Severe combined immunodeficiency encompasses various disorders, characterized by the impairment of the immune system. Both humoral and cell-mediated immunity are affected and the genetic background of each separate disorder varies.
Children born with SCID have a significant imbalance in their immune cell count: Absent T cells and further impairment in the functionality of B and NK cells, although the degree of severity varies depending on the particular type. Despite the type and phenotype, every individual affected by SCID possesses a dysfunctional immune system and is susceptible to various opportunistic infections.
During the first months after birth, maternal antibodies that have been passed down to the child manage to compensate for the innate ability of the person to produce their own antibodies. Maternal antibodies, however, have a brief life cycle. Once they cease to exist, low levels of T and/or B and NK cells render the patient unable to protect themselves against pathogens and produce functional immunoglobulins. Other vital components, which would normally contribute to immunity are dysfunctional or lacking: the thymus gland is hypoplastic, granulocytes are defective, tonsils and other lymphoid structures do not exist or are severely underdeveloped and lymphocytes are scarce in lymph nodes.
As a result, infections occur and persist. Symptoms compatible with pneumonia, otitis media and sepsis become evident, alongside rashes, diarrhea, hindered growth and fragility . Individuals exhibit the following infections as a result of the organisms inability to protect itself against all kinds of pathogens:
Additionally, affected individuals may develop generalized vaccinia due to a smallpox vaccine. Pneumonia due to P. jiroveci is frequently diagnosed in children suffering from SCID and poses a real challenge in terms of treatment .
A physician will suspect SCID if an infant frequently presents with infections of various kinds. Hospitals in the United States frequently apply the T-cell receptor excision circle method (TREC) in order to screen newborns for the immunodeficiency .
The diagnosis of SCID is established after a meticulous measuring of white blood cells (WBC) via a complete blood count (CBC). Immunoglobulin levels should also be quantified. An additional method involves testing for the proliferating reaction of white blood cells to mitogens, which can draw significant conclusions concerning the cell's capacity of responding to physiologic stimuli. In order to achieve a definitive diagnosis of SCID, a patient needs to exhibit a complete lack of T cells or a diminished number thereof, low lymphocyte levels and no cellular response to potent stimulators, such as mitogens.
Flow cytometry can also be used to quantify T, B and NK cell counts . Fibroblasts and adenosine deaminase levels are also determined and a test which inactivates the X chromosome will help to establish a potential X-linked type of SCID. Parents can also be tested for the most common genetic mutations and genetic counseling is mandatory only for future offspring.
Bone marrow transplantation is an option which could offer the patient an uncomplicated life. An identical donor is required, although partially matched bone marrow harvested from a parent can also be transplanted. Despite the theoretically excellent prognosis of patients who receive bone marrow transplantations, the procedure entails considerable risk, given that chemotherapy or radiation treatment is required to annihilate existing bone marrow before the transplant is performed.
Another option involves the administration of levamisole, thymosin or transfer factor, with an aim to boost the immune system. Enzyme replacement therapy has received approval for the treatment of SCID caused by an ADA deficiency. Such therapy cannot naturally cure the disorder but eliminate the risk of succumbing to one of the contracted infections.
A pioneering approach is gene therapy, which can be applied in cases of X-linked SCID or SCID that results from an ADA deficiency, when a compatible donor for bone marrow transplant cannot be found. Therapy has been attempted prior to the age of 4 months old, to eliminate the complications of leukemia or defective gene transduction; however, this type of treatment has to be further investigated before it can receive any type of approval  .
Patients with SCID should also be symptomatically treated for the various infections they contract. An accurate identification of the pathogen is required, since the organism cannot rid itself of the bacterial, viral, fungal or protozoan load and causative treatment should be promptly administered. The FDA has also issued suggestions regarding dietary habits of people who are affected by SCID: only pasteurized milk, fruit and vegetable juices should be consumed to avoid contracting opportunistic infections.
Individuals are diagnosed with SCID during the first months of their lives. If diagnosis is not achieved, the young patient is expected to succumb to complications and only reach the age of 18-24 months. Patients who are treated with enzyme replacement have normal lifespans but experience a degradation in their immunity and those who receive a bone marrow transplantation lead uncomplicated lives.
SCID involves disorders which are inherited via multiple patterns: X-linked, autosomal recessive or spontaneous mutations in more than 20 loci that have been identified. The type of inheritance pattern and the location of the mutation can by no means be associated with valid prognosis of the disease's severity.
The most common inheritance pattern for diseases of the SCID group is the X-lined pathway. The gene that encodes for the common γ-chain is defective; the γ-chain is a cytokine receptor component, present in the receptor complexes of six different interleukin receptors: IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21. This results in the dysfunction of T and B cells, as well as NK cells.
