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ANNUAL
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Primary B Cell
Immunodeﬁciencies:
Comparisons and Contrasts
Mary Ellen Conley,1,2 A. Kerry Dobbs,2
Dana M. Farmer,2 Sebnem Kilic,3 Kenneth Paris,4
Soﬁa Grigoriadou,5 Elaine Coustan-Smith,6
Vanessa Howard,2 and Dario Campana1,6
1
Department of Pediatrics, University of Tennessee College of Medicine, Memphis,
Tennessee 38163
2
Department of Immunology, St. Jude Children’s Research Hospital, Memphis,
Tennessee 38105; email: [email protected], [email protected],
[email protected], [email protected]
3
Department of Pediatrics, Uludag University, Faculty of Medicine, Bursa, 16059 Turkey;
email: [email protected]
4
Department of Pediatrics, Children’s Hospital of New Orleans, New Orleans,
Louisiana 70118; email: [email protected]
5
Department of Immunology, Barts and The London NHS Trust, London,
EC1A 7BE, UK; email: soﬁ[email protected]
6
Department of Oncology, St. Jude Children’s Research Hospital, Memphis,
Tennessee 38105; email: [email protected], [email protected]
Annu. Rev. Immunol. 2009. 27:199–227
Key Words
First published online as a Review in Advance on
December 16, 2008
X-linked agammaglobulinemia, hyper-IgM syndrome, common
variable immunodeﬁciency, Btk, TACI
The Annual Review of Immunology is online at
immunol.annualreviews.org
This article’s doi:
10.1146/annurev.immunol.021908.132649
c 2009 by Annual Reviews.
Copyright All rights reserved
0732-0582/09/0423-0199$20.00
Abstract
Sophisticated genetic tools have made possible the identiﬁcation of the
genes responsible for most well-described immunodeﬁciencies in the
past 15 years. Mutations in Btk, components of the pre-B cell and B
cell receptor (λ5, Igα, Igβ), or the scaffold protein BLNK account for
approximately 90% of patients with defects in early B cell development.
Hyper-IgM syndromes result from mutations in CD40 ligand, CD40,
AID, or UNG in 70–80% of affected patients. Rare defects in ICOS
or CD19 can result in a clinical picture that is consistent with common
variable immunodeﬁciency, and as many as 10% of patients with this
disorder have heterozygous amino acid substitutions in TACI. For all
these disorders, there is considerable clinical heterogeneity in patients
with the same mutation. Identifying the genetic and environmental factors that inﬂuence the clinical phenotype may enhance patient care and
our understanding of normal B cell development.
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INTRODUCTION
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The term primary B cell immunodeﬁciencies
encompasses a heterogeneous group of disorders that share the marked reduction or absence of serum immunoglobulins. In the past,
we thought of primary B cell immunodeﬁciencies either as single-gene defects of the immune
system or as multifactorial disorders, inﬂuenced
by a combination of susceptibility genes. However, recent studies have taught us that even
patients with the same single-gene defect may
demonstrate striking variability in clinical and
laboratory ﬁndings (1, 2). Although the speciﬁc
mutation in the gene of interest may account
for some of this variability (3–5), modifying genetic factors, the age of the patient, environmental exposures, and other factors play a role
as well. In the outbred human population, it is
clear that the lines between monogenetic and
polygenetic disorders are often blurred (6, 7).
The abnormal genes that are primarily responsible for antibody deﬁciencies, or that
function as susceptibility genes, may be intrinsic to the B cell lineage (8, 9), may encode
signal transduction molecules made by T cells
(10, 11), or, conceivably, may be derived from
myeloid cells or the stromal cells that provide
the essential microenvironment for B lineage
cells. Identifying the genes responsible for immunodeﬁciency and the modifying factors may
help clarify the regulatory requirements for
normal B cell development and the underlying basis for some common disorders, such as
autoimmunity.
All antibody deﬁciencies are associated with
an increased susceptibility to infection with
encapsulated bacteria, particularly Streptococcus
pneumoniae and Haemophilus inﬂuenza (12, 13–
16). The infections seen in affected patients are
those typically associated with these two organisms. Bronchitis and pneumonia are common
and often lead to chronic lung disease. Small
children usually have recurrent otitis, whereas
sinusitis predominates in adults (17, 18). Giardia infections are also common in all types of
antibody deﬁciencies (13, 19, 20). Other infections tend to be more limited to a subset of anti-
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Conley et al.
body deﬁciencies. Regardless of the speciﬁc diagnosis, all patients with antibody deﬁciencies
are treated with gammaglobulin replacement.
