Page 519 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPTEr 35 Primary T-Cell Immunodeficiencies 499

pathway encompasses the NF-κB essential modulator (IKKγ, or are normal, and responses to mitogens are normal in most
NEMO), IKK1 (IKKα), and IKK2 (IKKβ). Upon activation of patients. Some patients suffer bacterial infections as well as chronic
the complex, IKK2 phosphorylates inhibitors of NF-κB, which EBV viremia, and HSCT has been sometimes successful. 42
are degraded, therefore allowing nuclear translocation of NF-κB EBV-induced lymphoid proliferation and lymphoma (OMIM
and DNA binding. Patients present with oral thrush, pulmonary #613011) can also be caused by biallelic mutations in the IL-2
38
43
infections, and invasive bacterial infections. Evaluation of the inducible T-cell kinase (ITK) gene. X-linked lymphoproliferative
immune system reveals normal numbers of circulating T cells syndrome-1 (XLP, OMIM #308240) and -2 (XLP2, OMIM
but reduced NK cells. Responses to mitogens are variable, TREC #300635) are caused by hemizygous mutations in SH2DIA (XLP1)
44
levels are normal, and the TCR repertoire is intact. The B-cell and BIRC4 (XIAP), respectively. Patients can present with
−
+ +
38
compartment lacks memory B cells (T B NK ). HSCT is a overwhelming EBV infection causing liver necrosis and failure,
plausible choice for treatment; however, results so far are very aplastic anemia, or with chronic EBV infections culminating in
limited and variable. Like other NK-κB pathway disorders, malignant lymphoma. Some patients present with hypogam-
engraftment may be incomplete using current bone marrow maglobulinemia and antibody deficiency, and some others may
45
transplantation protocols. develop hemophagocytic lymphohistiocytosis. XLP2 is more
46
frequently associated with chronic colitis. Lymphocyte numbers
DOCK8 Deficiency and response to mitogens are typically normal, whereas NK-cell
Dedicator of cytokinesis 8 (DOCK8) deficiency (OMIM #243700) activity may be impaired. HSCT can reverse the susceptibility
is an autosomal recessive combined immunodeficiency combined to EBV. 45
39
with severe atopy. DOCK8 interacts with Rho guanosine tri-
phosphatases (GTPases) and is believed to be involved in COMBINED IMMUNODEFICIENCY WITH IMMUNE
cytoskeletal rearrangement, affecting cell adhesion and motility. DYSREGULATION AND SYNDROMIC FEATURES
Patients suffer recurrent respiratory infections and, less frequently,
invasive bacterial and fungal infections. In addition to severe PNP Deficiency
eczema, patients may have extensive warts and molluscum Purine nucleoside phosphorylase (PNP) deficiency (OMIM #
contagiosum. Food allergies, asthma, and anaphylaxis have also 613179) is an autosomal recessive multisystem syndrome caused
been documented. Immunological assessment shows great vari- by mutations in PNP, a key enzyme in the purine salvage pathway.
ability with variable number of T cells and B cells but increased PNP catalyzes the phosphorylation of guanosine, deoxyguanosine,
eosinophil counts. Responses to mitogens appear normal. IgG inosine, and deoxyinosine. This pathway is responsible for balanc-
is elevated, but other serum Ig levels and specific antibodies are ing the production of dephosphorylated purines and degradation
39
variable. Treatment is dictated by the various atopic and infec- to uric acid and salvage back to the nucleotide level. Lymphotoxic-
tious manifestations. ity is caused by accumulation of dGTP in mitochondria inducing
apoptosis, and T-cell toxicity may be related to the need for high
RHOH Deficiency deoxyguanosine phosphorylation activity in T cells. Indeed,
This is an autosomal recessive immunodeficiency caused by PNP-deficient mice created by gene targeting have no detected
mutations in the Ras homologue gene family member H gene PNP activity and demonstrate a sharp reduction in T-cell numbers
+
+
(RHOH; OMIM *602037), which is mostly expressed in the and function due to loss of double positive CD4 CD8 progenitors,
hematopoietic system. Upon ligation of TCR, RhoH undergoes as well as progressive loss of peripheral T cells.
phosphorylation on tyrosine residues and leads the recruitment Patients with PNP deficiency display similar abnormalities
4
of Zap-70 and Lck to downstream signaling pathways. Patients in T-cell maturation and function. The thymus appears partially
may present with persistent skin infections, granulomatous lung dysplastic. Circulating T-cell numbers are reduced, and T-cell
disease, and Burkitt lymphoma. Circulating lymphocytes, Igs, function is depressed. Igs and specific antibody levels may be
and antibody production are all normal, and in vitro responses variable. B- and NK-cell numbers are variable. Patients with
to mitogens are variable. 40 PNP deficiency typically present with a triad of features, including
recurrent infections, autoimmune manifestations, and various
COMBINED IMMUNODEFICIENCY WITH neurological abnormalities. Infections may be consistent with
EBV-INDUCED LYMPHOPROLIFERATION SCID, but severe bacterial infections have been mostly reported
in older patients with delayed presentation. Autoimmune features
EBV-induced chronic infection and lymphoproliferation is the include cytopenias, systemic lupus erythematosus (SLE), and
major clinical presentation of a growing number of newly arthritis, and neurological features consist of ataxia and various
described inherited immunodeficiencies. Inheritance can be degrees of behavioral and mental retardation. Diagnosis is
X-linked or autosomal recessive according to the gene affected. confirmed by demonstrating markedly reduced PNP enzyme
Hemizygous mutations in the magnesium transporter 1 (MAGT1) activity in red blood cells (RBCs) or T cells, reduced uric acid,
2+
gene (OMIM *300715) causes reduced TCR-mediated Mg as an increase of deoxyguanosine and other metabolites in blood
2+
well as Ca influx into T cells (OMIM #300853). This ultimately and urine, and by genetic analysis of the PNP gene. HSCT
results in abnormal downstream activity of transcription factors. may reverse the immunodeficiency, but not the neurological
Patient CD4 T cells are reduced, but the total numbers of CD3 manifestations.
cells, B cells, and NK-cells are normal. EBV related infections
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or lymphoma may develop at any age. A similar clinical picture DiGeorge Syndrome
(OMIM #615897) is found in patients with biallelic CTP synthase DiGeorge syndrome (DGS; OMIM #188400) comprises thymic
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1 (CTPS1; OMIM *123860) mutations. The nucleotide cytidine- hypoplasia, parathyroid hypoplasia, and outflow tract malforma-
5’-triphosphate (CTP) is needed for the metabolism of RNA tions of the heart. The syndrome is caused by a 1.8–3.0 Mb
and DNA. Circulating lymphocyte counts are variable, Ig levels hemizygous deletion in chromosome 22q11.2. Haploinsufficiency