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Advance Paper in Clinical
Combined T and B cells Deficiencies - SCID
Girish Kumar K
• Combined immunodeficiencies are those in which both
cell-mediated immunity and humoral immunity are
• The Severe Combined Immunodeficiency (SCID) comes
under such category.
Severe Combined Immunodeficiency
Severe, 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
SCID is classified into two, based on the predominant arm
of immunity impacted.
I. Arrest in T cells with normal B cell numbers [T(-),
II. Arrest of both T and B cell development [T(-), B(-)
• Most forms are due to an inheritable disorder, which can be
inherited as an X-linked recessive form or as an autosomal
Pathogenic Mechanism Of SCID
There 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
• 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,
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
• Natural killing (NK) cell numbers and function are also
•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
• 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
• 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
• 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).
• 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
• 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.
• Bone marrow transplants may be used to treat certain
• 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
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.
• 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.