This therapy is impressively successful, but it is
also expensive, costing approximately $50,000
per year for an average-sized adult. In the past
10 years, there has been a shift away from
monthly intravenous administration of gammaglobulin in a hospital or clinic setting toward weekly self-administration of subcutaneous gammaglobulin. Most patients feel that
the more consistent levels of serum IgG and the
convenience offer distinct advantages (21, 22).
There are three major categories of antibody deﬁciencies: (a) defects in early B cell
development, (b) hyper-IgM syndromes (also
called class switch recombination defects), and
(c) common variable immunodeﬁciency
(CVID). Distinguishing between the last two
categories may be difﬁcult. Patients in both
groups generally have a marked reduction in
serum IgG and IgA. The serum IgM is usually
markedly elevated in patients with defects in
class switch recombination and is often very
low in CVID, but it may be normal, or close
to normal, in patients with either disorder (13,
20, 23). Both hyper-IgM syndromes and CVID
have been reviewed recently (13, 16, 24–27)
and are not considered in great detail here.
DEFECTS IN EARLY B CELL
DEVELOPMENT
Defects in early B cell development are characterized by the onset of recurrent bacterial infections in the ﬁrst 5 years of life,
profound hypogammaglobulinemia, markedly
reduced or absent B cells in the peripheral circulation, and (in the bone marrow) a severe
block in B cell differentiation before the production of surface immunoglobulin-positive B
cells. Mutations in Btk, the gene responsible for
X-linked agammaglobulinemia (XLA), account
for approximately 85% of affected patients (28).
Approximately half of the remaining patients
have mutations in genes encoding components
of the pre-B cell receptor (pre-BCR) or BCR,
including μ heavy chain (IGHM ); the signal
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transduction molecules Igα (CD79A) and Igβ
(CD79B ); and λ5 (IGLL1), which forms the surrogate light chain with Vpre-B (9, 29–35). A
small number of patients with defects in BLNK,
a scaffold protein that assembles signal transduction molecules activated by cross-linking of
the BCR, have been reported (30, 36). Btk is
expressed in myeloid cells and platelets, as well
as B cells (8, 37–39); BLNK is expressed in B
cells and monocytes (40, 41); and the remaining
genes are B cell speciﬁc.
X-Linked Agammaglobulinemia
XLA is often considered the prototype immunodeﬁciency. It was one of the ﬁrst immunodeﬁciencies described, and it was certainly the
ﬁrst immunodeﬁciency for which a laboratory
ﬁnding (agammaglobulinemia) explained the
clinical symptoms and dictated successful therapy (subcutaneous gammaglobulin). In 1952,
Bruton (12) reported the case of an 8-yearold boy with multiple episodes of pneumococcal sepsis associated with the complete absence of the serum globulin fraction as detected
by protein electrophoresis. Additional patients
were soon described (42, 43). When agammaglobulinemia was seen in children, it occurred
predominantly in boys and often followed an
X-linked pattern of inheritance (42, 43). By
contrast, affected adults were almost equally divided between males and females, and a clear
pattern of inheritance was rarely obvious (44–
48). The adult-onset disorder came to be known
as CVID. In the early 1970s, it was shown
that patients with XLA had markedly reduced
numbers of B cells in the peripheral circulation, whereas the number of B cells was usually normal in the adults with CVID (49–52).
In 1993, two groups reported that XLA resulted
from mutations in a cytoplasmic tyrosine kinase
called Btk or Bruton’s tyrosine kinase (8, 37).
Btk
Btk is a member of a family of cytoplasmic tyrosine kinases, called Tec kinases, that includes
Tec, Itk, Rlk, and Bmx, as well as Btk (53–56).
These enzymes are predominantly expressed in
hematopoietic cells; in fact, most cell lineages
contain more than one family member. B cells
and platelets express Btk and Tec; T cells express Itk, Rlk, and Tec; and myeloid cells, including mast cells, express Btk, Tec, Itk, and
Rlk. Family members (which are activated by
growth, differentiation, or survival signals) are
characterized by a C-terminal kinase domain
preceded by SH2 and SH3 domains, a prolinerich region, and an NH2-terminal PH (pleckstrin homology) domain.
