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1220 Part IX: Lymphocytes and Plasma Cells Chapter 80: Immunodeficiency Diseases 1221

and other conditions of neonatal erythroderma. 106–109 Male infants with 3-kinase inhibitor may reduce lymphoproliferation and hepatosple-
NEMO deficiency can also present with severe skin manifestations nomegaly in patients with activating PI3KD mutations. 29,30
resembling Omenn syndrome.
T-CELL IMMUNODEFICIENCIES WITH IMPAIRED
Treatment NUCLEAR FACTOR-κB ACTIVATION
In preparation for allogeneic HSCT, the only curative treatment avail-
56
able, patients require aggressive nutritional support, correction of Following TCR signaling, the complex composed of MALT1, BCL-10,
hypoproteinemia, and treatment or prevention of infections with antibi- and caspase recruitment domain-containing protein (CARD)-11 pro-
otics, antifungals, and immunoglobulin replacement therapy. Immune teins is activated, resulting in recruitment of TRIF-related adaptor
suppression with steroids or cyclosporine is beneficial in controlling molecule (TRAF) 6 and activation of IKK, permitting nuclear translo-
T-cell–mediated tissue damage. cation of the p50 and p65 subunits of NF-κB and consequently induc-
118
tion of activation of NF-κB–dependent genes. Mutations of MALT1,
CARD11, 119,120 and IKBKB (encoding for the IKKβ component of the
121
DEFECTS OF T-CELL–RECEPTOR SIGNALING IKK complex) genes are associated with increased susceptibility to bac-
Definition terial, viral and fungal infections. Although the number of circulating
TCR ligation promotes activation of the p56Lck kinase, which medi- T lymphocytes is normal, generation of memory T cells is impaired and
ates phosphorylation of components of the CD3 complex. This allows proliferative responses to CD3 stimulation are decreased. Patients with
recruitment and phosphorylation of the zeta-associated protein CARD11 mutations have a block in B-cell development at the transi-
of 70 kDa (ZAP-70), activation of downstream signaling molecules, tional stage, 119,120 and virtual absence of class-switched memory B cells
release of Ca from intracellular endoplasmic reticulum stores, and is observed in patients with IKBKB mutations. 121
2+
initiation of Ca influx. Mutations of lymphocyte-specific protein As reported above, mutations of the IKBKG/NEMO gene are
2+
tyrosine kinase (LCK), ZAP-70, and of other TCR-associated signaling responsible for X-linked immunodeficiency with ectodermal dysplasia,
molecules (RHOH, MST1, IL-2–inducible T-cell kinase [ITK]) result whose clinical manifestations may also include opportunistic infections,
in various forms of CID with dysfunctional T cells. 110–115 Finally, PI3K, resembling CID. Finally, gain-of-functions mutations of the IKBA gene,
composed of a p110δ and a p85 subunit, is involved in generation of that prevent phosphorylation and degradation of the IKB-α subunit of
phosphatidylinositol 4,5-triphosphate (PIP ) and activation of mamma- the IKB complex, cause T-cell immunodeficiency with ectodermal dys-
3
lian target of rapamycin (mTOR) and AKT. Activating mutations of the trophy. The immunologic phenotype includes deficiency of memory T
PI3KD gene (encoding for the PI3K subunit p110δ) results in increased cells, impaired in vitro proliferation of naïve T cells to TCR/CD3 stim-
activation-induced cell death of T lymphocytes, and consequently ulation, and hypogammaglobulinemia with inability to mount specific
122
immunodeficiency. 29,30 antibody responses. In addition to TCR signaling, activation of toll-
like receptor (TLR) and tumor necrosis factor (TNF) pathways can also
be compromised, causing increased susceptibility to a broad range of
Clinical and Laboratory Features pathogens (pyogenic bacteria, mycobacteria, Candida, other opportu-
Patients with these disorders present with early onset and severe infec- nistic pathogens). 123
tions. Warts, molluscum contagiosum, infections caused by herpes
viruses, and a high risk of Epstein-Barr virus (EBV)-driven lymphop-
roliferative disease have been reported in patients with LCK, RHOH, CORONIN-1A DEFICIENCY
and MST1 deficiency, and with activating PI3KD mutations. 29,30,110,113,114 Coronin-1A is an actin regulator that is predominantly expressed in
Moreover, autoimmunity and lung granulomatous disease may also hematopoietic cells, plays a key role in regulating T-cell survival and
occur. From a laboratory standpoint, selective loss of CD8 lymphocytes migration. Mutations affecting both alleles of the CORO1A gene have
+
is observed in patients with ZAP-70 deficiency, and although the num- been reported in patients with CID and an increased risk of severe
ber of CD4 lymphocytes is preserved, in vitro response to mitogens varicella and EBV lymphoproliferative disease. 124,125 The immunologic
+
is markedly reduced, consistent with a signaling defect. 111,112 Patients phenotype includes naïve T-cell lymphopenia with normal numbers of
with LCK, RHOH, MST1, and ITK deficiency and with gain-of-func- B and NK cells, oligoclonal T-cell repertoire and reduced number of
tion PI3KD mutations have a reduced number of naïve CD4 T cells. circulating invariant NKT (iNKT) cells and mucosa-associated invari-
+
Oligoclonality of the T-cell repertoire and an increased proportion of ant T (MAIT) lymphocytes. Immunoglobulin serum levels are low, and
exhausted CD8 T memory (T EMRA ) cells have been reported in these antibody responses to antigens are absent. The disease can be treated by
+
patients. 29,30,107,113–115 allogeneic HSCT. 124
Differential Diagnosis CD27 DEFICIENCY
Differential diagnosis of ZAP-70 deficiency includes MHC class I defi- The CD27 costimulatory molecule regulates survival and activation of
ciency and CD8α deficiency, two conditions characterized by a severe T, B, and NK cells. CD27 deficiency is a CID with risk of EBV lymphop-
reduction of CD8 lymphocytes. Patients with CD8α deficiency have an roliferative disease. In vitro T-cell proliferation to mitogens and antigens
+
unusual population of CD3 TCR αβ CD4 CD8 cells that have normal is reduced. Immunoglobulin serum levels may be initially high, but
–
+
+
–
126
proliferative responses and usually survive to adulthood, although a late patients eventually become hypogammaglobulinemic.
death from infections has been reported. 116,117 The other defects of TCR
signaling have an overlapping phenotype. Ultimately, biochemical and
molecular tests are needed to define the diagnosis. CTPS1 DEFICIENCY
Cytidine 5-triphosphate synthase 1 (CTPS1) is involved in de novo
Treatment synthesis of cytidine 5-triphosphate (CTP), a nucleotide required for
The only curative treatment of this group of disorders is allogeneic HSCT. DNA and RNA metabolism. Impaired de novo synthesis of CTP causes
Treatment with rapamycin (an mTOR inhibitor) or phosphoinositide a proliferation defect in both T and B lymphocytes. CTPS1 mutations

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