The World Health Organization recognizes approximately 70 primary immune deficiencies
including X-Linked Agammaglobulinemia, Common Variable Immune Deficiency
(Hypogammaglobulinemia), Selective IgA Deficiency and Severe Combined Immune deficiency.
SCID leads to severe Tand B-cell dysfunction. It is generally considered to be the most
serious of the primary immunodeficiency diseases. Without intervention, death in children
occurs by age 2 years.
1:100,000 live births. Higher incidence recently
reported (1:50,000 to 1:75,000 live births), probably because of better
identification of affected subjects.
Of all SCID cases, 50% are X-linked (gene
mapped to Xq13) and 50% are various forms of autosomal recessive.
Approximately 25% of the patients with an autosomal recessive SCID are
Janus-associated kinase 3 (JAK3) deficient and 40% are adenosine
deaminase (ADA) deficient. Gene mapped to 8q11, 5p13.
The pathophysiology and molecular biology vary according to
the type of immunodeficiency. However, the lack of Tand B-cell function is the common
endpoint in all forms of SCIDS.
X-Linked form: Mutation of the common gamma chain of the interleukin (IL-2R, IL-4R, IL-7R,
IL-9R, IL-15R) resulting in loss of cytokine function. Loss of IL-2R
function leads to the loss of a lymphocyte proliferation signal. Loss of
IL-4R function leads to the inability of B cells to class switch. Loss of
IL-7R function leads to the loss of an antiapoptotic signal, resulting in a
loss of T-cell selection in the thymus. Loss of IL-7R function is also
associated with the loss of a T-cell receptor (TCR) rearrangement. Loss of
IL-15R function leads to the ablation of NK cell development. Lymphopenia
occurs primarily from the absence of CD3+ and NK cells. Variable levels of B
cells occur, which do not make functional antibodies.
Autosomal recessive SCID includes different types.
- Janus-Associated Kinase 3 (JAK3) Deficiency: JAK3 is a protein tyrosine kinase (PTK) that associates with the common
gamma chain of the IL receptors. Lymphopenia occurs primarily from the
absence of T cells (CD3+) and NK cells. Normal or high levels of B cells
occur, which do not make functional antibodies.
- Adenosine Deaminase (ADA) Deficiency: Lymphopenia occurs from the death of T and B cells secondary to the
accumulation of toxic metabolites in the purine salvage pathway. Functional
antibodies are decreased or absent.
- Purine Nucleoside Phosphorylase (PNP) Deficiency: Same as ADA deficiency with circulating B cells normal in number. B-cell
function is poor, as evidenced by the lack of antibody formation.
- Bare Lymphocyte Syndrome: This is a deficiency of major histocompatibility complex (MHC). The
lymphocyte count is normal or mildly reduced, the CD4+ are decreased, and
the CD8+ are normal or mildly increased. The B-cell ...