Hoa research paper

Hoa Le
Developmental genetics paper
Bio 351
03/05/09
War with SCID-
Severe Combined Immunodeficiency
a Life-Threatening Syndrome

Introduction:
Every single day, people from all over the world painfully suffer and die from many causes. Many of these causes, such as accident, poison, and diseases, in general are preventable if everybody were more cautious and watched what they were doing and what they were consuming. On the other hand, causes such as Severe Combined Immunodeficiency (SCID), a fatal genetic disorder that people cannot prevent, must be battled with several different methods like treatments.
In this paper, I will explain how this silent, but deadly SCID, our enemy is, the different types of techniques it uses to destroy humans and other mammals, the ways to recognize this silent enemy, and lastly, several effective methods people use to conquer SCID.

The silent but deadly SCID:
A hetero-genous group of inherited disorders, SCID, sometimes called bubble boy disease, is characterized by the incapability to mount humoral and cell-mediated immune responses (Aiuti 2007, Macchi 1995, Vernau 2007). SCID became extensively recognized during the 1980’s which is when people learned of David Vetter, a boy in the movie “The Boy In The Bubble” who had SCID. Because David was born without a working immune system, he lived in a plastic germ-free bubble for twelve years and then died from an unsuccessful bone marrow transplant.
Patients diagnosed with SCID who do not fight back with any treatment usually do not live past the first two year of life (Vernau 2007). SCID, the most severe form of immunodeficiency (Milner 2008), deactivates or causes to malfunction two important weapons of the human body which is B and T lymphocytes (Lorke 2008). Without a sufficient number of normal B and T cells, the body will be easily infected with viruses, fungi, and bacteria. SCID opens wide the door for other aggressive invaders to attack the human body and can affect many other mammals as well. SCID is a rare monogenic disorder; currently estimates are that 1 in every 50,000 to 100,000 births may be affected (Cavazzana 2000). The incidence of the disease may be higher due to death from infections before diagnoses.
Different forms of SCID:
There are several forms of SCID: the most common type is X-linked SCID (XSCID) which accounts for 50% of all human SCID (Cavazzana 2000, Vernau 2007). Adenosine deaminase (ADA)-deficient SCID is the second most frequent type, next is the mutation of the JAK-3 protein kinase, mutation of the IL-7RA, null mutations in RAG-1 or RAG-2, mutation in Artemis gene, ZAP-70, MHC class II, and many other more (Aiuti 2007, Cavazzana 2000, Macchi 1995).
XSCID, a life-threatening primary immunodeficiency, is caused by mutations in the IL2RG gene encoding the common cytokine receptor gamma chain of receptors IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 (Aiuti 2007, Cavazzana 2000, Chinen 2007, Hacein 2003, Macchi 1995, Noguchi 1993, Pike 2007, Ravin 2006, Schmalstieg 1995, Thrasher 2005, Thrasher 2006, Vernau 2007). Thus, inducing the complete absence of mature T, natural killer (NK) cells and has nonfunctional B cells (T-, B+, NK-) (Chinen 2007, Macchi 1995, Thrasher 2005, Vernau 2007). Since X-chromosome inactivation in obligate carriers of XSCID, it is more likely that males will be a carrier compared to female (Schmalstieg 1995). Because females have two X-chromosomes, if they have a mutation which disrupts the IL2RG gene on one X chromosome, they still have the other one that can compensate for the mutation. However, males have only one X-chromosome and one Y-chromosome; if mutation disrupts IL2RG gene, their immune cells still produce but with the absence of yc receptors (Schmalstieg 1995). Because the receptors are unable to respond to stimulation, immune dysfunction and SCID sets in (Chinen 2007, Ravin 2006).
ADA SCID, the second most common form of SCID, is characterized by impaired lymphocyte development and function due to the defect of adenosine metabolism (Cassani 2008, Chan 2005). Adenosine deaminase (ADA) is an essential enzyme needed by all body cells to produce new DNA. ADA is a housekeeping enzyme of purine metabolic pathway and constitutive express (Aiuti 2007). Another important role of this enzyme is to break down toxic metabolites (Cassani 2008). In the absence of this enzyme, toxic metabolites will accumulate and begin to kill lymphocytes such as B, T, and NK cells (T-, B-, NK-) (Carbonaro 2008, Cassani 2008). This mutation occurs equally among males and females because the ADA gene is located on chromosome band 20q13.11 (Cassani 2008).
Mutation of the JAK-3 protein kinase, the third most common form of SCID, prevents cell proliferation and differentiation (Macchi 1995). As the T cell is activated, JAK3 is up-regulated and signaling pathways, including the signal transducers and activators of transcription (STATs) (Macchi 1995). Deficiency in JAK3 gene is normally due to the absence of common gamma chain or the alpha chain of the IL-7 receptor, which leads to the absence of T and NK cells (T-, B+, NK-) (Cavazzana 2000, Macchi 1995). Mutation of the JAK-3 also occurs equally among males and females because JAK3 gene is located on chromosome band 19p13.1 (Macchi 1995).
Mutation of the IL-7RA, RAG-1 or RAG-2, Artemis gene, ZAP-70, MHC class II, and many other types of SCID rarely occur (Cavazzana 2000). Most of these mutations occur in less than three percent of all SCID cases and also occur equally among both genders because mutation of the gene does not locate on the sex chromosomes.

