SCID pathogenesis and diagnosis

SCID pathogenesis and diagnosis

Abstract:

In this article, severe combined immunodeficiency disease has been discussed. This disease has severe effect on the immune system. It is basically an inherited disease and develop through mutation in the gene of chromosome, it has been categorized into several types. As its lethal disease, so if proper treatment like gene therapy, immunoglobulin therapy or Hematopoietic stem cell therapy not been performed, its leads to death.

   SCID pathogenesis and diagnosis

Introduction:

Severe combined immunodeficiency syndrome is one of an inherited disorder that passes from parents to off springs. And it belongs to heterogeneous class of disorders. The person who is suffering from this has abnormal production and functioning of B-cells, T-cells and natural killer (NK) Cells. It leads to immune system deficient or result in weakened immune system.  As the result the person who is suffering from SCID cannot tolerate even mild infection. It is a fatal disease. Its typically occurs at the age of 3 to 6 months when the effect of immunoglobulins that were maternally transmitted has been vanished. Almost in every type of SCID there are low or may be absence of T lymphocytes.

On the basis of lymphocytes patients are divided into two categories.

1. Those who can produce B lymphocytes are names as T-B+ SCID.
2. And those who are unable to produce B lymphocytes are name T-B-SCID.

Classification is also based on absence or presence of natural killer cell (NK). In both categories there is very low count for lymphocytes that is about 2.7 × 10*9/l. (Fischer A, Cavazzana-Calvo M, De Saint Basile G, et al. 1997).

 SCID signs:

Basically, it’s happen at early stage of life and it seems to occur at 1 3-6 months after birth. Even that baby face serious issue with mild infection. Symptoms of SCID includes

 Diarrhea,

 Coughs,

 Colds,

Thrush,

Rashes,

Eczema,

 Poor development.

Also, there is an infection known as pneumocystis pneumonia. If it is present, it shows that their immune system is not working, and they may be suffering from SCIDs for SCID. {www.ncbi.nih.gov] [Nov,2000 Fischer].

Diagnosis:

Parents should consult towards their doctors if they see weight loss or poor feeding, growth of their baby. If treatment done at early stages of disorder, then it proves to be less fatal disease in baby.

Causes and Abnormalities/Types:

Causes:

As SCID is inherited disorder so it is basically a genetic disease that leads to disfunction of T cells. Not only T cells, but B & NK cells also get affected by this. As these cells play role in infection against microbes so destruction of these cells leads to destruction of the immune system. Sometimes SCID is also caused by deficiency of enzyme adenosine deaminase.

Types of SCID:

x-linked (gamma chain):

There are different molecular defects that may lead to the SCIDS. One of the most common x-linked form of SCID which is also named as X-SCID. This type of SCID occurring almost 45% of all population. Mutation occurs in gene that present on X chromosome that codes chain. This chain called cY, common gamma chain. This mutation in gene leads to low T lymphocytes and NK phenotype but level of B lymphocytes is high. Although B cells are there in high count, but still, they have no function as for B cells to work properly, T cells are not there for their help. This form of SCID is X linked recessive trait and males are affected by this. Females could be carrier of it but not affected. According to some reports, about 69 to 90 % of children that is suffering X-linked SCID has abnormal expression of gamma chain.

Abnormality in purine metabolism:

ADA deficiency:

It has been seen that about 15% of all cases of SCID is due to deficiency of ADA. In this, mutation occur in ADA gene at 20q13 (Hershfield MS, 2003) that encodes enzyme adenosine deaminase.  This enzyme is involved in conversion of adenosine into inosines, absence of this enzyme leads to accumulation of metabolites of deoxyadenosine and adenosine. As a result, there is production of toxic byproducts metabolites in lymphocytes that leads to death of cell.  In this, B, T and NK cells are also affected. Besides immune system ADA deficiency can also lead to the other problems including liver toxicity, behavioral problems deafness (Buckley RH, 2011). It is autosomal recessive trait that effect both girls and boys.

