Introduction
Severe Combined Immunodeficiency is a syndrome where the body's complete lack of immune system causes the person to be highly prone to infections that could ultimately lead to end organ damage and fatality.
Unerlying Causes
SCID occurs when the adaptive immune responses mediated by T cells, B cells and Natural Killer Cells are completely devoid.The defects in lymphocytosis and maturation of lymphocytes are usually responsible for lack of Immune cells in most SCIDs (severe combined immunodeficiency). SCIDs have mutagenic lineage and inheritance is usually the cause of SCIDs in newborns. Children are particularly affected by SCID and symptoms develop after a few weeks from birth. Recurrent progressive infections are usually the indicators of SCID.
Severe Combined Immunodeficiency could be categorized into two according to the mode of inheritance: X-linked SCIDs & Autosomal Recessive SCID. There are other types of SCIDs that are caused by the metabolic pathway defects such as ADA deficiency & PNP deficiency.
From several types of SCIDs, X-Linked SCID is the form that is most widely seen, 45% of all SCID cases, in affected boys. In severe combined immunodeficiency, the mode of inheritance follows simple Mendalian genetics. Thus, mothers are the carriers of the SCID gene which is located on the X-chromosome, hence the name X-linked, causing the male descendents to show symptoms of the disease, while female descendents having two copies of X-chromosomes, one from the father and one from the mother, become silent carriers of the gene.
A few other types of SCIDs are inherited in an autosomal recessive form, namely JAK3 deficiency, Omenn Syndrome, Bare Lymphocyte Syndrome, IL2 production deficiency, & ZAP70 deficiency.
Molecular Aspects
A few common examples of molecular abnormalities in SCID are stated below.
In X-linked SCID, mutations of the common gamma chain of IL receptors (IL2R, IL4R, IL7R, IL9R, IL15R, IL21R) occur, resulting in the inability of the cytokines to bind to the receptors, leading to absence of immune response mediated by those cytokines, which are usually interleukins (ILs).
JAK3 is a tyrosine kinase protein that interacts with the common gamma chain in IL receptors. The lack of this protein leads to the same result as having gamma chain mutations on IL receptors.
IL2 Production deficiency is a defect that could lead to the absence of cytokines for interactions with cell surface receptors like IL receptors, thus resulting in symptoms similar to SCID.
Bare Lymphocyte syndrome is another type of severe combined immunodeficiency that is caused by the absence of MHC class I and class II molecule expression. MHC class I and class II molecules are responsible for expressing antigens on the cell surface for antigen-antibody complex formation.
ZAP-70 deficiency is the deficiency of zeta-chain associated protein, which is a type of tyrosine kinase, important in T cell signaling and positive & negative selection of T cells.
Omenn syndrome is one SCID that is caused by Artemis defect, RAG1 and 2 deficiencies. Artemis is an enzyme involved in V(D)J recombination that's responsible for the making T cell repertoire.
ADA deficiency is the lack of Adenosine deaminase enzyme that breaks down purine, that results in the build-up of metabolic intermediate, deoxyadenosine triphosphate, that is cytotoxic and inhibits the enzymes necessary for lymphocyte proliferation.
Diagnosis of SCID
An initial prompt for SCID is usually the recurrent progressive infections, most commonly Pneumonia, caused by Pneumocytis carinii, (which is also known as interstitial pneumonitis), gastrointestinal tract infections caused by enterovirus, rotavirus, etc., and skin infection, especially the skin spesis caused by Streptococcus spp, etc. in Omenn Syndrome SCID. The children of SCID usually develop normally for first few months of life and are common to have persistent bronchitis like respiratory infection.
In most occasions, infections progressively worsening and persistent clue-in the possibility of SCID. A complete blood count & absolute lymphocyte count tests are usually ordered. Lymphocyte typing to distinguish the absent lymphocyte and Immunoglobulin measurement for existing Ig's is helpful in the process of diagnosis. A lymphocyte count of lower than 2.8x10^9/liter is indicative for possible SCID occurrence.
Though absence of lymphoid tissue could be used to detect SCID, most children have very small lymph nodes and tonsil. Chest X-rays could show signs of lung hyperinflation due to chronic bronchitis. IgG levels may show up normal as they are maternal in orgin.
Treatment
Severe Immune Deficiency, known as the "bubbly boy" disease, though sounds fatal, is completely curable by bone marrow transplant. Sometimes, in SCIDs with specific lymphocyte deficiencies, Intravenous Ig could be administered every three weeks to replace the absent immunoglobulin in blood stream. The onset of symptoms of most SCIDs is within a few months of life, although lack of specific types of T cells could take longer for the symptoms to show, as maternal transplacental migration of antibodies mask the absence of specific antibodies.
Conclusion
SCID is an immune deficiency that is completely curable by bone marrow transplant and many patients of SCID usually live normal lives after the transplant if the immune system reconstitution is successful. However, the diagnosis at an early stage, before the end organ damage, is essential, as Bone Marrow Transplant could lead to fatal complications if end organ damage is present. Bone Marrow Transplant and/or long term Immunoglobulin replacement therapy are required to treat SCID.
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