Implications Of Severe Combined Immunodeficiency Biology Essay

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Severe combined immunodeficiency a rare genetic defect found in new born. The immune system is highly damaged and thus making the disease fatal in nature. Several genes are associated with this disease. Early detection of the disease is the only way out to cure. For the past few years, there have been usages of gene therapy and bone marrow transplantation which give effective results for the treatment. This review summarizes the types, diagnosis and future treatment of SCID which will assist in management of the disease better.

INTRODUCTION

The immune system is a massive defence system of our body. Immunodeficiency is a condition where the immune system is malfunctioning and leads to various infections. Thus leading to a condition where the cells are not protected. These conditions will vary from severe, resistant, commonly occurring diseases. [1] The deficiency of the immune system are distinguishably divided into two; namely, primary and secondary immunodeficiency [1]. Primary immunodeficiency is caused due to a genetic defect i.e. heredity in nature. It majorly affects the adaptive and innate immunity. The B cells, T cells, phagocytic cells or the complement cascade are the four foremost affected regions of the immune system. [1]

Disorder of the adaptive immunity being the T (cell mediated immunity) and B cells (humoral mediated immunity). It is seen that the most of the T cell defects are combined with the B cell deficiencies. The innate immunity being the first line of defense identifies the pathogenic organism and attacks it through phagocytosis. The complement cascade mechanism also recognizes the foreign antigen and undergoes opsonisation. [2]

SCID

It is a paediatric emergency condition which is fatal in nature. The severe combined immunodeficiency was commonly known as 'Bubble boy disease' in the 70's. A boy named David Vetter was detected with X- linked SCID [3]. The characteristic factor of this disease is the lack of immune response (severe defect in the B and T cells) to various recurrent infections. [2] This fatal disease occurs at the first stages of life. New treatments are taking a step forward in this and save life upto 80%. The occurrence ratio of SCID is 1:75000 births [4]

CLASSIFICATION

As we look into the general classification of the disease that discloses the molecular and cellular mechanisms of SCID we see a lot of variations in the outcome of disease. Severe combined immunodeficiency is classified as autosomal recessive denoted as (AR) and the X- linked denoted as (XL) [5]. The table 1 summarizes the different types of SCID along with their location at the choromosome [5].

Table 1- Kuby, immunology, chapter 19, page no 433. [5]

The chromosome carries a certain amount of information and if that is mutated then it will lead to a disorder state. One copy of the gene is affected and the other is dominant this will lead to a condition called 'autosomal recessive'. The various AR defects seen in SCID are -

Reticular dysgenesis

RAG-1/RAG-2 deficiency

ADA deficiency

JAK-3 deficiency

ZAP-70 deficiency

PNP deficiency [5]

A very careful analysis of the disease will lead to the recognition of the different types.

Reticular dysgenesis is a defect in the stem cell which affects the production and maturation of the lymphocytes. This is a one of the rare types [5]. It clearly indicates that the lymphoid progenitor cell is affected. The associated feature to this condition is granulocytopenia and deafness. [6] The defect affects the highly compartmentalised areas eg: mitochondria [5].

Another defect found is in the somatic recombination. The defect is in the recombinase activating gene (RAG-1/2) that aid the V(D)J recombination. The normal functioning of the RAG-1/RAG-2 is to introduce a double stranded break to the recombination signal sequence (RSS). Damaged V(D)J recombination therefore result in the decreased T and B lymphocytes production. The identification of this SCID condition is by the deletion of RAG1 and RAG2 gene. This condition also leads to the mutation of DNA-dependent protein kinases [6]. This mutation is also seen in the Omenn's syndrome after the genome sequencing [6]. Characteristic feature of this syndrome are diffuse erythrodermia, hepatosplenomegaly, protracted diarrhea. There are no B cells circulating even though serum shows high levels of IgE. The syndrome a low V(D)J recombination due to leaky mutations in either one of the gene. These data are not sufficient in order to account for the Omenn's syndrome [6].

Adenosine deaminase deficiency (ADA) leads to the accumulation of deoxynucleotides. There is an increase of 50 to 1000 fold in the erythrocytes,lymphocytes and bone marrow of the child [7]. The T lymphocytes are completely non-functional but the B cells progressively decreased as the immunoglobbulins are transferred to the child during birth. Features associated to these are neurological features, deafness, liver manifestations, costochondral junction flaring. There is an elevation in the levels of S-adenosyl homocysteine [6].The deficiency of ADA leads to interference in the normal post-thymic T lymohocyte function. As the effect of T cell maturation is not studied directly hence the differentiation of the T lymphocytes could be studied in identifying the role adenosine deaminase [8].

