Advance Paper in Clinical Immunology

Combined T and B cells Deficiencies - SCID

Presented By: Girish Kumar K III MSc Biomedical Sciences

• Combined immunodeficiencies are those in which both cell-mediated immunity and humoral immunity are impaired.• The Severe Combined Immunodeficiency (SCID) comes

under such category.

Severe Combined ImmunodeficiencySevere, combined immunodeficiency (SCID) is a group

of heterogeneous disorders associated with lack of both T- and B-cell function.

Babies with SCID can't produce IgG, so once the IgG from the mother has gone, they easily get the types of infections that antibodies are not good at preventing

SCID is often called “bubble boy disease”. SCID became widely known during the 1970′s and 80′s, when the world learned of David Vetter, a boy with X-linked SCID, who lived for 12 years in a plastic, germ-free bubble.

SCID is classified into two, based on the predominant arm of immunity impacted.

I. Arrest in T cells with normal B cell numbers [T(-), B(+) SCID] II. Arrest of both T and B cell development [T(-), B(-) SCID]

• Most forms are due to an inheritable disorder, which can be inherited as an X-linked recessive form or as an autosomal recessive form.• The frequency of SCID is estimated to be 1:50,000 to

1:100,000 births.

Pathogenic Mechanism Of SCIDThere are several pathogenic mechanisms in SCID.• First, defects in cytokine receptors, which result in

impaired T-cell signal transduction pathways triggered by the cytokine receptors and lack of T-cell differentiation within the thymus.• Second, there are defects impacting the differentiation of

lymphoid progenitor cells, most commonly due to mutations in the recombinase-activating genes (RAG).• A third form of SCID occurs due to defects in the T cell

receptor (TCR) signalling cascade either in the TCR/CD3 complex.

• Defects due to abnormal enzymes involved in purine metabolism lead to the accumulation of intracellular toxins that block T- and B-cell differentiation.• Defective expression of MHC class I and MHC class II leads

to impaired intrathymic development of CD8 and CD4 T cells, respectively.

Deficiencies of Cytokine Receptors• The most common form of SCID is X-linked, due to a mutation in the

gamma chain of the IL-2 receptor.

• Children with SCID secondary to IL-2R(gamma chain) or JAK(Janus Kinase)-3 deficiency have no circulating mature CD3⁺ T cells because of maturation arrest of T-cell development within the thymus.

• B cells are present in normal or increased numbers but are deficient in function, presumably due to a lack of T helper cell function.

• Natural killing (NK) cell numbers and function are also deficient.

• IL-7 receptor ἀ chain deficiency results in lack of T-cell differentiation, proving the key role of IL-7 in human T-cell differentiation.

Deficiencies of Purine Salvage Enzymes• The most common of these disorders are adenosine deaminase (ADA)

and purine nucleoside phosphorylase deficiencies. • Both lead to the intracellular accumulation of metabolites with toxic

effects on T cells.• ADA catabolizes the deamination of adenosine and 2-deoxyadenosine,

converting these compounds into inosine. Therefore, the lack of ADA causes the intracellular accumulation of adenosine and 2-deoxyadenosine.• Purine nucleotide phosphorylase deficiency causes an accumulation of

deoxyguanosine, which is triphosphorylated to deoxy guanosine triphosphate (deoxyGTP).• DeoxyGTP has toxic effects on T lymphocytes, causing their selective

depletion.

Clinical Presentation• Children with SCID may develop infections caused by

organisms or vaccines.• Among the most dangerous is an organism called

Pneumocystis jiroveci, which can cause a rapidly fatal pneumonia if not diagnosed and treated promptly.• Another dangerous organism is the chicken pox virus

(varicella). In the patient with SCID, chicken pox can be fatal because it does not resolve and can progress to cause infection in the lungs, liver and brain.• Cytomegalovirus (CMV), which nearly all people carry in their

salivary glands, may cause fatal pneumonia in patients with SCID

• Other dangerous viruses for patients with SCID are the cold sore virus (Herpes simplex), adenovirus, para influenza 3, Epstein-Barr virus polioviruses, measles virus (rubella) and rotavirus.

• Fungal (yeast) infections in patients with SCID may be very difficult to treats such as oral thrush.

• Candida pneumonia, abscesses, esophageal infection or even meningitis may develop in patients with SCID.

• Persistent diarrhea, resulting in growth failure or mal absorption, is a common problem in children with SCID.

• Patients with SCID may also have a rash that is mistakenly diagnosed as eczema, but is actually caused by a reaction of the mother’s T-cells (that entered the SCID baby’s circulation before birth) against the baby’s tissues. This reaction is called graft-versus-host disease (GVHD).

Diagnosis• The average lymphocyte count for patients with all types

of SCID is 1,500 lymphocytes (per cubic millimeter)• The most definitive test to examine the function of the T-

lymphocytes is to place blood lymphocytes in culture tubes, treat them with various stimulants and then, incubate them for several days.• Normal T-lymphocytes react to these stimulants by

undergoing cell division.• In contrast, lymphocytes from patients with SCID

usually do not react to these stimuli

• The diagnosis of SCID can also be made before the baby is born.

• This can be done by molecular testing of cells from a chorionic villus sampling (CVS) or from an amniocentesis, where a small amount of amniotic fluid (which contains fetal cells) is removed from the uterine cavity.

Treatment• Bone marrow transplants may be used to treat certain

immunodeficiency conditions.• Passive immunity may sometimes be recommended to

prevent illness after you have been exposed to bacteria or other germs.• Patients with hypogammaglobulinemia are treated with

immunoglobulin infusions through a vein. These infusions raise blood immunoglobulin levels and protect against many infections.

Haematopoietic Stem Cell Transplantation• All forms of SCID can be corrected with HSC transplantation.• Best results are with stem cells obtained from an HLA-matched

related donor.

Gene Therapy• Both the X-linked form of SCID and ADA deficiency have been

corrected by gene therapy.• The original protocol involved: harvesting peripheral blood T

lymphocytes from the patients, transfecting the ADA gene using a retrovirus vector, expanding the transfected cells in culture, and re-administering them to the patient.

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