Immediately after Btk was identiﬁed, several
studies showed that it was activated through a
variety of cell surface molecules, including the
BCR and pre-BCR (57–59) and the IL-5 and
IL-6 receptors on B cells (60, 61), the highafﬁnity IgE receptor on mast cells (62), and the
collagen receptor glycoprotein VI on platelets
(39, 63, 64). Recently, there has been a great
deal of interest in the role of Btk in signaling
through CXCR4 on B cells (65) and the Tolllike receptors (TLRs) on myeloid cells and B
cells (66–70).
With activation, Btk moves to the inner side
of the plasma membrane, where it is phosphorylated and partially activated by a src family
member (71) (Figure 1). Btk then undergoes
autophosphorylation (72). Activated Btk and
PLCγ2 bind to the scaffold protein BLNK via
their SH2 domains, allowing Btk to phosphorylate PLCγ2 (73). This leads to calcium ﬂux
and activation of the MAP kinases ERK and
JNK (74). In addition, Btk phosphorylates several transcription factors and can be found in
the nucleus (75, 76).
The block in B cell differentiation in both
humans and mice that lack Btk provides strong
support for the importance of Btk in signaling through the pre-BCR and BCR. It is not
clear that signaling through any of the other
receptors or the migration of Btk into the nucleus contributes to the pathophysiology of
XLA. Affected patients have normal numbers
of platelets and myeloid cells. Most patients
with XLA lead active lives (18), which often
include participation in contact sports. However, unusual bruising or bleeding has not been
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μ heavy chain
Vpre-B
λ5
CD19
Igα
Igβ
P
Syk
P
P
P
P
P
P
P
PIP3
PIP3
PLCγ2
Btk
VAV
P
P
P
PI3K P
P
P
Lyn
Rac
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BLNK
Ca2+
PKC
P
P
HPK1
GRB-2
SOS
Ras
MAPK
NFAT
NF-κ
κB
AP1
Figure 1
Signal transduction through the pre-B cell receptor. With activation, there is clustering of the signal
transduction molecules Igα and Igβ. Their ITAM motifs are phosphorylated by a src family member, shown
here as lyn. Syk is then activated by binding to the phosphorylated ITAM motifs. Activated Syk
phosphorylates multiple tyrosine residues in the scaffold protein BLNK. Lyn also phosphorylates Btk and
CD19. Phosphorylated CD19 serves as a docking site for phosphatidylinositol 3-kinase (PI3K), which
produces PIP3. PIP3 acts as a docking site for the PH domains of Btk and PLCγ2. The SH2 domains of Btk
and PLCγ2 bind to phosphorylated tyrosines in BLNK, which allows Btk to phosphorylate PLCγ2.
Phosphorylated tyrosine residues that act as docking sites for SH2 domains are shown as red circles. NFAT,
NF-κB, and AP1 are transcription factors.
reported. This suggests that the absence of Btk
does not have a major impact on platelet function. It is more difﬁcult to determine the importance of Btk in mature B cell and myeloid function. Comparing the clinical ﬁndings in patients
with mutations in Btk to those in patients with
defects that are limited to signaling through the
BCR, such as μ heavy chain or Igα, will help
clarify whether Btk has a broader role in B cell
function.
Clinical Signs and Symptoms in XLA
Patients with XLA are usually healthy in the
newborn period but have the onset of recurrent
bacterial infections between 3 and 18 months
of age (14, 17, 77). In the current era, the mean
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Conley et al.
age at diagnosis in North America is 3 years,
but the median is 26 months (17). Most patients are recognized to have immunodeﬁciency
when they are hospitalized for a severe infection
such as sepsis, meningitis, or pneumonia with
empyema (pus in the pleural cavity). Notably,
many have had an earlier hospitalization for a
common viral infection, such as croup, diarrhea, or RSV (respiratory syncytial virus) pneumonia (17). These infections are not generally
considered worrisome in patients with XLA. As
many as one-third of patients are evaluated for
immunodeﬁciency when they are hospitalized
for a dramatic constellation of ﬁndings, including (a) pyoderma gangrenosum, perirectal abscess, cellulitis, or impetigo; (b) pseudomonas or
staphylococcal sepsis; and (c) neutropenia. This
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presentation is particularly common in patients
who are recognized to have XLA at less than
1 year of age (17).
