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severe combined immunodeficiency

 
Medical Encyclopedia: Severe Combined Immunodeficiency
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Diagnosis
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Definition

Severe combined immunodeficiency (SCID) is the most serious human immunodeficiency disorder(s). It is a group of congenital disorders in which both the humoral part of the patient's immune system and the cells involved in immune responses fail to work properly. Children with SCID are vulnerable to recurrent severe infections, retarded growth, and early death.

Description

SCID is thought to affect between one in every 100,000 persons, and one in every 500,000 infants. Several different immune system disorders are currently grouped under SCID:

  • Swiss-type agammaglobulinemia. This was the first type of SCID discovered, in Switzerland in the 1950s.
  • Adenosine deaminase deficiency (ADA). About 50% of SCID cases are of this type. ADA deficiency leads to low levels of B and T cells in the child's immune system.
  • Autosomal recessive. About 40% of SCID cases are inherited from the parents in an autosomal recessive pattern.
  • Bare lymphocyte syndrome. In this form of SCID, the white blood cells (lymphocytes) in the baby's blood are missing certain proteins. Without these proteins, the lymphocytes cannot activate the T cells in the immune system.
  • SCID with leukopenia. Children with this form of SCID are lacking a type of white blood cell called a granulocyte.

In order to understand why SCID is considered the most severe immunodeficiency disorder, it is helpful to have an outline of the parts of the human immune system. It has three parts: cellular, humoral, and nonspecific. The cellular and humoral parts of the system are both needed to fight infections—they recognize disease agents and attack them. The cellular system is composed of many classes of T-lymphocytes (white blood cells that detect foreign invaders called antigens). The humoral system is made up of B cells, which are the only cells in the body that make antibodies. In SCID, neither the cellular nor the humoral part of the immune system is working properly.

— Rebecca J. Frey


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Dictionary: severe combined immunodeficiency
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n. (Abbr. SCID)
A usually fatal congenital disorder of the immune system in which the body is unable to produce enough B cells and T cells to resist infection.


Children's Health Encyclopedia: Severe Combined Immunodeficiency
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Definition

Severe combined immunodeficiency (SCID) is the most serious primary or congenital human immunodeficiency disorder. It is a group of congenital (present from birth) disorders in which the immune system does not work properly. Children with SCID are vulnerable to recurrent severe infections, retarded growth, and early death.

Description

The immune system is composed of elements that are needed for the body to fight infections by recognizing disease agents and attacking them. It includes many classes of T-lymphocytes (white blood cells that detect foreign proteins called antigens). It also includes B cells, which are the only cells in the body that make antibodies. Natural killer (NK) cells are cells that destroy infected cells. In children with SCID, the immune system does not function properly because T, B, and NK cells are either absent or defective. When the immune system does not function correctly, the child is left open to repeated severe diseases and infections.

Several different immune system disorders are grouped under SCID. These include the following:

  • X-linked: The most common form of SCID accounts for about half of all cases. Because this is an X-linked condition, it occurs only in boys. Children with X-linked SCID have low T-cell and natural killer (NK) cell levels but elevated B-cell levels.
  • Adenosine deaminase deficiency (ADA): About 20 percent of SCID cases are of this type. ADA deficiency leads to low levels of B and T cells in the child's immune system.
  • Janus Kinase 3 (Jak3) deficiency: This form of SCID accounts for about 6 percent of cases. There are very low levels of T and NK cells, or they are not present at all. There is an elevated level of B cells. In this form of SCID the lymphocyte or white blood evaluation is identical to X-linked SCID but is autosomal recessive and, therefore, occurs in girls and boys.

Demographics

The rate of SCID is not perfectly documented. It is estimated that it occurs in between one in 50,000 and one in 500,000 infants. It is about three times more common in boys than in girls.

Causes and Symptoms

SCID is an inherited disorder. In all forms of SCID, B and T cells are non-functioning. They may or may not be present in various forms of SCID, but they are always non-functioning. In some forms of SCID, NK cells are also absent or non-funtioning.

For the first few months after birth, a infant with SCID is often protected by antibodies acquired before birth from the mother's blood. As early as three months of age, however, the SCID child begins to suffer from mouth infections (thrush), chronic diarrhea, otitis media, and pulmonary infections, including pneumocystis pneumonia. The child loses weight, becomes very weak, and if untreated eventually dies from an opportunistic infection.

When to Call the Doctor

If a child has unusual infections, unusually severe infections, infections with unusual organisms, or unusual complications of usual infections, a doctor should be consulted to evaluate for possible immune deficiency. This is particularly important if there is a family history of immune deficiency.

