Severe Combined Immunodeficiency

Severe Combined Immunodeficiency Definition

Severe combined immunodeficiency (SCID) is a type of genetic disorder that is characterized by an absence of the functional T-lymphocytes, which gives rise to a malfunctioning antibody response caused either by direct involvement with the B lymphocytes and/or through an improper B lymphocyte activation instrumented by non-functional T-helper cells.

Impairment of the B-cells and T-cells “arms” of adaptive immune system occurs as a result of defects in either of the several possible genes. It is the most critical variant of primary immunodeficiencies. At least 9 different known genetic mutations have been found to play a role in the development of this disease.

SCID is also known by various other names, such as:

  • Alymphocytosis
  • Thymic alymphoplasia
  • Glanzmann–Riniker syndrome
  • Bubble Boy Disease
  • Severe mixed immunodeficiency syndrome

Severe Combined Immunodeficiency Prevalence

SCID is a rare disease, occurring in almost 1 in every 100000 live births. However, some sources regard this as an underestimation of its true prevalence, and the real rate of prevalence is almost 1 in every 50000 live births. Reports in Australia indicate that almost 1 in every 65000 births have been found to be affected by SCID. As this condition is of a genetic nature, more cases of SCID are found in areas having a greater prevalence of consanguineous mating. For example, more cases of SCID are recorded in Morocco than in many other areas. Almost 1 out of every 2500 infants in Navajo population is born with this disorder.

Severe Combined Immunodeficiency Types

There are various types of the SCID which are caused by different forms of genetic mutations. These types are mentioned below:

  • X-linked severe combined immunodeficiency
  • Adenosine deaminase (ADA) deficiency
  • Purine nucleoside phosphorylase deficiency
  • Omenn syndrome
  • Bare lymphocyte syndrome
  • Janus kinase-3 (JAK3) mutation
  • SCID caused by lack of Artemis/DCLRE1C
  • Deficiencies of the CD3 Chains
  • Deficiency of CD45

Severe Combined Immunodeficiency Causes

The various factors responsible for SCID are discussed below:

X-linked Severe Combined Immunodeficiency

Most cases of SCID are caused by mutations within the gene encoding γc or common gamma chain, a protein that’s shared by receptors for the interleukins IL-21, IL-15, IL-9, IL-7, IL-4 and IL-2. These interleukins, along with their receptors, play an important role in the overall development and the differentiation of the B and T cells. As many interleukin receptors share the common gamma chain, mutations that give rise to a nonfunctional common gamma chain can cause major abnormalities in the interleukin signaling. This results in an almost complete underdevelopment and malfunctioning of the patient’s immune system, with low or completely absent NK cells and T cells and nonfunctional B cells.

Encoding of the common gamma chain is done by the IL-2 receptor gamma gene or the IL-2Rγ. It is located on X-chromosome. Due to this reason, immunodeficiency that results from IL-2Rγ mutations is referred to as X-linked severe combined immunodeficiency. It is inherited in X-linked recessive pattern.

Adenosine Deaminase (ADA) Deficiency

It is the second-most commonly occurring variant of SCID after the X-SCID, and is caused by the defective enzyme ADA (adenosine deaminase), which is essential for breaking down the purines. Accumulation of dATP is caused by lack of ADA. This metabolite inhibits the activities of ribonucleotide reductase, an enzyme that reduces the ribonucleotides to generate the deoxyribonucleotides. The overall effectiveness of the immune system depends upon the lymphocyte proliferation and consequently, the dNTP synthesis. Lymphocyte proliferation is hampered without the functional ribonucleotide reductase, which compromises the immune system.

Purine Nucleoside Phosphorylase Deficiency

This is a type of an autosomal recessive disease that involves mutations of the PNP or purine nucleoside phosphorylase gene. PNP is an essential enzyme in purine salvage pathway, the impairment of which can raise the dGTP levels which results in a T-cell toxicity and also deficiency.

Omenn Syndrome

Manufacturing of immunoglobulins require recombinase enzymes that are derived from recombination activating genes, namely, RAG-1 and RAG-2. They are associated with the first stage of the V(D)J recombination, a process by which the segments of a T cell or B cell’s DNA get rearranged to form one new B cell receptor or a T cell receptor. Certain mutations of RAG-1 and/or RAG-2 genes prevents the V(D)J recombination, which causes SCID.

Bare Lymphocyte Syndrome

This is an autosomal recessive condition in which the MHC class II does not get expressed on the cell surface of all the antigen presenting cells. The regulatory proteins of MHC class II are altered instead of the MHC II protein itself.

