Introduction
The Human body is exposed to various types of foreign substances such as microorganisms (Ex: Bacteria, Virus, Fungi, Parasites etc.).Some of them are not harmful but, some of them can infect human body and cause many diseases due to their capability of causing diseases (pathogenicity) and they are so called pathogens. Immune system defends the body against those pathogenic infections and gives protection. This ability to resist infections is called immunity. Immunity can be divided into two as innate immunity and acquired immunity. In innate immunity a general process occurs as the first line of defense, to protect body from any type of pathogens without any specificity and with immediate action which gives no further protection. In acquired immunity, with the contribution of lymphocytes, antibodies are produced against specific antigens and long term protection is provided with an immunological memory.
There are two types of lymphocytes which contribute in acquired immunity,
1. T cells
2. B cells
Bearing cell surface receptors T cells provoke the immune response and B cells produce antibodies.1 Acquired immunity can be divided into two as,
1. Humoral immunity
2. Cellular immunity / Cell – mediated immunity
Humoral immunity is mediated by circulating antibodies which are produced by B cells and it is a major defense against bacterial infections. Cellular immunity is mediated by T cells and it is responsible for delayed allergic reactions, rejection of transplants of foreign tissue. It is also a major defense against infections due to viruses, fungi, and a few bacteria and helps defend against tumors.1
Immunodeficiency means deficiency in the immune response.2Combined immunodeficiency describes a clinical syndrome in which both humoral and cell – mediated immunity mechanisms are defective.3
Severe Combined Immunodeficiency (SCID) – Definition
“SCID is a heterogeneous group of diseases involving T cell immunodeficiency with or without B cell immunodeficiency, resulting from any one of several genetic defects. The cases are characterized by severe lymphopenia with deficient cellular and humoral immunity”.4 In some resources it has been defined like this. “SCID comprises a group of inherited diseases characterized by a severe deficit in T cell development and function with variable defects in B cell and natural killer or NK cell development”.5
Synonyms for SCID
1. Bubble boy syndrome
2. Alymphocytosis
3. Glanzmann-Riniker syndrome
4. Severe mixed immunodeficiency syndrome
5. Thymicalymphoplasia
Classification and Causes
There are three main subdivisions6 of SCID as,
1. Typical or classic SCID
2. Atypical or leaky SCID
3. Variant SCID
Typical SCID can be classified into two major groups depending on lymphocytes5 and they can again be subdivided depending on natural killer(NK)6 cells.
1. T-B-SCID
a) T-B-NK+SCID
b) T-B-NK-SCID
2. T-B+SCID
a) T-B+NK+SCID
b) T-B+NK-SCID
In T-B-SCID patients are lack of both T and B cells. The most common cause of T-B-SCID is mutations of the recombinase- activating genes, RAG1 or RAG2. In generating T and B cell receptors for antigens a process called V(D)J gene rearrangement (this occurs only in developing lymphocytes during the early stages of maturation of T and B cells as the unique mechanism of genetic recombination) is required. The two enzymes RAG1 and RAG2 are responsible for introducing double-stranded DNA breaks, that initiateV(D)J gene rearrangements. With the abnormal function of RAG1 and RAG2, development of T and B cells is arrested early in ontogeny, producing T-B-SCID. There is a leaky form of SCID called Omenn’s syndrome (OS) which is caused by hypomorphic mutations of RAG1 or RAG2. In this syndrome a few Tand B cell clones may be generated but the full T and B repertoire fails to develop. Those few T and B cells may undergo secondary expansion. Therefore, patients with Omenn’s syndrome may not be markedly lymphopenic but the lymphocyte repertoire is oligoclonal and the outcome is severe immunodeficiency. When T-B-SCID is presented with affected RAG1 and RAG2 genes relative frequency is 10%5 and inheritance is autosomal recessive. There is a protein called ARTEMIS which is needed for repairing DNA, including the repair of DNA breaks generated during V(D)J recombination. A rare form of SCID occurs due to mutations of the gene encoding ARTEMIS. The gene is called DCLRE1C. Patients with this form of SCID also exhibit increased sensitivity to ionizing radiation. In cases of affected DCLRE1C gene, relative frequency is 10%5 and inheritance is autosomal recessive. Aforementioned SCID types with affected RAG1, RAG2 and DCLRE1C genes are examples for T-B-NK+SCID which means T and B cells are affected but NK cells are not.