Given the plethora of different disorders categorized under the term SCID, an accurate comprehensive incidence is difficult to estimate. However, a USA study found the incidence of the typical SCID type, the SCID type involving incomplete genetic mutations and Omenn syndrome to be averagely 1 in 60,000 births . Patients with SCID inherited via an autosomal recessive pattern is more commonly observed in areas where consanguinity is practiced.
The SCID group of diseases is in most of the cases a result of genetic mutation. A plethora of genes has been identified, whose defective structure is incriminated for the manifestations of severe combined immunodeficiency.
Almost 50% of the SCID disorders are attributed to a mutation in the gene that encodes for the common γ chain of interleukin-2 in chromosome X (X-linked pattern). The γ chain is a component of minimum 6 cytokine receptors and greatly impairs the system's immunity. This specific mutation in the IL-2RG gene leads to patients with low or no T cells and NK cells and normal or elevated B cells.
The next most frequently observed SCID type is induced by low levels of adenosine deaminase and, in this case, the patient has low levels of T, B and NK cells or a complete lack thereof. Another possible mechanism involves an impaired α -chain receptor of interleukin-7.
SCID sub-types that are inherited via an autosomal recessive pattern are results of mutations in the following genes, amongst others:
Consanguinity greatly increases the possibility of giving birth to offspring affected by one of the aforementioned SCID types .
Generally, irrespective of the genetic background, all SCID disorders lead to absent T cells, symbolized as T-. Some forms also feature low or absent B and NK cells (NK-, B-) or normal/high cells (NK+, B+). Regardless of whether B cells are normal in numbers, the lack of T cells renders their function impaired. They are unable to partake in the fight against pathogens or produce immunoglobulins. In cases where B cells are able to produce some immunoglobulins, the latter are dysfunctional as well.
SCID is a result of an inherited genetic mutation and can therefore not be prevented. However, the detection of the syndrome immediately after birth and the prompt administration of treatment can prevent complications and major infections. Therefore, screening tests can be used to attain early diagnosis, which can also lead to better surgical outcomes when a patient undergoes bone marrow transplantation .
The screening process is carried out in several states of the USA via the polymerase chain reaction (PCR) in the blood.
Severe combined immunodeficiency (SCID) is an inherited and potentially life-threatening group of disorders. They do not share the same genetic background, but most types are inherited via the X-linked pattern. Other types are attributed to the lack of adenosine deaminase (ADA).
The primary defects that occur as a result of SCID include the complete absence of T cells (cell-mediated immunity) and low levels of B or natural killer cells (NK); B cells are the basic constituent of humoral immunity. Even in cases when the B cell levels are normal, they fail to function properly and produce immunoglobulins in the complete absence of T cells.
The immune system of the patients is therefore rendered dysfunctional: individuals are increasingly susceptible to viral infections, lung infections and diarrheic phenomena as early as the first postnatal semester. Growth is hindered and failure to diagnose and treat these types of conditions result in death within 12 months.
The severity of primary immunodeficiency conditions and their genetic variety created the need for a World-Health-Organization-founded committee, with the primary aim of disorder classification according to the underlying pathophysiological alterations . The impaired immune system in primary immunodeficiency is not a result of an underlying condition but a congenital defect and 8 such broad categories have been established so far. One of them is severe combined immunodeficiency, whose disorders have been genetically localized and pinpointed during the past years .
Severe combined immunodeficiency (SCID) is a group of inherited conditions that lead to a dysfunctional immune system. Mutations in various genes have been incriminated, and each condition that belongs to the SCID group causes a certain degree of immunodeficiency.
All conditions lead to absent T white blood cells in the blood; T cells are an extremely important component of immunity, as they also influence the function of other cells (B cells), amongst others. Mild disease types lead to absent T cells, but normal T cells and Natural Killer cells. Severer symptoms are caused by diseases that lead to absent T cells and also low levels of T and Natural Killer cells. In the latter case, immunity is significantly compromised.
Symptoms are exhibited within the first 6 months of life. Up to that point, antibodies coming from the mother protect the infant from infection, until the immune system is ready to take action. Individuals who are affected by SCID, however, fail to produce their own antibodies and start to frequently suffer from infections. Typical infections include pneumonia, diarrhea, viral infections and fungal infections, each caused by a plethora of different microbes.
The diseases are diagnosed by performing a blood test in order to measure the levels of T and B cells. genetic tests are also available and some hospitals use the T-cell receptor excision circles test for screening purposes. Diagnosis must be made in time, because SCID will lead to death if left undiagnosed.
SCID can be treated with immunoglobulin administration, adequate antimicrobial treatment in case of infection or enzyme replacement, if the cause is enzyme deficiency. Patients should also be as protected as they can against infections. A bone marrow transplantation is the only way to cure the disease; the procedure is risky, however, and a compatible donor is not easy to find. Transplantation that is performed before the age of 3 years old has a remarkable prognosis.