Janus kinase-3 (JAK3) Mutation

Janus kinase-3 or JAK3 is a type of enzyme that assists in downstream transduction of γc signal. Mutations of its gene can lead to SCID.

SCID caused by lack of Artemis/DCLRE1C

The most critical form of SCID is noticed in the Navajo and the Apache people of United States, which is caused by the lack of a gene called Artemis or DCLRE1C. The absence of this gene makes it impossible for the bodies of affected children to repair the DNA or develop the disease-fighting cells.

Deficiencies of the CD3 Chains

There are 3 other forms of SCID which are caused by mutations in genes that encode the 3 individual protein chains making up another aspect of CD3, the T-cell receptor complex. These SCID-causing gene mutations give rise to CD3 e, d, or z deficiencies which are inherited in autosomal recessive patterns.

Deficiency of CD45

Mutations in gene encoding the CD45 can give rise to a form of SCID. It is a protein that is found on surface of all the white cells which are required for T-cell function. This form is inherited in an autosomal recessive pattern.

Severe Combined Immunodeficiency Symptoms

The most prevalent symptom observed in infants affected by SCID is the presence of several types of infections. These are generally not the same type of infections that are seen in normal children such as cough and cold. Instead, these infections can be quite serious and/or life threatening and may include meningitis, pneumonia or bloodstream infections. Organisms that give rise to infections in otherwise healthy children may be responsible for causing infections in SCID children. Alternatively, vaccines or organisms that generally do not affect children with normal immunity might cause infections in SCID patients. One of the most dangerous organisms that can give rise to rapidly fatal pneumonia is the fungus Pneumocystis jiroveci. Varicella, the chickenpox virus is another critical infection-causing organism. Although chickenpox can cause much discomfort in normal children, the condition is generally limited to skin and the mucous membranes and tends to resolve in a few days. In infants with SCID, chickenpox can be fatal. It does not resolve that easily and might metastasize to the lungs, the brain and the liver. The Cytomegalovirus or CMV which is normally present in the salivary glands of all individuals might give rise to fatal pneumonia in the infants having SCID. Some of the other dangerous viruses associated with severe combined immunodeficiency include the cold sore virus or Herpes simplex; parainfluenza 3; adenovirus; polioviruses; Epstein-Barr virus (the EBV or infectious mononucleosis virus); rubeola, the measles virus and rotavirus. Some of the other conditions that are prominently seen in SCID patients include:

  • Sepsis
  • Abscesses
  • Skin rashes
  • Weight loss
  • Malnutrition
  • Ear infections
  • Chronic cough
  • Sinus infections
  • Persistent diarrhea
  • Candida pneumonia
  • Esophageal infection
  • Interstitial lung disease
  • Profuse oral candidiasis
  • Candida fungal infections affecting the mouth (thrush)

Infant/s with SCID may develop a type of skin condition that is sometimes mistakenly believed to be eczema. However, it is actually a reaction of the mother’s T cells against the tissues of the baby. The T cells entered the babies’ circulation prior to his or her birth. This reactionary condition is known as graft-versus-host disease or GVHD.

Severe Combined Immunodeficiency Diagnosis

Diagnosis of SCID is generally suspected when the baby shows the clinical symptoms associated with this condition. Doctors can also conduct a complete blood count to evaluate the number of peripheral blood lymphocytes present in the child or in cord blood. If the initial tests reveal a low count of lymphocytes, this should further be confirmed by repetitions of the original test. If the lymphocyte count is still low, then the tests that counts the T cells and measures the T cell function needs to be done quickly to exclude or confirm the diagnosis. Special stains can be used to identify the various types of lymphocytes, namely:

  • T-lymphocytes
  • Killer T-lymphocytes
  • Helper T-lymphocytes
  • NK-lymphocytes
  • B-lymphocytes

The T-cell function tests are the most vital diagnostic tests as there are other conditions which might lead to a lower number of lymphocytes. Blood lymphocytes can be placed in culture tubes, treated with numerous stimulants and incubated for several days. The normal T-lymphocytes will react to stimulants by undergoing cellular division but lymphocytes taken from patients affected by SCID normally do not undergo any such changes. Tests for evaluating the immunoglobulin levels of SCID patients may also be carried out as they are normally very low in these patients.

It is possible to confirm the diagnosis of severe combined immunodeficiency in utero or prior to the baby being born in case there has been found a previously affected child in the family with the molecular defect been identified. This can be carried out by performing a chorionic villous sampling or CVS test which involves obtaining and testing the cells from placenta, or by amniocentesis, a process in which a sample of fluid that surrounds the baby is evaluated. The fluid contains fetal cells and is obtained from uterine cavity. In most of the cases, unless a termination of the woman’s pregnancy is considered due to an affected fetus, the diagnosis is ideally done at birth on the cord blood lymphocytes. It is so because there are some risks to the fetus associated with this procedure if the blood for lymphocyte studies is collected while the baby is in utero.