Diagnosis

The first screening test for SCID is a white blood cell count with a count of the lymphocytes (differential) because in most forms of SCID the lymphocyte count will be very low. Blood tests can then be done to test for the numbers of B, T, and NK type lymphocytes. If the numbers of all of these cell types are normal and SCID is still suspected, more specialized tests can be done to test the lymphocyte cell functions. Rarely there are children with SCID who have normal lymphocyte numbers and nonfunctioning cells.

Treatment

Patients with SCID should be treated aggressively with antibiotics for any infection, and intravenous immunoglobulin should be given to replace the antibiotics the children cannot make, but these treatments cannot cure the disorder. Bone marrow transplants are as of 2004 regarded as one of the few effective standard treatments for most types of SCID. For those children with ADA deficiency, ADA infusions are the accepted treatment of choice. Up to 95 percent of children who are treated with bone marrow transplants, especially those who are treated before three months of age, survive.

Investigational Treatments

As an example of gene therapy for SCID children with ADA deficiency, the child receives periodic infusions of his or her own T cells corrected with a gene for ADA that has been implanted in an activated virus. This should allow these cells to function normally. Other types of SCID have been treated with gene therapy, but these procedures have been put on hold due to serious complications (malignancies). Researchers are as of 2004 also investigating treating SCID in the yet unborn fetus, which has been done successfully a few times.

Prognosis

There is no cure for SCID. Nearly all untreated patients die before age two, most before one year of age. Children who are treated with bone marrow transplants have a much better prognosis.

Prevention

There is no known way to prevent SCID. Genetic counseling is recommended for parents of a child with SCID who are considering having more children and for potential parents who have a family history of the disease and believe they may be carriers.

Parental Concerns

Without prompt treatment SCID is nearly always fatal. Treatment can be very successful if done early, preferably within the first three months of life. Research is continuing into in utero treatment options, and some in utero treatments have been successfully carried out, so fetal screening may be helpful if there is a possibility that the child has SCID.

Resources

Books

Parker, James N., and Philip M. Parker. The Official Parent's Sourcebook on Primary Immunodeficiency. Red Hill, Australia: Icon Health, 2002.

Organizations

Immune Deficiency Foundation. 40 W. Chesapeake Avenue Suite 308, Towson, MD 21204. Web site: www.primaryimmune.org.

International Patient Organization for Patients with Primary Immunodeficiencies. Alliance House, 12 Caxton Street, London SW1H 0QS. Web site: www.ipopi.org

Web Sites

Ballard, Barb. The SCID Homepage, September 2004. Available online at www.scid.net/ (accessed November 14, 2004).

[Article by: Tish Davidson, A.M. Rebecca J. Frey, PhD]


Veterinary Dictionary: SCID
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Severe combined immunodeficiency disease. See combined immune deficiency syndrome disease.

Wikipedia: Severe combined immunodeficiency
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Severe Combined Immune Deficiency
Classification and external resources
ICD-10 D81.0-D81.2
ICD-9 279.2
DiseasesDB 11978
eMedicine med/2214
MeSH D016511

Severe combined immunodeficiency (SCID), or Boy in the Bubble Syndrome, (also known as "Alymphocytosis," "Glanzmann–Riniker syndrome," "Severe mixed immunodeficiency syndrome," and "Thymic alymphoplasia"[1]) is a genetic disorder in which both "arms" (B cells and T cells) of the adaptive immune system are crippled, 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. The most famous case is the boy David Vetter.

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. However, treatment options are much improved since David Vetter.

Contents

Prevalence

Classical SCID has a reported incidence of about 1 in 65,000 live births in Australia.[2]

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.[3] Ongoing research reveals a similar genetic pattern among the related Apache people.[4]

Types

Type Description
X-linked severe combined immunodeficiency Most cases of SCID are due to mutations in the gene encoding the common gamma chain (γc), a protein that is shared by the receptors for interleukins IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21. 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. Therefore, immunodeficiency caused by mutations in IL-2Rγ is known as X-linked severe combined immunodeficiency. The condition is inherited in an X-linked recessive pattern.
Adenosine deaminase deficiency The second most common form of SCID after X-SCID is caused by a defective enzyme, adenosine deaminase (ADA), necessary for the breakdown of purines. 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 The manufacture of immunoglobulins requires recombinase enzymes derived from the recombination activating genes RAG-1 and RAG-2. These enzymes are involved in the first stage of V(D)J recombination, the process by which segments of a B cell or T cell'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, causing SCID.[5]
Bare lymphocyte syndrome MHC class II 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 Janus kinase-3 (JAK3) is an enzyme that mediates transduction downstream of the γc signal. Mutation of its gene also causes SCID.[6]
Artemis/DCLRE1C Mortan Cowan, MD, director of the Pediatric Bone Marrow Transplant Program at the University of California-San Francisco, noted that 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. Without the gene, children's bodies are unable to repair DNA or develop disease-fighting cells. [3][4]

Detection

Several US states are performing pilot studies to diagnose SCID in newborns through the use of T-cell recombinant excision circles.[citation needed] Wisconsin and Massachusetts (as of February 1, 2009) screen newborns for SCID.[7][8]

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.