Pseudomonas and staphylococcus are commonly seen in patients with neutropenia (78)
but are rarely signiﬁcant problems in patients
with XLA after diagnosis and the initiation of
gammaglobulin therapy. Some XLA patients
who develop sepsis owing to these organisms
have a history of a viral infection immediately
preceding the dramatic presentation (17). In
young children, neutropenia and bone marrow suppression are sometimes seen after viral infections (79). We hypothesize that the
dramatic presentation in patients with XLA is
initiated by a viral infection that results in neutropenia. When one couples this ﬁnding with
the observation that XLA patients have an increased rate of hospitalization for common viral infections in infancy, one can speculate that
the lack of natural antibody makes these patients unusually vulnerable to viral infections in
infancy.
Once T cell immunity develops, most viral infections are tolerated without problems.
Many patients with XLA acquired hepatitis
C from contaminated gammaglobulin in the
late 1980s (80–82). However, these patients
had fewer problems with hepatitis C than patients with CVID, and most handled the infection as well as immunocompetent individuals who received other contaminated blood
products.
Enteroviral infections are the exception to
the rule. It has been recognized for over 30 years
that vaccine-associated polio, coxsackie, and
echo viral infections can cause serious problems
in a subset of patients with XLA (83–86). Interestingly, not all XLA patients who acquire these
infections develop severe or progressive disease
(87). Before vaccine policy changed from live
to killed polio vaccine in 1997, many boys with
XLA were given live polio vaccine before they
were recognized to have antibody deﬁciency.
Most had no unusual problems. There are adult
patients with XLA who had wild-type polio with
minimal sequelae many years before they were
known to have XLA (17, 88). The modifying
factors that confer susceptibility to severe enteroviral infections in patients with XLA have
not been identiﬁed.
In addition to problems with S. pneumoniae,
H. inﬂuenza, and Giardia, patients with XLA
and CVID have an increased incidence of pneumonias, joint infections, and prostatitis owing
to infections with mycoplasmas and ureoplasmas (89, 90). A small number of adolescents and
adults with XLA have developed slowly progressive vasculitis and/or cellulitis of the lower
extremities owing to infection with rare subspecies of Helicobacter (91). The basis for the
unusual susceptibility to these organisms is not
clear.
Laboratory Findings in XLA
XLA is a leaky defect in B cell development.
Almost all children with mutations in Btk have
measurable amounts of serum immunoglobulin
and a few B cells in the peripheral circulation
(92, 93). The number of B cells that can be detected tends to decrease with age (5, 92). This
probably reﬂects the normal decrease in B cell
production that is seen with aging (94). The
B cells in patients with XLA have a distinctive
phenotype that can be used to help support the
diagnosis in a patient with reduced numbers of
B cells. Although the intensity of CD19 expression is relatively homogeneous in normal controls, it is low and variable in patients with XLA.
By contrast, surface IgM expression is variable
in normal controls but high and homogeneous
in patients (Figure 2). Btk is expressed in monocytes and platelets, as well as B cells. This facilitates diagnosis, as over 90% of mutations in Btk
(including one-third of all amino acid substitutions) are associated with the absence of Btk in
monocytes (95).
Bone marrow studies in patients with XLA
demonstrate a strong block in differentiation
or proliferation at the pro-B cell to pre-B cell
transition (96–98). In normal children, between
10% and 25% of CD19+ cells in the bone
marrow are pro-B cells, as deﬁned by the expression of CD19, TdT, and CD34 and the absence of cytoplasmic or surface μ heavy chain.
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Control
Btk –
Igβ –
μ–
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Co
sIgM
CD19
CD38
CD21
CD22
Figure 2
B cell phenotype in patients with primary B cell immunodeﬁciencies. Ficoll density–separated peripheral
blood lymphocytes were stained with PE-labeled CD19 and FITC-labeled isotype control, anti-IgM, CD38,
CD21, or CD22. Shown are cells from a healthy control ( ﬁrst column from left), an 11-year-old patient with a
premature stop codon (R255X) in Btk (second column), a 15-year-old patient with a hypomorphic mutation
(G137S) in Igβ (third column), and a 5-year-old patient with a large deletion of the μ constant region on one
allele and a two base pair deletion (AA del in codon 168) in exon 2 of μ heavy chain on the other allele
( fourth column). The number of gated events shown is 17,000 to 19,000 in the healthy control sample and
100,000 to 150,000 in the patient samples. Figure adapted from Reference 33, with the permission of
American Association of Immunologists, Inc., copyright 2007.
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Conley et al.
