Combined T and B deficiencies
Deficiencies that affect both B and T lymphocyte numbers and/ or
their functions are life threatening. Such deficiencies are termed severecombined immunodeficiency (SCID).
The term SCID represents a groupof disorders associated with more than 20
different mutations and with a frequency of between one in 50 000 and one in
500 000 births. As some forms of SCID are inherited in an X-linked fashion ,
more boys than girls are affected, with the male : female ratio of
approximately 3 : 1.
Depending on the mutation involved, T and B cells may both be
decreased (T–B– SCID) or B cells numbers may be normal or
increased (T–B+SCID). In the latter, the absence of T
cells renders B cells functionally inactive, owing to the need for the
cytokines produced by TH cells for antibody production as described.
In either case, the disorder becomes apparent in the first few weeks
The disease is characterized by chronic viral and fungal infections.
Chronic diarrhea and oral Candida infections are common and in the presence of
other infections, the child fails to thrive. Affected infants may suffer
generalized viral infections if given live viral vaccines, such as the MMR and
polio vaccines. Laboratory tests show fewer than 3000 per mm3
circulating lymphocytes (where the reference range for an infant of six months
is between 4000 and 13 500 per mm3). The lymphocytes present are
functionally inactive and do not respond in
vitro to knownmitogens. Chest
X-rays show an abnormally smallor absent thymus.
Approximately 20% of T–B– SCID arises from
mutations in the gene encoding adenosine deaminase (ADA). The absence of this
enzyme results in the accumulation of metabolites, such as ADP, GTP and dATP,
which are toxic to small lymphocytes. A similar syndrome arises from deficiency
of the purine nucleoside phosphorylase (PNP) that results in an accumulation of
dGTP. Approximately 40% of cases of T–B+ SCID are
X-linked and arise from mutations in a polypeptide that forms part of the
receptor for several interleukins (ILs), so that affected lymphocytes are
unable to respond to interleukin signals.
If not diagnosed early and treated appropriately, children with SCID usually
die from infections in the first few years of life. Management of this
condition includes administering antiviral, antibacterial and antifungal drugs
and measures must be taken to avoid infection. Keeping such infants in totally
aseptic conditions is neither feasible nor ethical, since this would preclude
direct contact with other humans. Their immune system may be restored with a
bone marrow transplant. This can lead to long-term survival but is not without
danger, chiefly graft versus host disease. Gene therapy has been attempted with
some ADA deficient patients and, in a few cases, has been reported to be