Severe Combined Immunodificincy

The exact incidence of Severe Combined Immunodeficiency (SCID) is unknown, except that it is recognized as rare in most population groups. It is believed that its incidence is in the neighborhood of 1 in 100,000. This number may vary though, due to misdiagnosis, unreported cases, and the like. SCID is actually a group of disorders. These diseases are either X – linked or autosomal recessive in inheritance. This means both parents must carry the defective chromosome for the child to develop the disease in some cases, and only the mother in others.

Severe Combined Immunodeficiency represents a severe defect in T – and B – lymphocyte development (developing white blood cells) resulting in marked susceptibility to severe and complicated infections. (White blood cells are necessary for normal immunity.) The onset of infection usually occurs in the first six months of life. Severe Combined Immunodeficiency is considered to be the most serious of the primary immune disorders. This set of disorders arises because of the inheritance of abnormal genes from one or both parents. The most common form is found in males, and is transmitted via an abnormal X chromosome, provided by the mother. The second most common defect is transmitted to the infant because both parents have contributed an abnormal gene governing the production of a cell enzyme (adenosine deaminase (ADA) or nucleoside phosphorylase) needed for the development of immunity. (This type of inheritance is called autosomal recessive inheritance.)
There are additional forms of SCID which have been recognized in the past few years, in a number of cases, the defective genes have been identified. There are three main features of Severe Combined Immunodeficiency, one being, T-helper cells (a kind of white blood cell) function poorly or are absent, or the thymus gland may be small and functions poorly or is absent, and lastly, bone marrow stem cells, from which mature T – and B – lymphocytes (one of the five kinds of white blood cells, or leukocytes, circulating in the blood) arise, are absent, or defective. Little or no antibody production occurs. If the T – helper cells are absent or function poorly, normal functioning of T – and B – lymphocytes are impaired. If the thymus gland is absent or functioning poorly, this impacts negatively on the normal maturation process for T-helper and T-suppressor cells. In the absence of fully developed T – lymphocytes, the immune system can never function normally. If stem cells (or precursor cells for T- and B-cells) in the bone marrow are defective or absent, this eliminates or damages the original source of T – and B – lymphocytes. It is not known exactly why these defects occur. However, it is believed that the defect or error occurs during fetal development. As further research is carried out, different kinds of immune defects are being identified as the cause of the SCID phenotype. In cases of specific enzyme deficiency, immunodeficiency occurs because of a build up of metabolic poisons in the lymphocytes. These children may present at slightly older age than other infants with SCID perhaps because it takes time for the metabolic poisons to accumulate. This form of Severe Combined Immunodeficiency is also inherited through an autosomal recessive pattern, (two abnormal genes, one from each parent, are required).

Little or no antibody production occurs. If the T-helper cells are absent or function poorly, normal functioning of T – and B – lymphocytes are impaired. If the thymus gland is absent or functioning poorly, this impacts negatively on the normal maturation process for T – helper and T – suppressor cells. In the absence of fully developed T – lymphocytes, the immune system can never function normally. If stem cells (or precursor cells for T- and B-cells) in the bone marrow are defective or absent, this eliminates or damages the original source of T – and B – lymphocytes. It is not known exactly why these defects occur. However, it is believed that the defect or error occurs during fetal development. As further research is carried out, different kinds of immune defects are being identified as the cause of the SCID phenotype. In cases of specific enzyme deficiency, immunodeficiency occurs because of a build up of metabolic poisons in the lymphocytes. These children may present at slightly older age than other infants with SCID perhaps because it takes time for the metabolic poisons to accumulate. This form of Severe Combined Immunodeficiency is also inherited through an autosomal recessive pattern, (two abnormal genes, one from each parent, are required).

The treatment of choice for these children is bone marrow or stem cell transplantation. The ideal donor is a tissue matched relative. Matching is determined by testing the blood cells for surface proteins HLA-A, HLA-B, and HLA-D, with HLA-D being the most important match to insure significant survival. Prior to transplantation, the patient may undergo irradiation ( form of radiation therapy) or immunosuppressive chemotherapy (a group of chemicals that reduce the chances of rejection) to insure survival of the donated bone marrow or stem cell. This measure is taken to prevent graft-versus-host disease (a reaction of the engrafted tissue against the recipient) and to insure that all new B – and T – cells arise from the donor’s normal bone marrow stem cells. In the absence of a tissue matched sibling, patients can be given a T – cell depleted bone marrow transplant from a relative or other partially matched donor. However, graft – versus – host disease (reaction of the engrafted tissue against the recipient) or incomplete reconstitution can occur if no identical normal donor is available. Other sources of donor stem cells can come from the blood of the donor, if procedures are used to boost the number of stem cells that are present. An additional source of stem cells which can be used in the reconstitution of an infant with SCID is the cord blood of unrelated normal infants. In several research studies, it has been shown that saving cord blood samples from normal infants can provide additional resource; as for bone marrow or other stem cell transplants, one attempts to match the donated stem cells to the infant. Restoration of normal cellular immunity occurs three to six months following a successful transplantation, while normal antibody production may take one to three years. During this period, gammaglobulin therapy may be used to provide protection against recurrent pyogenic (pus producing) infections. When successful, this treatment corrects the patient’s immune system defect. Recent success rates for this procedure approach 80% for tissue matched bone marrow or stem cell donors. Other approaches to overcoming the patient’s immune defect have been reported, but with varying success. One method, for infants or children with adenosine deaminase(an enzyme abbrevated with ADA) deficiency has been to infuse normal red cells which are a source of this enzyme, or treat with a drug called PEG-ADA. Another way to treat SCID, is Gene Therapy. Gene Therapy is only an option when an ADA deficiency is the cause of SCID, (ADA deficiency causes 25% of all SCID cases). Requirements for gene therapy are as follows:
•The gene must be identified and cloned
• The cloned genes must be inserted in cells that can take up long term residence in the patient. This means removing the patient’s own cells, treating them in tissue culture, and then returning them to the patient.
•The cloned genes must be inserted in the DNA so that it will be transcribed (DNA -* RNA) and translated (RNA -* Protein) so that useable quantities of the enzyme are produced.

When all of these requirements are met, the patient is ready for gene therapy using a retrovirus (a virus whose genome is made up of RNA as opposed to DNA) as the genes vector (a plasmid that carries recombinant DNA in order to implant it into a cell and transform it). A retrovirus is made up 5 separate parts.
1.An “envelope” which surrounds the cell, and is derived from the host cell’s plasma membrane. This enables the retrovirus to couple with the host cell.

2.Multiple copies of the envelope’s protein, which is located in the envelope’s lipid bilayer.

3.A capsid. Which is a protein shell that contains the last two parts of a retrovirus.

5.The enzyme reverse transcriptase(a DNA polymerase that uses RNA as its template. It is able to make genetic information flow in the opposite direction (RNA -*DNA) (DNA -*RNA)).
The retroviruss doctors use to treat SCID, are slightly different. The RNA is a copy of human ADA genes, and the retrovirus doesn’t make the host cell create new viral cells, it creates new ADA genes. Because once the retrovirus connects with the patients target host cells, the reverse transcriptase makes a copy of the ADA gene, and inserts it into the DNA of the cell, thus making the host cell create more ADA. Most procedures use T- cells, or blood stem cells for retrovirus hosts, this is because they travel through, or have immediate access to the bloodstream, and live long, thus reducing the amount of times a year this procedure must be done.


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