Most infants are diagnosed with SCID before they reach the age of 6 months. Pilot studies are currently being conducted to evaluate the use of T-cell recombinant excision circles in detecting SCID.

Severe Combined Immunodeficiency Differential Diagnosis

There are a number of health conditions that show the signs and symptoms similar to that of SCID. Hence while determining a diagnosis of severe combined immunodeficiency; it is necessary to differentiate it from such similar conditions in order to make sure that the doctor can opt for the appropriate treatment option. The differential diagnoses for SCID include conditions such as:

  • Cystic Fibrosis
  • Leiner disease
  • T-Cell Disorders
  • Atopic Dermatitis
  • Lymphohistiocytosis
  • Letterer-Siwe disease
  • Agammaglobulinemia
  • Cartilage-Hair Hypoplasia
  • Graft Versus Host Disease
  • Wiskott-Aldrich syndrome
  • Primary immunodeficiency
  • Congenital TORCH infection
  • Bruton Agammaglobulinemia
  • Lymphoproliferative Disorders
  • T-Cell and B-Cell Combined Disorders
  • Other types of hypogammaglobulinemia
  • Human Immunodeficiency Virus Infection
  • X-linked Immunodeficiency with Hyper IgM
  • Immunologic Aspects of DiGeorge Syndrome
  • Cutaneous Manifestations of the HIV Disease
  • Hyperimmunoglobulinemia E (Job) Syndrome

Severe Combined Immunodeficiency Treatment

Bone marrow transplantation is the most widely used treatment method for curing severe combined immunodeficiency. It uses a matched unrelated or related donor, or one half-matched donor who might be either of the parents. The half-matched transplant type is referred to as haploidentical bone marrow transplants. These bone marrow transplants make it necessary to deplete the donor marrow of all the mature T-cells so that the chances of developing graft-versus-host disease (GVHD) may be avoided. Due to this reason, a properly functional immune system does take much longer to form in an individual undergoing a haploidentical bone marrow transplant when compared to another patient receiving matched transplant. Generally, transplants done during the first 3 months of life do have a high success rate nowadays. Doctors also have had some form of success with the in utero transplants that were carried out before the birth of the child as well as by using the cord blood that has rich amounts of stem cells. The in utero transplants allow the fetus to form a fully functional immune system within the sterile surroundings of the uterus. However, it would be difficult to detect or treat complications like GVHD if they occur.

Nowadays, gene therapy is also in use as an alternate measure for bone marrow transplant. A transduction of missing gene to the hematopoietic stem cells by using the viral vectors is currently being tested in X-linked SCID and ADA SCID.

Immunoglobulin (IVIG) replacement therapy can help to replace missing antibodies that result from B-cell defect. This form of treatment is recommended for patients who are over 3 months of age and have already developed infections.

Some non-curative methods to treat SCID are also in use. These include reverse isolation which involves using laminar air flow as well as mechanical barriers that isolate the affected patient from harmful pathogens that are present in external environment. Enzyme replacement therapy is another non-curative procedure used to treat ADA-SCID. In this procedure, the affected individual is given injections of polyethyleneglycol-coupled adenosine deaminase (PEG-ADA) that helps in metabolizing the toxic substrates of ADA enzyme as well as prevents their accumulation. Treatment using PEG-ADA can also help to restore T-cell function within a short term, which is usually enough to clear any signs of existing infections before doctors proceed with curative treatments like bone marrow transplant.

Severe Combined Immunodeficiency Complications

SCID patients can suffer from the following complications:

  • Sepsis
  • Meningitis
  • Pneumonia
  • Ear infections
  • Chronic diarrhea
  • Thrush infections
  • Hypogammaglobulinemia
  • Graft-versus-host disease (GVHD)

Severe Combined Immunodeficiency Prognosis

If left untreated, infants affected with SCID usually die within the first year of their life due to recurrent episodes of severe infections. An early diagnosis is necessary to prevent the development of any life-threatening infections or complications. Treatment with bone marrow transplantation or enzyme replacement can increase the chances of long-term survival. Patients who are uninfected, well-nourished, and younger than six months of age before transplantation enjoy the best outcomes. HSCT or allogeneic hematopoietic stem cell transplantation in individuals younger than 3 or 4 months of age is commonly associated with more positive outcomes. Patients with less severe forms of ADA mutations may survive into adulthood.

Severe Combined Immunodeficiency in Animals

SCID is also known to affect certain animals, such as Arabian horses, certain dog breeds and mice.

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