Page 515 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPTEr 35 Primary T-Cell Immunodeficiencies 495

The serine/threonine kinase recognizes open DNA ends and is
part of a complex involved in the nonhomologous end joining Adenosine Deaminase Deficiency
(NHEJ) pathway essential for DNA recombination. Clinical Adenosine deaminase (ADA) deficiency (OMIM #102700) is an
presentation is indistinguishable from SCID, with virtually absent autosomal metabolic disorder caused by deleterious mutations
T cells and B cells but normal NK cells. These patients may in the ADA gene (OMIM*608958). This is a critical enzyme that
15
present with severe neurological abnormalities. HSCT may be aids in the degradation and salvage of purine pathway metabolites
a curative option, although caution must be exercised during the and is essential for multiple processes, such as energy transfer
conditioning regimen because of the underlying defect in DNA and DNA metabolism. Damage to various tissues and lesions in
repair. the immune system are caused by toxic accumulation of unde-
graded metabolites, such as deoxyadenosine. Thymocytes are
DNA Ligase IV Deficiency particularly sensitive, but B cells and NK cells are also frequently
DNA ligase IV deficiency (OMIM #606593) is clinically pleo- affected. Because toxicity to lymphocytes is lineage specific and
− +
− −
morphic with presentations ranging from intact immunity to a time dependent, patients may present with T B or T B phe-
SCID phenotype. Other features include facial dysmorphia, notype. Some may have Omenn syndrome and present with
+ −
+ + 19
various degrees of developmental delay, and microcephaly. These T B or T B . Mutations that spare some ADA activity may
20
features are consistent with DNA ligase IV knock-out mice, which result in a delayed presentation. Patients with ADA deficiency
are characterized by defective lymphogenesis and neurogenesis. mostly present with typical SCID features or Omenn syndrome,
DNA ligase IV is a component of the NHEJ complex and par- while patients with “partial deficiencies” can present with CID,
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ticipates in the repair of DNA double-strand breaks that arise autoimmunity, and susceptibility to malignancy. Other associated
during DNA damage, such as from ionizing radiation, or the features include brain anomalies resulting in various levels of
endogenous recombination process. Hypomorphic mutations developmental delay and bone, liver, lung, and kidney anomalies.
in DNA ligase IV can be associated with increased sensitivity to Standard diagnostic tools for this disorder demonstrate barely
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radiotherapy, EBV-associated lymphoproliferation and T-cell detectable ADA enzyme activity and increased accumulation of
leukemia. Diagnosis may be challenging, with immune evaluation purine metabolites in blood or urine. The diagnosis can be
revealing low to absent T cells and B cells during infancy in confirmed by genetic analysis. Polyethylene glycol-conjugated
some patients, whereas in others diagnosis may be delayed to ADA (PEG-ADA) can be used for “detoxification”; however,
the second decade of life in individuals with various degrees of salvage of complete or even partial immunity may not be achieved,
22
lymphopenia and hypogammaglobulinemia. Microcephaly and and efficacy may be short lived. HSCT remains the treatment
developmental delay can help in the diagnosis if present. HSCT of choice if a full human leukocyte antigen (HLA)–matched
was attempted in patients with DNA ligase IV deficiency with related donor is available. For other patients, gene therapy is
limited success because of increased toxicity of conditioning gradually becoming standard of care. 23
regimens as well as graft-versus-host disease (GvHD).
Cernunnos Deficiency COMBINED IMMUNODEFICIENCY
Patients with Cernunnos deficiency (OMIM #611291) present (SCID PHENOTYPE)
early in life with profound T-cell lymphopenia, progressive
− −
decrease in B cells (T B SCID), and microcephaly. The syndrome Combined immunodeficiencies presenting with features typical
has an autosomal recessive pattern of inheritance. Cernunnos of SCID are summarized in Table 35.4.
(OMIM *611290) forms a complex with DNA ligase II and XRCC4
and likely plays an important role in the NHEJ pathway. Disrup- ZAP-70 Deficiency
tion of Cernunnos, like other members of this pathway, is ZAP-70 deficiency (OMIM #269840) is a rare CID with an
associated with radiosensitivity. Clinical presentation consists autosomal recessive pattern of inheritance. The disease was first
of recurrent infections, as in typical SCID, as well as developmental described as a novel immunodeficiency with normal numbers
delay, microcephaly, urogenital and bone malformations, and of circulating CD4 cells but CD8 lymphopenia. ZAP-70 is a
facial dysmorphic features. protein tyrosine kinase critical in mediating T-cell receptor
signaling. Upon phosphorylation and activation, ZAP-70 phos-
AK2 Deficiency (Reticular Dysgenesis) phorylates a host of downstream molecules culminating in T-cell
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Adenylate kinase-2 (AK2) deficiency, also known as reticular proliferation and maturation. Patients typically present within
dysgenesis (OMIM #267500), is a profound inherited immune defi- the first 2 years of life with repeated severe microbial infections
ciency characterized by severe lymphopenia and marrow failure. indistinguishable from SCID. However, unlike typical SCID,
The disorder has an autosomal recessive pattern of inheritance patients with ZAP-70 deficiency also present with palpable lymph
and is caused by mutations in the AK2 gene. 17,18 Mitochondrial nodes, visible tonsils, and a normal thymus shadow on imaging.
AK2 catalyzes the reversible phosphorylation between nucleoside Rarely, patients present with autoimmune manifestations, Omenn
triphosphates and monophosphates. AK2 defects are associated syndrome, hemophagocytic lymphohistiocytosis (HLH), sub-
with impaired mitochondrial energy metabolism and leukocyte cutaneous nodules, or lymphoma. 25,26
differentiation. Patients suffer repeated bacterial, viral, and fungal Immune evaluation reveals normal numbers of circulating
17
4,7
infections and have bilateral sensorineural deafness. Patients lymphocytes but marked reduction in CD8 cells. Responses
present in infancy with profound neutropenia and lymphopenia, to mitogens are depressed; however, the T-cell repertoire of CD4
the thymus is dystrophic, and TRECs are undetectable. Diagnosis cells appears normal. The thymus gland is fully developed with
is confirmed by genetic analysis. Bone marrow reconstitution can normal architecture and normal corticomedullary distinction,
be achieved with HSCT and remains the most effective modality including the presence of Hassall corpuscles. However, the
of treatment. corticomedullary ratio appears increased. B-cell number and Ig