial treatments of SCID have been gene therapy's first success; since 1999, gene therapy has restored the immune systems of at least 17 children with two forms (ADA-SCID and X-SCID) of the disorder.
An animal variation of the disease, an autosomal
recessive gene with clinical signs similar to the human condition, also affects the Arabian horse
. In horses, the condition remains a fatal disease, as the animal inevitably succumbs to an opportunistic infection within the first four to six months of life. However, carriers, who themselves are not affected by the disease, can be detected with a DNA
test. Thus careful breeding practices can avoid the risk of an affected foal
being produced.
Another animal with well-characterized SCID pathology is the dog. There are two known forms, an X-linked SCID in Basset Hound
s that has similar ontology to X-SCID
in humans, and an autosomal recessive form seen in one line of Jack Russell Terrier
s that is similar to SCID in Arabian horses and mice.
B cell
B cells are lymphocytes that play a large role in the humoral immune response . The principal functions of B cells are to make antibodies against antigens, perform the role of antigen-presenting cells and eventually develop into memory B cells after activation by antigen interaction...
s and T cell
T cell
T cells or T lymphocytes belong to a group of white blood cells known as lymphocytes, and play a central role in cell-mediated immunity. They can be distinguished from other lymphocytes, such as B cells and natural killer cells , by the presence of a T cell receptor on the cell surface. They are...
s) of the adaptive immune system
Adaptive immune system
The adaptive immune system is composed of highly specialized, systemic cells and processes that eliminate or prevent pathogenic growth. Thought to have arisen in the first jawed vertebrates, the adaptive or "specific" immune system is activated by the “non-specific” and evolutionarily older innate...
are impaired due to a defect in one of several possible genes. SCID is a severe form of heritable immunodeficiency
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,...
. It is also known as the "bubble boy
Boy in the bubble
Bubble boy, boy in the bubble and boy in the plastic bubble are colloquialisms used to describe a person who must live in a microbiologically sterile environment for medical reasons...
" disease because its victims are extremely vulnerable to infectious diseases and some of them, such as David Vetter
David Vetter
David Phillip Vetter was a boy from Shenandoah, Texas, United States who suffered from a rare genetic disease now known as severe combined immune deficiency syndrome . Forced to live in a sterile environment, he became popular with the media as the boy in the plastic bubble...
, become famous for living in a sterile environment.
SCID is the result of an immune system so highly compromised that it is considered almost absent.
Chronic diarrhea, ear infections, recurrent Pneumocystis jirovecii
Pneumocystis pneumonia
Pneumocystis pneumonia or pneumocystosis is a form of pneumonia, caused by the yeast-like fungus Pneumocystis jirovecii...
pneumonia, and profuse oral candidiasis
Candidiasis
Thrush redirects here. For the hoof infection see Thrush .Candidiasis or thrush is a fungal infection of any of the Candida species , of which Candida albicans is the most common...
commonly occur. These babies, if untreated, usually die within 1 year due to severe, recurrent infections unless they have undergone successful Hematopoietic stem cell transplantation.
Prevalence
The most commonly quoted figure for the prevalence of SCID is around 1 in 100,000 births, although this is regarded by some to be an underestimate of the true prevalence; and a figure of about 1 in 65,000 live births has been reported for Australia.Recent studies indicate that one in every 2,500 children in the Navajo
Navajo Nation
The Navajo Nation is a semi-autonomous Native American-governed territory covering , occupying all of northeastern Arizona, the southeastern portion of Utah, and northwestern New Mexico...
population inherit severe combined immunodeficiency. This condition is a significant cause of illness and death among Navajo children. Ongoing research reveals a similar genetic pattern among the related Apache
Apache
Apache is the collective term for several culturally related groups of Native Americans in the United States originally from the Southwest United States. These indigenous peoples of North America speak a Southern Athabaskan language, which is related linguistically to the languages of Athabaskan...
people.