T-B-NK-SCID means all T, B and NK cells are affected. The most common cause of T-B-NK-SCID is adenosine deaminase(ADA) deficiency. ADA is an enzyme required for the salvage of nucleotides within lymphoid cells. Deficiency of ADA causes about 15%5of SCID cases. Toxic metabolites of adenosine (deoxy-adenosine and deoxy-ATP) are accumulated within lymphoid cells causing their demise due to lack of ADA. ADA deficiency results in profound lymphopenia affecting T cells, B cells and NK cells. Relative frequency of this type is 20%5 and inheritance is autosomal recessive.Another form of T-B-NK-SCID named reticular dysgenesis is caused by mutations in a gene called adenylate kinase 2 (AK2) involved in the development of lymphocytes and other white blood cells in bone marrow. It is inherited as autosomal recessive and relative frequency is lesser than 1%.5 T cells, B cells, NK cells, leukocytes and platelets are affected.
When patient is lacking T cells with normal or increased B cells it is called T-B+SCID. It is caused by defects in one of four functionally related genes. The commonest form of this type of SCID is X-linked SCID which has a relative frequency of 50%5. It is due to a mutation of the gene encoding the IL-2 receptor γ chain. It is the signal-transducing chain common to the receptors for six cytokines (IL-2, IL-4, IL-7, IL-15 and IL-21). The functions of T and B cells are defected when responses to these cytokines are absent. Lack of response to IL-7 causes T lymphopenia because IL-7 is required in early stages of T cell development. For NK cell development IL-15 is required. Lack of IL-15 results in failure of NK cell development. Signal transduction through the previously mentioned cytokine receptors involves the interaction of the common γ chain with the tyrosine kinase JAK3. Therefore, mutations in JAK3 gene cause an autosomal recessive form of SCID, with a phenotype similar to X-linked SCID. Relative frequency of this type is 10%5. All above examples can be included into T-B+NK-SCID in which T cells and NK cells are affected but B cells are normal or increased.
When only T cells are affected while B cells and NK cells are not affected, it is called T-B+NK+SCID.It is due to loss of either a cytokine receptor or T cell antigen receptor both needed for the development and survival of T cells. Most common form is the deficiency of the α chain of the IL-7 receptor. Mutations in the proteins required for normal functioning and signal transduction by T cell receptor results in rare forms of SCID.5Mutations of CD45, CD3D, CD3E and CD247 cause T-B+NK+SCID.
Atypical SCID is also known as Omenn’s syndrome6 which was described above. In variant SCID there are persistently low T cells but no defect in known SCID genes.6
Clinical features
Typically, patients with SCID show symptoms during 1st year of life5, usually before 7 months7 of age with failure to thrive, recurrent infections caused by bacterial, viral and fungal pathogens, diarrhea due to parasitic or viral infection, pneumonia and oral candidiasis. Gaining weight is difficult and growth is delayed in babies. The most common symptom is severe infection. Gastrointestinal and respiratory systems are typically infected. These infections can be occurred by common pathogens such as adenovirus, respiratory syncytial virus, parainfluenza virus or opportunistic organisms of low grade virulence such as Candida, Pneumocystis carinii, cytomegalovirus. Systemic aspergillus and Candida infections are less common but usually fetal. Live vaccines such as BCG can cause severe infections in SCID patients. Persistent infections developing in SCID patients lead to malnutrition, growth impairment and early death. Most patients die within 2 years7 without a successful bone marrow graft. Patients are unable to reject allogenic cells therefore, graft-versus-host disease (GvHD) can be caused by transplacentally acquired maternal lymphocytes or by allogeneic cells following blood transfusions. Skin rashes or hepatosplenomegaly and lymphadenopathy are the ways which GvHD manifests. Tonsils and other lymphatic tissues may be absent. Thymic hypoplasia can be seen in radiographic studies. Over 80%5 of SCID patients, lymphopenia is a characteristic feature.
