Page 523 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPTEr 35 Primary T-Cell Immunodeficiencies 503

role in signaling responses to a variety of cytokines, such as system. Early diagnosis is critical to minimizing morbidity and
interferon-α (IFN-α), IFN-β, IFN; IL-2, -3, -6, -9, -10, -11, -12, improving quality of life, and with the increasing implementation
and -15; growth hormone fibroblast growth factor; epidermal of NBSs, patients now have a greater chance of being diagnosed
growth factor; and others. Cytoplasmic STAT1 is activated through shortly after birth. Importantly, measures that minimize exposure
tyrosine phosphorylation by members of the JAK kinase family, of patients to infections, including use of irradiated and filtered
which results in its translocation to the nucleus and subsequent blood products, avoidance of live vaccines, and nutritional
binding to target DNA segments. Typically, these patients harbor support, should also be considered as part of therapy.
de novo mutations in the DNA-binding domain of STAT1.
Although increased tyrosine phosphorylation of STAT1 or even THEraPEuTIC PrINCIPLES
enhanced DNA binding may be observed, STAT1 function is
altered and patients’ cells produce reduced amounts of IL–2, Management of Severe Combined
IFN-γ, and other cytokines, hence the designation of STAT1 Immunodeficiency
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dysfunction. HSCT has been attempted with variable degrees • Patients should be kept in a protective isolation environment, receive
of success. 61,62 prophylactic antibiotics, immunoglobulin replacement, and enhanced
nutrition.
RelB Deficiency • Patients should only receive cytomegalovirus (CMV)–free, irradiated
+ +
+
This is a newly described CID (T B NK ) that is inherited in an blood products and irradiated breast milk. Breast feeding should be
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autosomal recessive mode. The immunodeficiency is caused discontinued if the mother is CMV positive.
by mutations in RELB (OMIM *604758), a key component of • Live attenuated vaccines should be avoided.
• The immune defect in severe combined immunodeficiency (SCID),
the NF-κB pathway. Lymphocyte antigen receptors, multiple and in many cases of combined immunodeficiency (CID), can be
cytokines, and infective agents all use the NF-κB signaling corrected by administration of allogeneic hematopoietic stem cell
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pathway. The pathway consists of five members, including RelA, transplantation (HSCT).
RelB, c-Rel, and the precursor proteins NF-κB1 (p105) and • Best results are achieved using an human leukocyte antigen (HLA)–
NF-κB2 (p100), which are processed to the active forms p50 identical family donor.
and p52, respectively. Two NF-κB pathways are recognized, the • Patients with autologous T cell should receive myeloablative conditioning
to improve engraftment and sustained long-term immune reconstitution.
classical pathway, mediated by RelA, and the alternative (non- • Gene therapy should be offered in selected types of SCID, such as
canonical) pathway, which uses RelB. Activation of RelB requires adenosine deaminase (ADA) deficiency, whereas this procedure remains
inducible processing of p100 and p52. Unlike the classical pathway, experimental in other conditions.
which is engaged by many receptors, the alternative pathway is
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used by TNFRSF12A, LTβR, CD40, and BAFF-R. Patients with
RelB deficiency present in the first year of life with failure to Newborn Screening
thrive, recurrent infections, and autoimmune disorders. In vitro Patients with SCID usually die of overwhelming infections or
responses to mitogens are depressed, the TCR repertoire is suffer associated catastrophic complications once maternally
restricted, and TRECs are abnormal. Production of specific transferred antibodies have been metabolized, usually within
antibodies in response to vaccination is impaired. The thymus 3–6 months after birth. However, if diagnosed early and before
appears moderately dysplastic. Both memory T and B cells are the onset of complications, most of these patients can be treated
reduced or absent. 63,65,66 HSCT has been successful in two patients successfully with HSCT.
who received the procedure. TRECs, which are produced during programmed gene rear-
rangement of progenitor T cells in the thymus, were identified
STK4 (Mst1) Deficiency as a useful biomarker of both thymic function and the production
This is an autosomal recessive combined immunodeficiency of newly formed T cells. Since the thymus is invariably dysfunc-
characterized by a progressive loss of T cells and declining function tional in SCID, the use of TREC detection in blood from Guthrie
(OMIM #614868). The deficiency is caused by biallelic mutations spots serves as an ideal NBS tool. 67
in serine threonine kinase 4 (STK4). STK4 functions as a pro- NBS utilizing TRECs detects most cases of phenotypic SCID,
apoptotic factor by promoting Fas-mediated apoptosis. STK4-null especially those who have lymphocytopenia of less than 300–500
+
mice demonstrate increased apoptosis leading to T- and B-cell CD3 cells/µL. It may also detect other conditions where the
lymphopenia, as well as depletion of the thymus gland. Patients patient presents at birth with profound lymphopenia—such as
present with oral thrush and mucocutaneous candidiasis, recurrent ataxia telangiectasia, Nijmegen breakage syndrome, Di George
bacterial and viral lung infections, and EBV-induced B-cell syndrome, CHARGE, Rac2 and DOCK8 deficiencies, as well as
lymphoproliferation. Skin manifestations include disseminated trisomy. 21
warts and molluscum contagiosum. Evaluation of the immune However, cases that are phenotypically similar to SCID, such
system reveals progressive decrease in T and B cells and an altered as ZAP-70 deficiency or other CIDs with a severe phenotype
+
TCR Vβ repertoire. Serum Igs, including IgE, are elevated, and (CD3 >300–500 cells/µL) may be missed. This highlights the
autoantibodies have been observed. Autoimmune cytopenias need consider other methodologies, such as next generation
have also been reported. HSCT is the treatment of choice. sequencing, which have the capacity to detect these cases at birth.
DIAGNOSIS, MANAGEMENT, AND TREATMENT OF Isolation
T-CELL AND COMBINED IMMUNODEFICIENCY Patients with primary immunodeficiency are susceptible to
recurrent and opportunistic infections, posing an immediate
The current approach to management and treatment of primary threat to life. As a preventative measure, isolation and the provi-
immunodeficiencies involves prevention and treatment of infec- sion of an aseptic environment are recommended and have been
tions, and when attainable, restoration of a functional immune shown to protect against infections for extended periods. The