Types
| Type | Description >- | X-linked severe combined immunodeficiency X-SCID X-linked severe combined immunodeficiency 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 .... |
mutation Mutation In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic... s in the gene encoding 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... (γc), a protein that is shared by the receptors for interleukin Interleukin Interleukins are a group of cytokines that were first seen to be expressed by white blood cells . The term interleukin derives from "as a means of communication", and "deriving from the fact that many of these proteins are produced by leukocytes and act on leukocytes"... s IL-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... , IL-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... , IL-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 :... , IL-9 Interleukin 9 Interleukin 9, also known as IL9, is a cytokine belonging to the group of interleukins.-Further reading:... , IL-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 IL-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... . These interleukins and their receptors are involved in the development and differentiation of T and B cells. Because the common gamma chain is shared by many interleukin receptors, mutations that result in a non-functional common gamma chain cause widespread defects in interleukin signalling. The result is a near complete failure of the immune system to develop and function, with low or absent T cells and NK cells and non-functional B cells. The common gamma chain is encoded by the gene IL-2 receptor gamma, or IL-2Rγ, which is located on the X-chromosome. For this reason, immunodeficiency caused by mutations in IL-2Rγ is known as X-linked severe combined immunodeficiency. The condition is inherited in an X-linked recessive X-linked recessive X-linked recessive inheritance is a mode of inheritance in which a mutation in a gene on the X chromosome causes the phenotype to be expressed in males and in females who are homozygous for the gene mutation X-linked recessive inheritance is a mode of inheritance in which a mutation in a gene on... pattern. >- | Adenosine deaminase deficiency Adenosine deaminase deficiency Adenosine deaminase deficiency, also called ADA deficiency or ADA-SCID, is an autosomal recessive metabolic disorder that causes immunodeficiency. It occurs in fewer than one in 100,000 live births worldwide.... |
adenosine deaminase Adenosine deaminase Adenosine deaminase is an enzyme involved in purine metabolism. It is needed for the breakdown of adenosine from food and for the turnover of nucleic acids in tissues.-Reactions:... (ADA), necessary for the breakdown of purine Purine A purine is a heterocyclic aromatic organic compound, consisting of a pyrimidine ring fused to an imidazole ring. Purines, including substituted purines and their tautomers, are the most widely distributed kind of nitrogen-containing heterocycle in nature.... s. Lack of ADA causes accumulation of dATP. This metabolite will inhibit the activity of ribonucleotide reductase, the enzyme that reduces ribonucleotides to generate deoxyribonucleotides. The effectiveness of the immune system depends upon lymphocyte proliferation and hence dNTP synthesis. Without functional ribonucleotide reductase, lymphocyte proliferation is inhibited and the immune system is compromised. >- | Omenn syndrome Omenn syndrome Omenn syndrome is an autosomal recessive severe combined immunodeficiency associated with mutations in the recombination activating genes , affecting circulating levels of both B-cells and T-cells.-Symptoms:... |
V(D)J recombination V(D)J recombination VJ recombination, also known as somatic recombination, is a mechanism of genetic recombination in the early stages of immunoglobulin and T cell receptors production of the immune system... , the process by which segments of a B cell B cell B cells are lymphocytes that play a large role in the humoral immune response . The principal functions of B cells are to make antibodies against antigens, perform the role of antigen-presenting cells and eventually develop into memory B cells after activation by antigen interaction... or T cell T cell T cells or T lymphocytes belong to a group of white blood cells known as lymphocytes, and play a central role in cell-mediated immunity. They can be distinguished from other lymphocytes, such as B cells and natural killer cells , by the presence of a T cell receptor on the cell surface. They are... 's DNA are rearranged to create a new T cell receptor or B cell receptor (and, in the B cell's case, the template for antibodies). Certain mutations of the RAG-1 or RAG-2 genes prevent V(D)J recombination V(D)J recombination VJ recombination, also known as somatic recombination, is a mechanism of genetic recombination in the early stages of immunoglobulin and T cell receptors production of the immune system... , causing SCID. >- | Bare lymphocyte syndrome Bare lymphocyte syndrome Bare lymphocyte syndrome is a condition caused by mutations in certain genes of the major histocompatibility complex. It is a form of severe combined immunodeficiency.-Presentation:... |
MHC class II MHC class II MHC Class II molecules are found only on a few specialized cell types, including macrophages, dendritic cells and B cells, all of which are professional antigen-presenting cells .... is not expressed on the cell surface of all antigen presenting cells. Autosomal recessive. The MHC-II gene regulatory proteins are what is altered, not the MHC-II protein itself. >- | JAK3 |
c signal. Mutation of its gene also causes SCID. >- | Artemis/DCLRE1C |
Although researchers have identified about a dozen genes that cause SCID, the Navajo and Apache population has the most severe form of the disorder. This is due to the lack of a gene designated Artemis DCLRE1C Protein artemis is a protein that in humans is encoded by the DCLRE1C gene.- Function :This gene encodes a nuclear protein that is involved in VJ recombination and DNA repair... . Without the gene, children's bodies are unable to repair DNA DNA Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in... or develop disease-fighting cells. |
Detection
Several US states are performing pilot studies to diagnose SCID in newborns through the use of T-cell recombinant excision circles. Wisconsin and Massachusetts (as of February 1, 2009) screen newborns for SCID.Despite these pilot programs, standard testing for SCID is not currently available in newborns due to the diversity of the genetic defect. Some SCID can be detected by sequencing fetal DNA if a known history of the disease exists. Otherwise, SCID is not diagnosed until about six months of age, usually indicated by recurrent infections. The delay in detection is because newborns carry their mother's antibodies
Antibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
for the first few weeks of life and SCID babies look normal.
Treatment
The most common treatment for SCID is bone marrow transplantBone marrow transplant
Hematopoietic stem cell transplantation is the transplantation of multipotent hematopoietic stem cell or blood, usually derived from bone marrow, peripheral blood stem cells, or umbilical cord blood...
ation, which has been successful using either a matched related or unrelated donor, or a half-matched donor, who would be either parent. The half-matched type of transplant is called haploidentical and was perfected by Memorial Sloan Kettering Cancer Center in New York and also Duke University Medical Center which currently does the highest number of these transplants of any center in the world. David Vetter
David Vetter
David Phillip Vetter was a boy from Shenandoah, Texas, United States who suffered from a rare genetic disease now known as severe combined immune deficiency syndrome . Forced to live in a sterile environment, he became popular with the media as the boy in the plastic bubble...