Treatment

The most common treatment for SCID is bone marrow transplantation, 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.[9] 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 vectors is being tested in ADA SCID and X-linked SCID. The first gene therapy trials were performed in 1990, with peripheral T cells. In 2000, the first 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 [10]. 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 only 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

Main article: Severe combined immunodeficiency (non-human)

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 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.[11] 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.[12]

Another animal with well-characterized SCID pathology is the dog. There are two known forms, an X-linked SCID in Basset Hounds that has similar ontology to X-SCID in humans[13], and an autosomal recessive form seen in one line of Jack Russell Terriers that is similar to SCID in Arabian horses and mice.[14]

References

  1. ^ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 1-4160-2999-0. 
  2. ^ Yee A, De Ravin SS, Elliott E, Ziegler JB (2008). "Severe combined immunodeficiency: A national surveillance study". Pediatr Allergy Immunol 19: 080130211941085. doi:10.1111/j.1399-3038.2007.00646.x. PMID 18221464. http://www.blackwell-synergy.com/openurl?genre=article&sid=nlm:pubmed&issn=0905-6157&date=2008&volume=&issue=&spage=. 
  3. ^ a b "News From Indian Country - A rare and once-baffling disease forces Navajo parents to cope". http://indiancountrynews.net/index.php?option=com_content&task=view&id=2109&Itemid=1. Retrieved 2008-03-01. 
  4. ^ a b Li L, Moshous D, Zhou Y, et al. (2002). "A founder mutation in Artemis, an SNM1-like protein, causes SCID in Athabascan-speaking Native Americans". J. Immunol. 168 (12): 6323–9. PMID 12055248. http://www.jimmunol.org/cgi/pmidlookup?view=long&pmid=12055248. 
  5. ^ Haq IJ, Steinberg LJ, Hoenig M, et al. (2007). "GvHD-associated cytokine polymorphisms do not associate with Omenn syndrome rather than T-B- SCID in patients with defects in RAG genes". Clin. Immunol. 124 (2): 165–9. doi:10.1016/j.clim.2007.04.013. PMID 17572155. http://linkinghub.elsevier.com/retrieve/pii/S1521-6616(07)01181-3. 
  6. ^ Pesu M, Candotti F, Husa M, Hofmann SR, Notarangelo LD, O'Shea JJ (2005). "Jak3, severe combined immunodeficiency, and a new class of immunosuppressive drugs". Immunol. Rev. 203: 127–42. doi:10.1111/j.0105-2896.2005.00220.x. PMID 15661026. http://www.blackwell-synergy.com/openurl?genre=article&sid=nlm:pubmed&issn=0105-2896&date=2005&volume=203&spage=127. 
  7. ^ "Wisconsin First State in Nation to Screen All Newborns for Severe Combined Immune Deficiency (SCID) or "Bubble Boy Disease"". http://www.slh.wisc.edu/news/scid_080402.dot. 
  8. ^ "NEWBORN SCREENING FOR PRIMARY IMMUNODEFICIENCY DISEASE". http://www.cga.ct.gov/2008/rpt/2008-R-0564.htm. 
  9. ^ "Severe Combined Immunodeficiency (SCID): Immunodeficiency Disorders: Merck Manual Professional". http://www.merck.com/mmpe/sec13/ch164/ch164l.html. Retrieved 2008-03-01. 
  10. ^ Press release from the European Society of Gene Therapy
  11. ^ FOAL.org, an organization promoting research into genetic lethal diseases in horse
  12. ^ "The New DNA Test for Severe Combined Immunodeficiency (SCID) in Arabian Horses"
  13. ^ Henthorn PS, Somberg RL, Fimiani VM, Puck JM, Patterson DF, Felsburg PJ (1994). "IL-2R gamma gene microdeletion demonstrates that canine X-linked severe combined immunodeficiency is a homologue of the human disease" (abstract only). Genomics 23 (1): 69–74. doi:10.1006/geno.1994.1460. PMID 7829104. http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WG1-45PMSC1-FK&_user=409397&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000019483&_version=1&_urlVersion=0&_userid=409397&md5=30a567571392ace6f5a8bac4114b2fd5. 
  14. ^ Perryman LE (2004). "Molecular pathology of severe combined immunodeficiency in mice, horses, and dogs". Vet. Pathol. 41 (2): 95–100. doi:10.1354/vp.41-2-95. PMID 15017021. 

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Immune disorders: Lymphoid and complement immunodeficiency (D80-D85, 279)
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Metabolic disease: DNA repair-deficiency disorder
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