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1218 Part IX: Lymphocytes and Plasma Cells Chapter 80: Immunodeficiency Diseases 1219

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trait, and its phenotype is identical to that of X-linked SCID (T B NK T-cell engraftment derived from maternal cells that cross the
SCID). 53,54 In contrast, autosomal recessive IL-7R deficiency caused by placenta occurs in more than 50 percent of infants with SCID. Most
mutation of the α chain is characterized by the selective lack of T cells often asymptomatic, it may cause skin rash or, less frequently, typical
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(T B NK SCID). 55 graft-versus-host disease with generalized rash, liver disease, profuse
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diarrhea, jaundice, and severe hematologic abnormalities (thrombocy-
Severe Combined Immune Deficiency as a Result of Defective topenia, anemia, leukopenia) that are indicative of marrow damage. 72,73
Signaling Through the T-Cell Receptor Transfusion of un-irradiated blood products often leads to fatal graft-
One of the distinctive features of developing thymocytes is the expression versus-host disease.
of the pre–T-cell receptor (TCR), that is composed of a pre-Tα chain,
a TCRβ chain, and the CD3 γ, δ, ε, and ζ chains. Signaling through the Laboratory Features of Severe Combined Immunodeficiency
pre-TCR permits rearrangement of the TCRα chain and expression of a Syndrome
mature TCRαβ. Alternatively, thymocytes may express the γδ chains of An absolute lymphocyte count less than 2000/μL should prompt imme-
the TCR. Rearrangement of the TCR loci is accomplished by means of diate investigation for SCID, regardless of the severity of clinical symp-
the V(D)J recombination, whereby the lymphoid specific recombination toms. Typically, infants with SCID have markedly reduced or absent
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activating gene 1 (RAG1) and recombination activating gene 2 (RAG2) circulating T cells which are unable to proliferate in vitro in response to
proteins mediate DNA cleavage at the variable (V), diversity (D), and mitogens and specific antigens. However, T lymphocyte count may be
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joining (J) elements of the TCR loci. The DNA double-strand break of preserved, at least in part, in SCID infants with maternal T-cell engraft-
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the coding ends is initially sealed as a hairpin, followed by nonhomol- ment, with “leaky” variants of the disease, or with somatic reversions
ogous endjoining via the nuclease Artemis (encoded by the DCLRE1C that allow for some autologous T-cell development. Finally, T-lymphocyte
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gene). Eventually, joining of coding (and signal) elements is mediated by count can be normal or modestly reduced in patients with functional
a series of proteins, that include the Ku70/80 heterodimer, XRCC4, DNA T-cell immunodeficiencies (see other combined immunodeficiencies;
ligase IV (LIG4), DNA-protein kinase catalytic subunit, and Cernunnos/ defective thymic development).
XLF. Defects in V(D)J recombination affect both T- and B-cell develop- Maternal T-cell engraftment and “leaky” SCID with residual devel-
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ment and hence cause T B NK SCID, because this process is also essen- opment of autologous T cells are characterized by the expression of
tial to mediate rearrangement of the immunoglobulin genes, a key step the CD45R0 memory/activation antigen on the surface of circulating
in B-cell development. RAG1 or RAG2 deficiencies account for 3 to T lymphocytes (whereas most T cells in normal infants have a naïve
20 percent of all SCID cases in different series. 42,56 Artemis (DCLRE1C), CD45RA phenotype).
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DNA-protein kinase catalytic subunit, LIG4, 59,60 and Cernunnos/ TCR excision circles, consisting of circularized signal joints, are
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XLF deficiencies are less frequent and their cellular and clinical phe- a byproduct of V(D)J recombination and are exported to the blood by
notypes extend beyond impaired T- and B-cell development, because recent thymic emigrants. Levels of TCR excision circles in circulating
enzymes that mediate DNA double-strand break repair are ubiquitously lymphocytes are particularly high in newborns and infants, and pro-
expressed, and their deficiency results in increased cellular radiosensi- gressively decline with age. Because TCR excision circles cannot be
tivity. 57–61 The phenotype of LIG4 deficiency can be extremely variable, detected in infants with SCID, assessment of TCR excision circle levels
from T B NK SCID to mild or no immunodeficiency, whereas Cernun- by polymerase chain reaction has been successfully introduced for new-
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nos/XLF deficiency is characterized by significant T-cell lymphopenia born screening for SCID. 76
and progressive decrease in the number of B cells. Although the number of circulating B lymphocytes can vary
Defects of the CD3 δ, ε, or ζ chains affect signaling through the depending on the nature of the genetic defect, serum immunoglobulin
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pre-TCR and the TCR and hence cause autosomal recessive T B NK levels are low in infants with SCID (see Table 80–2). Normal serum IgG
SCID. 62–64 In contrast, CD3γ deficiency is associated with mild T-cell levels early in life reflect transplacental passage of maternal immuno-
lymphopenia and a variable clinical phenotype. 65,66 globulins. Antibody response to immunization antigens is abolished.
Mutations of the TCRα constant (TCRA) gene cause impaired dif- Eosinophilia may be observed in SCID, and IgE serum levels may
ferentiation of T cells expressing TCRαβ. 67 be elevated in spite of hypogammaglobulinemia. Cytopenias, caused
Mutations of CD45, a pan-leukocyte tyrosine phosphatase that has by infections or marrow damage, may also be present. Autoimmune
been implicated in signaling through the TCR and the B-cell receptor, hemolytic anemia is frequent in PNP deficiency. Marrow abnormali-
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have been reported in few patients with T B NK SCID. 68,69 ties (dysplasia or aplasia) can be observed in ADA, PNP, Cernunnos/
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XLF, 79,80 and LIG4 deficiencies.
Clinical Features of Severe Combined Immunodeficiency The diagnosis of ADA and PNP deficiency is facilitated by the
Syndrome demonstration of increased levels of deoxyadenosine triphosphate
Despite genetic heterogeneity, SCID is characterized by a consistent and deoxyguanosine triphosphate, respectively, in red blood cells.
clinical phenotype. Interstitial pneumonia, often sustained by P. jirovecii, Differential diagnosis of SCID includes secondary forms of immu-
cytomegalovirus (CMV), adenovirus, parainfluenza 3 virus, respiratory nodeficiencies, especially HIV infection, congenital rubella, and CMV
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syncytial virus, chronic diarrhea, failure to thrive, and persistent can- infections, severe malnutrition, marrow failure syndromes, and defects
didiasis are common features (see Table 80–1). Typically, infections of vitamin B and folate metabolism. 83,84
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develop in the first months of life. Skin manifestations (maculopapular
rash, erythroderma, alopecia) are also common, especially in infants Therapy, Course, and Prognosis of Severe Combined
with maternal T-cell engraftment. Hypoplastic lymphoid tissue (tonsils, Immunodeficiency Syndrome
lymph nodes), and absence of a thymic shadow on chest radiography SCID is a medical emergency and is inevitably fatal if untreated. Con-
are characteristic. 70 firmation of diagnosis by appropriate laboratory assays, referral to a
Because of the inability to control replication of live microorgan- tertiary care center, and aggressive treatment of infections should be
isms, administration of live-attenuated vaccines often leads to severe, immediately initiated in infants with possible SCID. High-dose intrave-
life-threatening complications in infants with SCID. 71 nous sulfamethoxazole-trimethoprim (20 mg/kg) is effective in treating
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