, the original "bubble boy", had one of the first transplantations but eventually died because of an unscreened virus, Epstein-Barr (tests were not available at the time), in his newly transplanted bone marrow from his sister. Today, transplants done in the first three months of life have a high success rate. Physicians have also had some success with in utero transplants done before the child is born and also by using cord blood which is rich in stem cells.
More recently gene therapy
Gene therapy
Gene therapy is the insertion, alteration, or removal of genes within an individual's cells and biological tissues to treat disease. It is a technique for correcting defective genes that are responsible for disease development...
has been attempted as an alternative to the bone marrow transplant. Transduction
Transduction (genetics)
Transduction is the process by which DNA is transferred from one bacterium to another by a virus. It also refers to the process whereby foreign DNA is introduced into another cell via a viral vector. Transduction does not require cell-to-cell contact , and it is DNAase resistant...
of the missing gene to hematopoietic stem cells using viral
Virus
A virus is a small infectious agent that can replicate only inside the living cells of organisms. Viruses infect all types of organisms, from animals and plants to bacteria and archaea...
vector
Vector (molecular biology)
In molecular biology, a vector is a DNA molecule used as a vehicle to transfer foreign genetic material into another cell. The four major types of vectors are plasmids, viruses, cosmids, and artificial chromosomes...
s is being tested in ADA SCID and X-linked SCID. In 1990, four-year-old Ashanthi DeSilva became the first patient to undergo successful gene therapy. Researchers collected samples of Ashanthi's blood, isolated some of her white blood cells, and used a virus to insert a healthy adenosine deaminase (ADA) gene into them. These cells were then injected back into her body, and began to express a normal enzyme. This, augmented by weekly injections of ADA, corrected her deficiency.
In 2000, a gene therapy "success" resulted in SCID patients with a functional immune system. These trials were stopped when it was discovered that two of ten patients in one trial had developed leukemia
Leukemia
Leukemia or leukaemia is a type of cancer of the blood or bone marrow characterized by an abnormal increase of immature white blood cells called "blasts". Leukemia is a broad term covering a spectrum of diseases...
resulting from the insertion of the gene-carrying retrovirus near an oncogene
Oncogene
An oncogene is a gene that has the potential to cause cancer. In tumor cells, they are often mutated or expressed at high levels.An oncogene is a gene found in the chromosomes of tumor cells whose activation is associated with the initial and continuing conversion of normal cells into cancer...
. In 2007, four of the ten patients have developed leukemias. Work is now focusing on correcting the gene without triggering an oncogene. No leukemia cases have yet been seen in trials of ADA-SCID, which does not involve the gamma c gene that may be oncogenic when expressed by 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...
.
Trial treatments of SCID have been gene therapy's first success; since 1999, gene therapy has restored the immune systems of at least 17 children with two forms (ADA-SCID and X-SCID) of the disorder.
SCID in animals
SCID mice were and still are used in disease, vaccine, and transplant research, especially as animal models for testing the safety of new vaccines or therapeutic agents in people with weakened immune systems.An animal variation of the disease, an autosomal
Autosome
An autosome is a chromosome that is not a sex chromosome, or allosome; that is to say, there is an equal number of copies of the chromosome in males and females. For example, in humans, there are 22 pairs of autosomes. In addition to autosomes, there are sex chromosomes, to be specific: X and Y...
recessive gene with clinical signs similar to the human condition, also affects the Arabian horse
Arabian horse
The Arabian or Arab horse is a breed of horse that originated on the Arabian Peninsula. With a distinctive head shape and high tail carriage, the Arabian is one of the most easily recognizable horse breeds in the world. It is also one of the oldest breeds, with archaeological evidence of horses...
. In horses, the condition remains a fatal disease, as the animal inevitably succumbs to an opportunistic infection within the first four to six months of life. However, carriers, who themselves are not affected by the disease, can be detected with a DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
test. Thus careful breeding practices can avoid the risk of an affected foal
Foal
A foal is an equine, particularly a horse, that is one year old or younger. More specific terms are colt for a male foal and filly for a female foal, but these terms are used until the horse is age three or four. When the foal is nursing from its dam , it may also be called a suckling...
being produced.
Another animal with well-characterized SCID pathology is the dog. There are two known forms, an X-linked SCID in Basset Hound
Basset Hound
The Basset Hound is a short-legged breed of dog of the hound family. They are scent hounds, bred to hunt rabbits and hare by scent. Their sense of smell for tracking is second only to that of the Bloodhound....
s that has similar ontology to X-SCID
X-SCID
X-linked severe combined immunodeficiency 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 ....
in humans, and an autosomal recessive form seen in one line of Jack Russell Terrier
Jack Russell Terrier
The Jack Russell terrier is a small terrier that has its origins in fox hunting. It is principally white-bodied smooth, rough or broken-coated which is commonly confused with the Parson Russell terrier and the Russell terrier with the term "Jack Russell" commonly misapplied to other small white...
s that is similar to SCID in Arabian horses and mice.