Page 1240 - Williams Hematology ( PDFDrive )

1214 Part IX: Lymphocytes and Plasma Cells Chapter 80: Immunodeficiency Diseases 1215

TABLE 80–2. Common Adaptive Immunodeficiencies: Laboratory and Clinical Features* (Continued)
Humoral Immunity
Lymphocytes* Serum Immunoglobulins (Ig)
Cellular Antibody
B T NK Immunity M G A E Responses Common Infections
MHC class II deficiency + +/− + + N/↓ ↓ N/↓ ↓ +/− Bacteria, viruses, fungi
TAP-1, TAP-2 deficiency + +/− +/− +/− N N N N +/− Bacteria, viruses, fungi
(MHC class I deficiency)
Other well-defined immunodeficiency syndromes
Ataxia-telangiectasia + + + +/− N/↑ N/↓ N/↓ ↓ +/− Bacteria
Wiskott-Aldrich + +/− + +/− ↓ N ↑ ↑ +/− Bacteria
syndrome
Hyper IgE Syndromes
STAT3 deficiency (AD) +/− + + +/− N N N ↑↑ +/− Staph, Candida
DOCK8 deficiency (AR) +/− +/− +/− +/− ↓ N N ↑↑ +/− Candida, viruses, fungi
GATA 2 deficiency (AD) − + − +/− N N N N +/− Atypical mycobacteria,
viruses, fungi
IPEX, IPEX-like + (lack of + + N N ↑ ↑ + Autoimmunity, Staph,
Tregs) Candida, CMV
*Natural killer lymphocytes (NK), T cells (T), B cells (B).
Normal levels (+), reduced or absent levels (−); normal (N), elevated (↑), or reduced (↓) serum immunoglobulins.

require treatment with granulocyte colony-stimulating factor (G-CSF), phenotype similar to AID deficiency. The three UNG deficient patients
at least on a temporary basis. reported to date have a history of frequent bacterial infections, lymph-
adenopathy, and an excellent response to IVIG therapy. 23
Autosomal Recessive Hyperimmunoglobulin M with CD40
Mutations
Autosomal recessive hyperimmunoglobulin M caused by mutations X-Linked Anhydrotic Ectodermal Dysplasia with Immunode-
in CD40 have been reported, mostly in consanguineous families. 16,22 ficiency Caused by Mutations in Nuclear Factor-κB Essential
Affected members have similar clinical and laboratory findings as those Modulator
with CD40L mutations. Treatment and prognosis of CD40 deficiency is Definition Anhydrotic (or hypohidrotic) ectodermal dysplasia is
similar to XHIGM. a rare syndrome with partial or complete absence of sweat glands,
sparse hair growth, and abnormal dentition. A subset of these patients
Autosomal Recessive Hyperimmunoglobulin M Syndrome has an X-linked mode of inheritance and immunodeficiency char-
Caused by an Intrinsic B-Cell Defect acterized by low-serum IgG levels, variably elevated IgM levels, and
Definition AID is expressed only in B cells undergoing CSR or decreased antibody responses. This syndrome results from mutations
SHM and is thought to affect DNA editing. Because of milder in the IKBKG gene encoding NEMO, a key subunit of I-κB kinase that
23
symptoms, the diagnosis of AID deficiency is often established later regulates NF-κB dimerization and nuclear transfer. Most affected
24
in life. boys have a hypomorphic NEMO mutation that allows some func-
Clinical Features AID-deficient patients present with recurrent tion, and present with bacterial (S. pneumoniae, S. aureus) and often
bacterial infections, mostly affecting the upper and lower respiratory atypical mycobacterial infections. Loss-of-function mutations cause
tract. In contrast to patients with XHIGM, AID-deficient individuals the X-linked dominant condition of incontinentia pigmenti in females
have an excellent long-term prognosis, especially if given IVIG pro- and are embryonically lethal in males. A similar phenotype with auto-
phylaxis. Most affected individuals present with striking lymphoid somal dominant inheritance is caused by gain-of-function mutations
hyperplasia involving tonsils and lymph nodes as a result of marked in IKBA. 25
follicular hyperplasia. The number of circulating T- and B-cell subsets Clinical Features A review of 72 individuals with NEMO muta-
are normal, including normal proportion of memory B cells; however, tions has demonstrated a wide spectrum of clinical phenotypes. Thir-
26
all CD27 memory B cells fail to isotype switch and only express IgM ty-two different mutations of NEMO were identified, with 70 percent
+
and IgD. Mutations of AID affect the entire gene and include missense, being associated with ectodermal dysplasia, 86 percent with serious
nonsense mutations, and small deletions. pyogenic infections, 39 percent with mycobacterial infections, 19 per-
UNG is expressed in proliferating cells, including B cells undergo- cent with serious viral infections, and 21 percent with inflammatory
ing CSR. Following AID-induced deamination of cytosine into uracil bowel disease. One-third of this cohort of NEMO patients died prema-
residues on single-stranded DNA, UNG deglycosylates and removes turely (mean age: 6.4 years).
uracil residues, thus leading to a single-stranded DNA break. The repair Treatment Treatment with IVIG is useful but does not pre-
of the DNA nick leads to successful CSR and SHM. Because AID and vent the occurrence of serious complications. Symptomatic treatment
UNG are functionally closely linked, lack of UNG results in a clinical depends on those complications.

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