JAK are non-receptor tyrosine kinase that aids the functioning of the cytokine [9]. The type I and II associate with the Janus kinase family. JAK 3 associates with one single receptor chain which is the IL-2 γ chain. The pairing of the γchain and other ligands will form receptors of IL-2,4,7,9,15 and 21 [9]. The mutation in the germline of the receptor chain will lead to SCID. JAK3 phosphorylates STAT5A and 5B. Morphology were seen to be related when the STAT's were absent in the T cells. These deficiencies in the JAK3 kinase will cause fault in the signalling pathway of the cytokines [9].

ZAP-70 assists in initiating T-cell responses by the antigen receptor. ZAP-70 is a cytoplasmic tyrosine kinase. This 70 kD molecule is found in the TCR stimulated jurkat cells. The deficiency of this causes lack of T lymphocytes in the peripheral blood. The CD8 cells are decreased [10].

Purine nucleoside phosphorylase deficiency follows the ADA pathway. This process produces excess of deoxyguanosine and deoxyguanosine triphosphate which leads to apoptosis of the lymphocytes. This deficiency is characterised by hypertonia, hypotonia, neoplasia, neutropenia etc [11].

The second section classification is X-linked SCID denoted as SCID-X1. In this disease the IL-2Rγ chain is non-functional because of the mutations. This gamma component functions in the cytokine signalling pathway [12] .The defect is found in the locus Xq13. [5]

The defect in the gamma chain receptor of IL-2,4,7,9,21. There is a remarkable decrease in the NK Cells and T lymphocytes [6] .The deficiency accounts 50% of the cases. The defect in the receptor will lead to immunological interruption and thus causing the absence of Tcells, B cells. The reconstitution of immune system is done by bone marrow transplantation [13].

DIAGNOSIS & TREATMENT

Early diagnosis of severe combined immunodeficiency is vital. The symptoms are not seen at the first few months of the neonatal stage as the immunoglobulins are circulating within the system obtained by the mother's placenta during birth. [14]

SCID infants suffer from chronic cough. Prolong respiratory infection is an evidence of interstitial pneumonitis. Chest radiographs need to be taken. Furthermore, the recurrent oral or gastrointestinal candidiasis is also observed. This condition is seen only after few months of life. Skin sepsis is also often avoided as an important diagnostic factor. A full routine test of the baby could also reduce the susceptibility to this fatal disease. [14]

Most evident presentations are due to the viruses,fungi or intracellular bacteria that must cause the early testing of the diseased condition [14] . Pneumocystis carnii pneumonia is common causative agent of the respiratory infection in SCID. It is found in the bronchoalveolar specimens and hence detected only through lung biopsy. Immunofluorescence is the most widely available technique [14]. Also genome detection through PCR is one of the most utilized techniques. Apart from the respiratory samples for the detection, other samples such as urine, blood, bronchoalveolar washings and lung, bowel, lymph node or skin biopsy material are important to detect the extent and the stage of the infection. Histochemical staining of the biopsy material may confirm the disease. [14]

Immunoglobulin measurement gives false results because IgG are originally obtained from the mother [14]. Furthermore, Isohaemagglutinins are used to measure the IgM production. But the absence of specific titre fails the detection. Next method for detection is the lymphocyte phenotyping using monoclonal antibodies and fluorescent activated cell sorter (FACS) analysis. The metabolic activity of ADA and PNP can also be another method to detect SCID. [14]

Mutations are detected generally by screening genomic DNA using single-stranded conformational polymorphism analysis (SSCP) [15]. This is followed by screening the exons which are defective. Though the sensitivity is high it gives still a certain cases unidentified [15].

Another detection method called the re sequencing microarray which detects the mutations present on the genes. This method utilizes probes representing exons and flanking regions of defective gene. DNA is extracted from the blood, primers are created for the PCR amplification [16].

TREATMENT

Drug therapy is generally not a part of the treatment as the bases of the disease is genetic mutation [17]. For treating SCID drugs such as OctagamIV, immune globulin (IgG)IV, bivigam IV, flebogamma DIF IV. All of these are used to strengthen the body's defense mechanism. These drugs also help in increasing the blood count [18].