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Pre-B cells, CD19+ /CD34− /TdT− cells that
have cytoplasmic μ heavy chain but no surface
IgM, comprise 35–60% of CD19+ cells, and
mature B cells that express CD19 and surface
IgM comprise 20–40% of the bone marrow B
lineage cells. By contrast, in patients with defects in Btk, 75–90% of the CD19+ cells bear a
pro-B cell phenotype, and less than 10% have a
typical pre-B cell phenotype. Furthermore, patients with mutations in Btk have an unusual
population of CD19+ cells that appear to be
stalled between the pro-B cell and pre-B cell
stage of differentiation. These cells, which constitute 5–10% of the total CD19+ cells in patients with XLA, continue to express CD34 and
TdT, but they also express cytoplasmic μ heavy
chain (Figure 3) (98).
ClgM
Mutations in Btk
Over 600 different mutations in Btk have been
identiﬁed (99, 100). Single base pair substitutions, or the insertion or deletion of less
than ﬁve base pairs, account for more than
90% of these mutations. The remaining mutations include large deletions, duplications,
inversions, complex combinations of insertions and deletions, and retrotransposon insertions (101, 102). Several factors contribute to
this striking variability. First, similar to other
X-linked disorders that are lethal without medical intervention, XLA is maintained in the
population by new mutations (28). As these
new mutations occur independently, they can
involve multiple sites throughout the gene.
Control
Btk (W588X)
Btk (C506F)
μHC (frameshift)
μHC (AS)
μHC (AS)
TdT
Figure 3
Bone marrow cells from patients with defects in B cell development were stained for CD19, cytoplasmic μ
heavy chain, and TdT and then analyzed by ﬂow cytometry. The cells shown were within the CD19+ gate.
(Top row) Cells from a healthy 6-year-old control, a patient with a premature stop codon in Btk (W588X),
and a patient with an amino acid substitution in Btk (C506F). (Bottom row) Cells from patients with defects in
μ heavy chain: one patient with the codon 168 frameshift mutation and two brothers with the alternative
splice defect at codon 433. The stalled pro-B cells in the patients with mutations in Btk are seen in the upper
right-hand corner, and the pre-B cell-like cells in the patients with defects in μ heavy chain are seen in the
lower left-hand corner.
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Second, Btk is highly conserved. Human and
murine Btk are 98% identical in amino acid sequence, suggesting minimal tolerance for any
alteration in sequence.
Our laboratory has identiﬁed 186 different
mutations in Btk in 226 unrelated families (99).
No single mutation accounts for more than 3%
of the total. In many families, it is possible to
identify the source of the new mutation in Btk.
The mother of a patient with sporadic XLA has
an 80% chance of being a carrier, but the maternal grandmother is a carrier only 25% of the
time (28). These percentages, which are similar to that seen in other X-linked immunodeﬁciencies (103), can be explained by the fact
that most new mutations occur in male gametes
(104–106). In our studies on XLA, it is often
possible to show that the allele bearing the mutation in Btk came from the unaffected maternal
grandfather or great-grandfather (28).
We have identiﬁed two families with two
alterations in Btk. In one family, two affected brothers had an amino acid substitution
(Y418H) near the ATP binding site and a premature stop codon (K625X) in the carboxyterminal portion of the kinase domain. Their
mother was heterozygous for both alterations;
however, their healthy maternal grandfather
had the amino acid substitution at codon 418
but did not have the premature stop codon
at codon 625 (107). Analysis of polymorphic
markers ﬂanking Btk clearly demonstrated that
the mutant allele in the affected boys was inherited from their maternal grandfather without crossovers, indicating that the second alteration had arisen in the sperm that gave rise to
the mother or during the in utero development
of the mother.
To determine if the amino acid substitution
in the 58-year-old grandfather had a deleterious
effect, we examined his serum immunoglobulin concentrations, titers to vaccine antigens, and peripheral blood B cells. The serum
IgG and IgA were within the normal range
(690 mg dl−1 and 85 mg dl−1 , respectively), but
the serum IgM was slightly low (36 mg dl−1 ,
with the normal adult male range being 48–
263 mg dl−1 ). Titers to vaccine antigens, in-
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cluding pneumococcus, were normal; however,
the number of CD19+ B cells in the peripheral
circulation was only 0.85% (6–20% is considered normal). Monocytes from this man and his
affected grandson were analyzed by ﬂow cytometry for expression of Btk. No Btk was seen in
the monocytes of the child with both alterations
in Btk; however, cells from the grandfather had
normal amounts of Btk (107).