Reticular dysgenesis

 This is the one of the severe kinds of SCID. Although it occurs very rare but if we compare it with other forms of SCIDS, it can lead to severe infections at the early stage of life. Moreover, it tremendously decreases the count of T and natural killer (NK) cells. This condition is caused by mutation which occurs in adenylate kinase (AK) 2 gene in the mitochondria. This enzyme is involved in maintain the level of adenosine diphosphate. Deficiency of AK2 gene leads to the increased apoptosis of lymphoid and myeloid precursors. (Lagresle-Peyrou C, Six EM, Picard C, et al,2009).

• Alpha chain of IL-7 receptors:

In this, mutation occur in gene present on chromosome no 5, encodes alpha chain IL -7 receptor {growth factor receptor component]. The affected one has B and NK cells but not have T cells. And B cells do not perform their function.

Its occurrence is 11%. It referred to as autosomal recessive trait so effect both genders.

• Janus kinase:

In this, mutation occur in gene present in chromosome 19. This gene encodes enzyme called Janus kinase 3. This is a kinase enzyme that is only activated by cytokines. This enzyme play role in production of cY (gamma chain) that is mentioned above. In absence of this enzyme, result in production level high of B and NK lymphocytes and T cells level low, as discussed earlier in case of X linked SCID.

It is autosomal recessive trait so effect girls and boys both. It occurs at ratio of 10% in population cases of SCID. {www.niaid.nih.gov} {Cavazzana, Blackwell}

• CD3 chain:

In this, mutation occur in gens that encodes for 3 protein chains that produce another component of T cells CD3. These mutations lead to deficiency of CD3&.

This is also autosomal recessive trait.

• CD45:

In this mutation occur in gene that encodes CD45. CD45 is basically a protein present on white blood cells surfaces, that is  vital for functioning of T cells.

It is also autosomal recessive trait. {www.childrenhospital.org}

SCID treatment:

Firstly, there should be provision of environment that should be infection free so that tests and further analysis performed protectively. However, there are certain tests that are performed for confirmation of SCID.

Initial treatment:

Firstly, child would have to admit in hospital room that should be germs free or filterable. Child must resist or confined to that room, not allowed to play or meet with anyone except parents or guardian. Further analysis and tests are then taken to diagnose the type of SCID. In order to detect genetic defects, specialized tests are performed so that any other infection it is detected. Sometimes, central line method is performed for SCID. In this, usually there is insertion of silicon tube in large vein and fitted on chest. It permits blood to taken so that intravenous medicine given without usage of needles.

Medication:

In order to get protection again various infections, several medications are given like antibiotics, antifungal and antiviral. Often, medication is taken in form of syrups.

Methods of treatment:

There are basically three main ways for treating the patients with SCID.

1. Hematopoietic stem cell transplantation.
2. Gene therapy
3. Immunoglobulin therapy

Hematopoietic stem cell transplantation:

HSCT is basically an effective method for treatment for SCID. Mostly children who is suffering from this disease are treated by this method. Stem cells, that are main cells of body through which other cells of body can develop, are present in bone marrow. So, this method is also called bone marrow transplant. In this, Stem cells are taken from healthy person then these stem cells are introduced in the child with SCID. After infusion these cells start multiplying and create an immune system for the patient. SCID is not considered as homogeneous disease. SCID treatment and transplantation significantly depends on the patient condition, degree of human leukocyte antigen (HLA) mismatch among patient and the donor and SCID subtypes. After transplantation, these hematopoietic stem cells eliminate the toxic chemotherapeutic conditioning and increase the reconstitution of immune system.

There are several issues that must be considered before stem cells transplantation, and these are:

1. Graft rejection
2. B and T cells immune reconstitution.

Conditioning for HSCT:

There are several factors that may influence the decision for conditioning, these are donor type, recipient age and SCID type.

