Severe Combined Immunodeficiency (SCID) is a rare, life-threatening immunological disorder characterized due to the lack of B-lymphocyte and T-lymphocyte functioning. Sporadic (occasional) malfunctioning of natural killer (NK) cells can also result this condition.
This collective deficiency in immune response is the direct result of defects at the genetic level. Individuals become more vulnerable to potentially fatal infections such as chicken pox, meningitis, pneumonia and other systemic infections. Babies, who are born with this condition, usually die within a year of their birth in the absence of an early diagnosis and treatment.
SCID is also known as “bubble boy disease” after David Vetter who was born in 1971 with this disease. An isolated plastic chamber was used to protect Vetter from the infections; however, he could only survive for a decade and died due to an unsuccessful bone marrow transplant.
SCID - 60 seconds
Root Causes and Risk Factors
SCID is a type of primary immunodeficiency disease which weakens the body’s immune system; hence leading to the body’s inability to fight even minor infections. With the advancements in the research, scientists have categorized several molecular factors that can cause genetic distortions resulting in SCID.
Till date, fourteen different types of SCID have been recognized. Most of the forms of SCID follow an inheritance that is recessive in nature. The following two forms of SCID are relatively more prevalent.
Severe Combined Immunodeficiency
X-Linked SCID (XSCID)
This is the most frequent type of SCID with approximately 50% of the incidence. Mutation in the interleukin 2 receptor gamma (IL2RG) gene on X-chromosome is the primary cause for XSCID. IL2RG play a crucial role in development of surface receptors on lymphocytes. These receptors upon activation by cytokines help the cells to mature and multiply. X-linked inherited mutations in IL2RG disrupt its functioning, creating a faulty “common gamma chain subunit”, which is a part of several defective interleukin (IL) receptors.
IL2RG also activates an important signaling molecule, JAK3 on Chromosome 19. Mutations in JAK3 also contribute to defective IL receptors.
As a result of these mutations, T-lymphocytes which play a major role in foreign body location and maintaining the natural defense mechanism of the body remain underdeveloped.
As the root cause of this disease lies on X-chromosome, females are natural carriers of these mutations because of the existence of two X-chromosomes. However, because of the same fact, they become less prone to the manifestations of this disease. In females, the spare X-chromosome with normally functioning IL2RG and JAK3 pathways play a crucial role in combating the effects of faulty chromosome. Hence, XSCID majorly affects males due to the absence of any proxy defense machinery.
Adenosine Deaminase (ADA) Deficiency SCID
As evident from the name, this type of SCID is caused due to the deficiency of ADA enzyme. ADA deficiency SCID is often considered to be the consequence of spontaneous mutations. Also, there may be various other genetic factors involved.
ADA is a vital component for the production of new DNA, development of lymphocytes, and disposal of toxic metabolites from the body. Formation of ADA is governed by a gene located on Chromosome 20. The mutations in this gene result in an incomplete enzymatic reaction, causing accumulation of the transient substrates and metabolites inside the cells. These chemicals start showing toxic manifestations to the extent of killing the immature lymphocytes. The immune system of the patient becomes severely compromised and is often lethal in absence of prompt treatment.
Other forms and the causes of SCID are mentioned below:
Alpha Chain of the IL-7 Receptor deficiency SCID
This is the third most common form of SCID with 11% of the incidence. It is due to the mutation in the gene that encodes the alpha chain of the IL-7 receptor (IL-7Rα).There is a deficiency of T-cells, which further leads to the non-functioning of B-cells.
Janus Kinase 3 deficiency SCID
It results due to the gene mutation that encodes an enzyme, which is present in the lymphocyte named Janus Kinase 3. The patients with this type of SCID are quite similar to X-linked SCID.
CD3 Chains deficiency SCID
Three other forms of SCID results due to genetic mutations leading to deficiency of CD3δ, ε or ζ protein chains.
CD45 deficiency SCID
It is due to mutations in the genes that are responsible for coding CD45 protein, which further is responsible for the correct functioning of T-cells.
Some More Causes of SCID
There are five more types of SCID, which result due to gene mutations that encodes proteins which promote the growth of immune recognition receptors on T and B cells. These five types are:
- Recombinase activating genes 1 and 2 (RAG1 and RAG2) deficiency –also known as Omenn’s Syndrome
- Artemis deficiency
- Cernunnos deficiency
- Ligase 4 deficiency
Further Reading