Signs and Symptoms of SCID:
Since SCID is a dangerous, destructive but silent enemy; we much know how to recognize it when it invades our body. Many infants with SCID experience chronic diarrhea, skin rashes, ear infections, sinus infections, oral thrush, pneumonia, and meningitis (Chinen 2007). Patients with SCID also grow more slowly (Chinen 2007). Signs of SCID will not show in newborns or in the first month of age because antibodies from the mother still circulate in the baby’s blood (Chinen 2007). Families with a history of SCID are strongly advised to test for SCID when pregnant.

Treatment for SCID:
Fortunately, there is cure for this fatal, genetic disease. Stem cell transplant, also called bone marrow transplant (BMT), is the most effective treatment for SCID (Fumihiko 2005). The second choice of treatment for most patients is gene therapy.
Stem cell transplant introduces bone marrow cells into the body with the hope that the new cells will rebuild the immune system. Studies had showed that patients who receive BMT from an HLA-matched sibling are estimated to have a 95% chance of survival in the first five years (Chinen 2007) and 90% chance of survival the next five to fifteen years (Grunebaum 2006, Thrasher 2005). On the other hand, patients who receive BMT from an HLA-haploidentical estimated to have only 60-75% of surviving the first five years and a significant risk of graft-versus-host disease (Thrasher 2005, Vernau 2007). After a successful BMT, the median time to achieve normal T-cell function is 8-9 months, and normal B-cells is approximately 14-15 months (Borghans 2006, Carlier 2007, Haddad 1998, Neven 2009). Stem cell transplant can correct the immunodeficiency, but some survivors from the treatment have shown marked neurologic abnormalities such as mental retardation, motor dysfunction, and sensorineural hearing deficit (Honig 2007). Many other patients may also encounter immunologic problems (Vernau 2007). As a result, many patients need to continue indefinitely on prophylactic immune globulin therapy (Vernau 2007).
Gene therapy is another successful treatment for SCID, especially for patients diagnosed with XSCID (Aiuti 2002, Ravin 2006, Thornhill 2008, Thrasher 2005, Thrasher 2006). Gene therapy is a form of molecular medicine which uses the addition of a corrected copy of a gene to the somatic cells of the patients and starts to produce healthy immune cells (Cavazzana 2000). Studies have shown that gene therapy was able to provide full correction of disease phenotype and has proven highly effective for long-term restoration of immunity in SCID patients (Cavazzana 2000, Ravin 2006, Thornhill 2008). Similar to BMT, some patients treated for SCID with a form of gene therapy have developed complications (Schwarzwaelder 2007).

Conclusion:
SCID is a life-threatening, autosomal recessive disease which causes severe abnormalities of the immune system. This strong and violent enemy rarely occurs, but it can take a valuable infant’s life in a short period of 24 months if not immediately treated. SCID can come in different forms, such as XCID, ADA CID, and JAK-3. This fatal enemy destroys the two important weapons, T and B cells, of humans and other mammals and widely opens the door to other invaders such as viruses, bacteria, and fungi to infected and destroy its host. In order to fight SCID, we much recognize where SCID is positioned. SCID can be located in any infants who suffer multiple times from chronic diarrhea, skin rashes, ear infections, sinus infections, oral thrush, pneumonia, and meningitis. BMT and gene therapy are currently the only two effective methods we can use to battle SCID. After successful combat against SCID, most patients will develop complications because war always create catastrophe on both sides.

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