For the general management of the SCID patient, they are first prevented from the opportunistic organisms. Intravenous immunoglobulins are given as prophylaxis measure. This method is not valid for long term treatment. The SCID patient should be isolated in a sterile germ free environment [18].

Knowledge of the disease and the different mutations through various diagnostic methods is important for the use of gene therapies. One of the methods to treat SCID is allogenic bone marrow transplantation (BMT). Engraftment of normal haematopoietic stem cells lead to production of the normal lymphoid system [19]. The benefit of this method being the lack of the T lymphocytes the graft is not rejected and the normal cells grow properly over the patient's which improves the condition of the patient. HLA identical donor is preferred as they will reduce the rejection rate. X-SCID patients can undergo this treatment with help of the immunoglobulin therapy [19] .For the treatment of ADA deficiency enzyme replacement therapy is used where in a substituted enzyme (Polyethylene glycol) conjugated ADA. This technique is used worldwide since 1985 and it's been proved safe [19].

GENE THERAPY

The basic concept of genetic material transferred into a non- functional cell to correct the expression of the gene. Here virus vectors were used to integrate the cell genome that could handle the stability of the gene. Enzyme replacement therapy treated patients with ADA deficient cells where taken and injected into modified oncoretrovirus. This procedure gave ample amount of T cells which were further injected to patients suffering. This method did not correct the expression [19]. SCID -X which showed somatic mutation had mild immunodeficiency and showed the presence of T cells. A detailed analysis of T cell antigen showed a normal signalling pathway of IL-7 which will give sufficient amount of T cells instead of the T cell antigen receptor rearrangements. This is a natural gene therapy method for the mild deficiency [20].

FUTURE ASPECTS

Recombination activating gene encodes for enzymes that help in the rearrangement and recombination of immunoglobulins. A very recent method in treating SCID is through genetic engineering.

Meganucleases are endonucleases that recognize large sequences of DNA. These homing endonucleases form homodimers and cleave palindromic or pseudo palindromic sequences. One of the families of homing endonuclease LAGLIDADG meganuclease cleaves the human RAG1 gene. Long linker molecules were used and by creating a single chain molecule with heterodimer structure which mimics the meganuclease structure. These structures interact with the meganuclease LAGLIDADG and restrict the formation of the homodimer. These different monomeric sequences form a single chain molecule which will induce high recombination. This technique enables the gene correction for the monogenetic disease i.e. this is effectively used in a leaky SCID condition. [21]

Another magical surgery done to get reproducible results very recently is the used of four-zinc finger chimeric endonucleases (ZFNs). This is can be used for permanent alterations of the gene coding human IL2Rγ. This γchain receptor is linked to SCID-X1 [22]. With the help of homologous recombination the cells genome attain integrity and stability, especially of the double stranded break. These endonuclease protein combine together with the ability of zinc-finger domain that will specifically bind to a section of triple hydrogen bonded DNA. This will cut a particular restriction site and insert the double stranded break in the genome [22]. The resulting cut DNA is encoding the IL2Rγ. ZFN's shows a potential future in treating SCID [22].

CONCLUSION

Severe combined immunodeficiency has showed a progress in the treatment of patients. Molecular scissors can now replace the BMT and enzyme replacement therapy. But this progress will take some years of research. Gene therapy is still a preferred technique and depending on the mutation variations in them is certain. SCID if detected in the early stages can be cured and corrected through various treatment technique and can change the scenario from a dreadful fatal disease to curable one.

SEVERE COMBINED IMMUNODEFICIENCY (SCID)GRAPHICAL REPRESENTATION

TYPES DIAGNOSIS TREATMENT & FUTURE

ASPECTS

Intravenous immunoglobulins

BMT

Enzyme replacement therapy

Gene therapy

FUTURE ASPECTS - the use of meganuclease to treat the RAG 1 defect in SCID patients.

Use of molecular scissors in correcting genome mutation (ZFNs).

Routine test

Immunofluorescence

Biopsy and their histochemical staining

Lymphocyte phenotyping using monoclonala antibodies and FACS

Detection of mutation using SSCP

Detection re sequencing microarray

Reticular dysgenesis

RAG-1/RAG-2 deficiency

ADA deficiency

JAK-3 deficiency

ZAP-70 deficiency

PNP deficiency

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