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1216 Part IX: Lymphocytes and Plasma Cells Chapter 80: Immunodeficiency Diseases 1217

Figure 80–1. Disruption of the normal T-cell
pro NK development by mutations of genes known
to cause a severe combined immunodefi-
ciency disease phenotype. B, B lymphocyte;
CLP, common lymphocyte progenitor; γc, com-
mon gamma; Gran-P, granulocyte progenitor;
HSC, hematopoietic stem cell; JAK3, Janus-as-
sociated tyrosine kinase 3; MHC, major histo-
compatibility complex; Mono-P, monocyte
pro T progenitor; NK, natural kill lymphocyte; ORAI1,
calcium release-activated calcium channel pro-
IL 7R tein 1; T, T lymphocyte; TAP-1/2, transport-as-
sociated protein 1/2; ZAP70, zeta-associated
Rag 1,2 TAP 1,2 protein of 70 kDa.

pro B
Rag 1,2
Artemis
Cernunnos
DNA ligase 4

who died with overwhelming infections, intractable diarrhea, thrush, extend beyond the immune system, reflecting the fact that ADA is a
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and profound lymphophenia. The SCID phenotype represents a het- general housekeeping enzyme.
erogeneous group of genetic disorders that are characterized by a severe Purine Nucleoside Phosphorylase Deficiency Purine nucleoside
impairment of T-lymphocyte development and function (Fig. 80–1). 42–44 phosphorylase (PNP) is another enzyme of the purine salvage pathway.
Depending on whether the development of B and/or NK lymphocytes is PNP catalyzes the phosphorylation of inosine, guanosine, and
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also affected, SCID can be classified into four distinct immunologic phe- deoxyguanosine. In the absence of PNP, high intracellular levels of
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notypes: (1) T B NK SCID (the most common variant); (2) T B NK deoxyguanosine triphosphatase cause lymphoid and neuronal toxicity.
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SCID; (3) T B NK SCID; or (4) T B NK SCID (see Table 80–2). The Immature thymocytes are particularly susceptible to PNP deficiency.
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term combined immune deficiency (CID) is used to define disorders with Accordingly, the immunologic phenotype of PNP deficiency is char-
residual development and/or function of T lymphocytes. Unless treated acterized by decreased T-cell counts, whereas B and NK lymphocytes
by allogeneic HSCT or, in selected cases, by gene therapy or enzyme are often unaffected. PNP deficiency accounts for 1 to 2 percent of all
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replacement therapy, SCID is inevitably fatal. forms of SCID, and is inherited as an autosomal recessive trait.
Adenylate Kinase 2 Deficiency Another rare variant of autoso-
mal recessive SCID, reticular dysgenesis, is characterized by extreme
MOLECULAR DEFECTS AND PATHOGENESIS OF lymphopenia, absence of neutrophils, and sensorineural deafness. The
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SEVERE COMBINED IMMUNE DEFICIENCY disease is caused by mutations of adenylate kinase 2 that result in apop-
tosis of myeloid precursors of neutrophils, and of lymphoid progenitor
SCIDs are mendelian disorders, and their overall prevalence is esti- cells. 49,50
mated to be approximately 1 in 50,000 births. In Western countries, the
most common form of SCID is inherited as an X-linked trait; however, Severe Combined Immune Deficiency as a Result of Defects of
a variety of autosomal recessive forms are also known. SCID can be Cytokine-Mediated Signaling
grouped in different categories that illustrate the various pathogenetic Thymic T-cell progenitors depend on interleukin (IL)-7 for cell prolifer-
mechanisms involved in T-cell development. ation. The IL-7 receptor (IL-7R) is composed of an α chain (encoded by
the IL7R gene) and a common γ chain (γc), that is shared also by IL-2R,
Severe Combined Immune Deficiency as a Result of Increased IL-4R, IL-9R, IL-15R, and IL-21R, and is encoded by the IL2RG gene,
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Apoptosis of Lymphocyte Precursors located on the X chromosome. Cytokine-mediated signaling through
Adenosine Deaminase Deficiency Approximately 5 to 10 percent of γc—containing receptors involves activation of Janus-associated
infants with SCID have a deficiency of adenosine deaminase (ADA), the tyrosine kinase 3 (JAK3). In humans, defects of IL-7–mediated signal-
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enzyme that converts adenosine and deoxyadenosine into inosine and ing abrogate T-cell development, whereas impaired signaling through
deoxyinosine, respectively. In the absence of ADA, high intracellular IL-15R affects development of NK cells. X-linked SCID, caused by
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levels of adenosine, deoxyadenosine, and their toxic phosphorylated IL2RG mutations, represents approximately 30 percent of all cases of
metabolites cause apoptosis of lymphoid precursors, and hence result in SCID, and is characterized by lack of T and NK lymphocytes but normal
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the virtual absence of T lymphocytes, that is usually associated with marked development of B cells (T B NK SCID). B-lymphocyte function, how-
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reduction of B and NK lymphocytes (T B NK SCID). ADA-SCID ever, is severely compromised by both the lack of T-cell help and non-
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is inherited as an autosomal recessive trait, and its clinical manifestations functional γc. JAK3 deficiency is inherited as an autosomal recessive
Kaushansky_chapter 80_p1211-1238.indd 1217 9/18/15 10:00 AM