The Severe Combined Immunodeficiency

Published Date: 02 Nov 2017

Abstract- Severe combined immunodeficiency a rare genetic defect found in young new born. The early detection is the only way to cure the disease. Now with immense knowledge on gene therapy and transplantation, the molecular world is putting its best foot forward in healing scid.

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 occuring diseases. The deficiency of the immune system are distinguishably divided into two; namely, primary and secondary immunodeficiency. 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.

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. [1, 2]

SCID

A paediatric emergency condition to be learnt in the present and future is the disease called ‘SCID’. The severe combined immunodeficiency is 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. 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

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).

Figure 1-kuby immunology

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

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. The defect affects the highly compartmentalised areas eg: mitochondria [5]. Diversity in the immunoglobulins has different factors contributing to it. One of the methods is 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 syndrome after the genome sequencing. 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. [7,1978]. 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. [8,2009 update ]. 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. [9,ada2]

JAK are non-receptor tyrosine kisnase that aid the functioning of the cytokine. 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. 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.[10]

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.[11]

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. [12]