Diagnosis
SCID can be detected prenatally.8 If the mutations leading to SCID are found during studying the family history and when there is a risk pregnancy SCID can be detected by sequencing DNA of the fetus using the cells taken from chorionic villus sampling (CVS) or an amniocentesis. But the test is so expensive. As an example, by detecting mutations of RAG gene in fetal samples using sequencing methods, fetuses affected with RAG-dependent SCID and OS could be investigated.9By prenatal diagnosing morbidity and mortality could be decreased.10
Early diagnosis of SCID is rare because each type of white blood cells in newborns are not routinely counted by the doctors. Typically, babies just over six months8 are diagnosed with SCID because of failure to thrive and recurrent infections. One of the easiest ways to diagnose SCID in children is to count lymphocytes in peripheral blood or cord blood. This can be done by a complete count and a differential count. Normal lymphocyte count in infant blood during first few months is more than 4000 mm-3.11 In patients with all types of SCID it is about 1500 mm-3.11 Blood tests also show significantly lower T cells than normal levels and lack of antibodies. Although B cells are present their ability to produce antibodies is poor. Every immunoglobulin class is depressed including IgA, IgE, IgG and IgM but, it will take a few months to show IgG deficiency.11 As characteristic features of SCID, low antibody levels and lacking of specific antibodies after vaccination or a natural infection can be denoted. In the differential diagnosis congenital HIV has to be considered but is easily excluded by PCR tests for the virus. In patients with lymphadenopathy and hepatosplenomegaly lymphoreticular malignancy may need to be considered. By a histopathologist with experience of SCID and GvHD biopsies from liver, bone marrow, skin and lymph nodes should be reviewed. It may be essential to confirm T-cell engraftment (maternal or otherwise) using chromosome markers. Newborn screening (NBS) for SCID is being increasingly used worldwide for better outcomes.12
Management
Early management
Due to viral or fungal pneumonia, infants affected with SCID present respiratory distress. For possible Pneumocystis carinii infections co-trimoxazole should be given immediately. Patient should be transferred urgently to an expert pediatric centre where diagnosis could be confirmed and specific treatment can be arranged. Time should not be wasted trying to diagnose and treat infection before transfer.
Subsequent management
In early infancy untreated SCID is fatal. After identifying, treating infections and diagnose of SCID is confirmed, treatment should be initiated. Hematopoietic stem cell transplantation (HSCT) from a human leucocyte antigen (HLA) identical or haplo-identical family donor is the treatment for diagnosed SCID. The identical treatment is HSCT from an identical sibling because its percentage of success is close to 100%.7Percentage of success is 80%7 with a haplo-identical sibling or a HLA-matched unrelated marrow. Treating SCID with HSCT before age of 3.5 months5causes good immune reconstitution and 95%5of those patients survive long term. Parent should be acknowledged on practicalities and risks of HSCT. Delayed treatments or infections impair the outcome. Main complications following HSCT are infections and GvHD. As an alternative transplantation of stem cells from HLA-matched cord blood can be used. In the recipient preconditioning is not required to provide space within the marrow. To minimize GvHD, T-cell depletion of the donor marrow is necessary. After HSCT some patients need regular immunoglobulin infusions because they fail to engraft donor B-cells.7With regular injections of bovine ADA, some patients with ADA deficiency can be maintained. Intravenous immunoglobulin replacement therapy is beneficial for SCID patients.13
Gene therapy has been used to treat SCID patients with common γ chain deficiency and ADA deficiency. This was done by ex vivo gene transfer to hematopoietic stem cells, isolated from the patient’s bone marrow. That gene reconstituted stem cells were transfused into patients. The successful results of gene therapy for two children with SCID-X1 disease was published by Cavazzana-Calvo et al.14 Complete immune reconstitution of the lymphoid system was resulted by this therapy with T, B and NK cell counts comparable to age-matched controls.14The first to be enrolled in gene therapy trials were patients with ADA deficiency. Kohn et al also conducted a trial with ADA deficient patients.15The most commonly used vectors to introduce genetic information into hematopoietic stem cells and/or progenitor cells are RNA viruses.
In addition to aforementioned treatments, patients with SCID should be aided by family, friends, siblings, and all other surroundings. They should be treated with love and affection. They should be given every support to balance both physical and mental health. These patients especially children should be prevented from infections. Sometimes they should be isolated from other children who are not in the family and also from own siblings who associate with an infectious environment such as kindergarten, school, etc. Siblings should be properly vaccinated. Children with SCID should not be taken to public places where they are exposed to infectious agents. Diet is also important although there are no special diets for SCID patients. Sometimes children with SCID cannot absorb food normally whom can be lead to poor nutrition. In such conditions intravenous feeding can be used.11 Non-irradiate blood or platelet transfusions and live virus vaccines are dangerous for SCID patients.11
SCID in animals
Regarding to SCID, in disease, vaccine and transplantation research, SCID mice are used. Arabian horse is also affected by SCID. In horses it is fatal because, during first four to six months of life they get opportunistic infections.16 Carriers who are not affected by the disease can be identified by DNA tests. If breeding practices were done carefully, producing an affected foal can be avoided.17Dog is another animal that shows well characterized SCID pathology. X-linked SCID in Basset Hounds has similar ontology to SCID in humans.18In one line of Jack Russell Terriers an autosomal recessive form can be seen that is similar to SCID in Arabian horse and mice.29
Conclusion
SCID is a genetic disorder. It must be diagnosed at proper stage. Not only the treatment but also proper caring will reduce the harmful consequences.
Originally published 15.10.2019