Page 836 - Hematology_ Basic Principles and Practice ( PDFDrive )

722 Part VI Non-Malignant Leukocytes

Genetic Variants Associated With CVIDs
Diagnostic and Therapeutic Approach to Defects in Humoral Immunity
A few genes have been reported to be associated with CVID (see Fig. • Defects in humoral immunity may be caused by intrinsic defects
51.3), including transmembrane activator and CAML interactor in B-cell development and function, or caused by combined
(TACI; TNFRSF13B), CD19, CD81, CD20, CD21, B-cell activating immunodeficiency disorders where lack of T-cell help is the
factor receptor (BAFF-R; TNFRSF13C), NFKB1, and NFKB2. TACI primary cause of B-cell dysfunction.
is a TNF receptor superfamily member, which is expressed at high • Age-specific norms must be used for children. Immunoglobulin
levels on activated B cells and marginal zone B cells, and binds two (Ig)G levels at birth reflect the maternally transferred antibody,
ligands, BAFF and APRIL. Like other TNF receptor superfamily which nadir between 2 and 6 months, then progressively rise
members, TACI assembles as a trimer or higher order multimer. with age. IgA and IgM levels rise continually with age until the
teenage years.
Heterozygous and homozygous mutations in TACI have been docu- • Based on enumeration of T, B and natural killer cells, X-linked
mented in 10% to 15% of CVID patients; however, they are also agammaglobulinemia (XLA; absence of B cells) can be rapidly
found at a lower frequency in the general population. Thus, the ruled out.
presence of TACI mutations is considered to be a predisposing factor • The finding of hyper-IgM with low IgG should prompt a work-up
to CVID, rather than a disease-causing factor. for CD40L deficiency, CD40 deficiency, activation-induced
Mutations in CD19, CD81, and CD21, which are all com- cytidine deaminase (AID), and uracil-DNA glycosylase (UNG).
ponents of the B-cell coreceptor, have been reported in few indi- The likelihood of each of these is of course different depending
viduals. These defects do not affect B-cell development but impair on gender and family history. It is important to note that CD40L
signaling, causing hypogammaglobulinemia, low number of switched deficiency may present with a normal IgM.
memory B cells, and poor antibody response to T-independent • The diagnosis of common variable immunodeficiency
disorders (CVIDs) should only be made once other causes
antigens. have been ruled out, and should be made with caution, if at
CD20 is a surface molecule involved in B-cell development and all, in children under 4 years of age. Disorders such as XLA,
plasma cell differentiation. Autosomal recessive CD20 deficiency is autosomal recessive agammaglobulinemia, various hyper-IgM
characterized by recurrent infections, low serum IgG, with normal or syndromes, and XLP should be specifically considered and
elevated IgA and/or IgM. ruled out. Other diseases that may masquerade as CVID include
BAFF-R deficiency is very rare. It has variable clinical presenta- other combined immunodeficiencies, cystic fibrosis, HIV, and
tion, with CVID-like features or even absence of symptoms. Labora- conditions leading to Ig loss such as protein-losing enteropathy.
tory findings include hypogammaglobulinemia, low numbers of Medications may mimic the symptoms of CVID. Finally, in
circulating B cells and a defective proportion of memory B cells, and adults hypogammaglobulinemia may herald the development
of thymoma or lymphoid malignancies, and therefore may be
normal antibody response to T-dependent antigen but a defective secondary to evolving neoplasia.
response to carbohydrate antigens. • Treatment of XLA and the hyper-IgM syndromes other than
A variable clinical phenotype has been also reported in patients CD40L deficiency is long-term intravenous Ig replacement, which
with haploinsufficiency of the p50 subunit of NF-κB (encoded by is very effective.
the NFKB1 gene), causing defective signaling through the canonical • Experts disagree on whether CD40L deficiency should be
NF-κB signaling pathway. In addition to recurrent infections and treated with early HSCT, and currently there are no clear
progressive lung disease, patients often present with autoimmunity predictors to determine who is likely to suffer from opportunistic
(hemolytic anemia, thyroiditis, alopecia) and lymphadenopathy. infections. A patient with CD40L deficiency who has developed
However, genotypically affected individuals may also remain asymp- cryptosporidium infection and sclerosing cholangitis generally has
a much worse outlook with HSCT.
tomatic even through adulthood. Heterozygous mutations of the • Treatment of CVID with HSCT is generally reserved for those
NFKB2 gene (affecting mostly the noncanonical NF-κB signaling with an alternate requirement for allogeneic transplant such
pathway) cause recurrent infections (especially due to HSV, varicella- as lymphoid malignancy or lymphoproliferation, which requires
zoster virus [VZV], and Giardia), central adrenal insufficiency, continual immunosuppression.
hypopituitarism, alopecia, trachyonychia, and growth deficiency.
Hypogammaglobulinemia, a low number of memory B cells, Treg
lymphocytes, T follicular helper (Tfh) cells, and NK lymphocytes
have been demonstrated. AID deficiency, and follows an abnormal pattern in patients with
UNG deficiency.
Treatment is based on regular administration of Igs, as well as
B-CELL–INTRINSIC DEFECTS OF CLASS-SWITCH prompt recognition and therapy of infections.
RECOMBINATION Defects in CSR have also been reported in patients with mutations
in INO80 (encoding for a chromatin remodeling complex) and
Maturation of the antibody response is marked by class-switch MSH6 (involved in the DNA mismatch repair pathway). The latter
recombination (CSR) and by somatic hypermutation (SHM). With group of patients is at increased risk of cancer.
CSR, the µ heavy chain is replaced by other Ig heavy chains. With
SHM, mutations are introduced in the Ig V region, allowing affinity
maturation. Following CD40LG–CD40 interaction and activation Other Immunoglobulin Defects
of the NF-κB signaling pathway, expression of activation-induced
cytidine deaminase (AID) and of uracil-DNA glycosylase (UNG) Gain-of-function mutations of the PIK3CD gene (encoding for the
occurs in germinal center B lymphocytes (see Fig. 51.3). AID acts on p110δ catalytic component of PI3K) cause an immunodeficiency
the DNA of Ig heavy chain switch regions and converts cytidine to characterized by nodular lymphoid hyperplasia, progressive lung
uridine, which is recognized and removed by UNG. The abasic sites disease with bronchiectasis, chronic or recurrent herpesvirus viremia
are cleaved by a DNA endonuclease. DNA repair then brings together (CMV, EBV, VZV, HSV), and hepatosplenomegaly. There is an
two different switch regions, allowing CSR. increased risk of lymphomas, which are not necessarily associated
Mutations in AID and UNG are inherited as autosomal recessive with EBV infection. The immunologic phenotype includes CD4
traits. Patients suffer from recurrent bacterial infections. Autoimmune lymphopenia, a reduced proportion of naive T cells, expansion of
+
manifestations have been observed in several patients. Circulating B effector memory and “exhausted” CD8 T cells, defective T-cell
cells are present, but there is a severe reduction of all Ig isotypes with proliferation, variable Ig levels (often with low IgG2), reduced pro-
the exception of IgM, which is often elevated. Lymphadenopathy is portion of memory B cells, and poor antibody responses. In these
common and is associated with expansion of germinal centers. patients, increased PI3K signaling causes hyperactivation of the
Somatic hypermutation is severely compromised in patients with AKT–mammalian target of rapamycin (mTOR) pathway, shifting the