There are several conditioning agents that are given before the transplant include usulfan, cyclophosphamide, melphalan, fludarabine, thiotepa and treosulfan, a less toxic analogue of busulfan (latter M, Rao K, Amrolia P, et al. 2011). Depending on the specific SCID diagnosis, the phenotype. we will evaluate transplant approaches.

Gene therapy:

Gene therapy is also used to treat SCID. Currently, gene therapy is available but it on experimental basis with patient who have defects in ADA and IL2RG gene. Gene therapies usually involves replacement of abnormal gene with normal copy gene containing stem cells. (Cavazzana-Calvo et al., 2000; Aiuti et al., 2002, 2013).

“Natural” gene therapy has been in patients with SCIDx1:

In 1996, first case of natural gene therapy was introduced. In this patient with ADA deficiency has unexpected development of T lymphocytes. In this ADA gene is revered by mutation and started the production of ADA enzyme, through this partial correction has been seen in SCID patient (Hirschhorn et al. (1996)).

At the age of 6, this patient has only mild T lymphocytopenia and had IL2RG gene mutated sequence (wild type). It was observed that before or during the differentiation of T-cells, the mutation of IL2RG gene had been reverted (Stephan et al., 1996). In all cases of SCID, there is a severe reduction in the number of T cells. With gene therapy, doctors fix these numbers.

Steps in gene therapy:

There are following steps in performing a gene therapy.

1. First, the abnormal stem cells which contained conation defective gene are excised from bone marrow or blood of child suffering from SCIDs. Then these stem cells sent to the lab for further examination and fixation.
2. In the lab, doctors make copies of the gene that caused the SCID. These copies are normal genes and do not contain the mutation. The normal gene is then put into a virus, which has been deactivated and can no longer spread infection.
3. Then, the virus which contain normal gene is mixed with the stem cells of the patient.
4. Then this virus starts penetration in the stem cells and normal genes become permanent part of patient’s stem cells and starts dividing and create more copes. The “corrected” hematopoietic stem cells are now able to make normal T cells.

The first clinical trial of gene therapy for SCID X1:

In 1999, a first clinical trial is initiated in Paris on 10 SCID X1 patients who are lacking HLA matched donor. Within 3 to 6 months gene therapy leads to the normal development of T cells in the eight of the patients. In vitro functional assays showed that the T cells could be activated by antigens and could secrete cytokines. The vector copy number was ∼1 per cell (Hacein-Bey-Abina et al., 2003).

Gene therapy for ADA deficiency:

The ADA enzyme is involved in metabolism of purine as we have already discussed. The lack of this activity leads to the accumulation of dATP and toxic deoxyadenosine (Kohn et al., 2019). The ADA deficiency may lead to other medical issues including brain and lungs diseases. Children who have ADA deficiency can be treated by enzyme replacement therapy (ERT). In this therapy, child is suffering from this require weekly intramuscular injections of drugs containing adenosine deaminase enzyme. These drugs boost the immune system of the patient. One of the striking features of this gene therapy is that it does not show any genotoxic effects.

The efficiency and safety of this therapy in clinical trials leads to the formation of first drug of gene therapy named strimvelis. This is remarkable success in the history of gene therapy. Furthermore, HIV-derived SIN LV vectors for ADA were engineered and used in the clinic. SIN LV–mediated gene therapy for ADA deficiency has enabled at least 51 of the 53 treated patients to discontinue ERT (Kohn et al., 2019).

Immunoglobulin therapy:

Before this therapy, treatment of child suffering SCID is started by giving him drugs which include various antifungal, antiviral and antibiotics to combat the infections. Then, or Ig, an infusion of antibodies designed to boost the child’s immune system. The Ig is obtained through human plasma donors. These antibodies recognized and attached with respective antigen, so they are vital part of the immune system/response, like in the destruction of harmful agents i.e bacteria. Child should be called for therapy at time of diagnosis.

Conclusion:

Among primary immunodeficiency, severe combined immunodeficiency is one of lethal disorder. As this develop through various genetic defects. Children with SCIDs has to thrive for their survival. Initially there was no cure of this disease but with passage of