A Y418H mutation had been reported in
a patient with typical XLA; therefore, it was
important to determine the functional consequences of this alteration. Btk− cells from the
chicken B cell line DT40 were transfected with
either wild-type or Y418H Btk and then stimulated with anti-IgM. The cells bearing the
Y418H mutation consistently showed a 15–
25% decrease in calcium ﬂux and IP3 production at 0.5 min when compared with cells that
received the wild-type Btk vector (107). These
ﬁndings suggest that even a mild reduction in
Btk function can result in a decreased number
of B cells. Furthermore, a reduced number of B
cells is the most consistent feature in XLA.
In a second family, a boy with XLA, his two
cousins, and his maternal grandfather had two
amino acid substitutions in Btk. In the ﬁrst alteration, the wild-type isoleucine at codon 305,
within the SH2 domain, was replaced with a
serine, and in the second alteration, the wildtype glycine was replaced with alanine at codon
556 in the kinase domain. Neither of these alterations has been described in other patients.
Monocytes from both the patient and his grandfather had normal amounts of Btk as analyzed
by ﬂow cytometry.
Perez de Diego et al. (108) recently reported studies in a third family in which the
affected boy had two amino acid substitutions
in Btk. One alteration, an arginine to histidine
at codon 641 in the kinase domain, has been
reported in several other patients with XLA
(99, 109). The second alteration, an alanine to
valine at codon 230 in the SH3 domain, had
not been reported previously. The boy’s mother
was heterozygous for both alterations. However, his maternal grandmother, two aunts, and
two cousins had only the A230V alteration. One
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of the healthy male cousins with the A230V
alteration had 13% CD19+ B cells, indicating
that this alteration is a polymorphism that does
not affect the function of Btk. The A230V alteration is the only reported polymorphism in
Btk that changes the amino acid sequence but
not the function. It has been seen only in this
family.
The occurrence of two alterations in Btk in
these three families is unexpected. Because XLA
is uncommon, occurring with a frequency of
ﬁve to ten cases per million births (110), and because most mutations have occurred relatively
recently, one must assume that two rare events
altered the same segment of DNA. This raises
the issue of factors that might predispose a segment of DNA to mutation. In two of the families described above, analysis of multiple family
members showed that the two alterations occurred independently on the same allele. This
made us wonder if there were features of the
Btk locus that might inﬂuence the development
of new mutations.
We addressed this question by analyzing
four single nucleotide polymorphisms at the Btk
locus. The ﬁrst two were in intron 1, and the
last two were in the 3 untranslated region, 30–
35 kb distal to exon 1. The Btk haplotype of
47 unrelated males with XLA was compared
with that of their unaffected fathers. Two haplotypes accounted for 74% of the individuals,
and both haplotypes were seen with equal frequency in the patients and their fathers. Of the
two families in which we identiﬁed two alterations in Btk, one family had the alterations on
one of the common haplotypes. In the other
family, the alterations were on an uncommon
haplotype that was seen in two patients but in
none of the fathers. These preliminary results
do not rule out the possibility of local characteristics of the DNA that make it more vulnerable to mutation. Future studies may examine additional single nucleotide polymorphisms
and expand the haplotype analysis to sites as
far as 1 megabase away. It may be that minor
variations in DNA sequence inﬂuence chromatin structure and therefore susceptibility to
mutation.
Genotype/Phenotype Correlation
The great diversity in Btk mutations makes it
more difﬁcult to examine genotype/phenotype
correlations. Furthermore, objective measurements of disease severity are not deﬁned easily. We chose to focus on age at diagnosis, the
plasma IgM, and the number of B cells in the
peripheral circulation (5). Mutations were divided into two broad categories, mild and severe. Mild mutations were amino acid substitutions and splice defects that occur at sites in
the consensus sequence that are conserved but
not invariant. These mutations conceivably allow the production of some Btk. Even amino
acid substitutions that ablate the kinase activity may be associated with some function as a
scaffold protein, provided by the PH, SH3, and
SH2 domains (111). All the remaining mutations were considered severe, including premature stop codons, frameshift mutations, splice
defects found at invariant sites in the splice consensus sequence (the ﬁrst two and last two base
pairs of each intron), large deletions and duplications, and complex mutations.
In an analysis of 110 patients from 94
unrelated families, the mild mutations were associated with later age at diagnosis ( p = 0.04)
and a higher number of B cells in the peripheral
circulation ( p = 0.09). However, the marker
showing the best correlation with mild mutations was higher plasma IgM ( p < 0.001) (5).
Although the age at diagnosis did not correlate
with either the percentage of circulating B cells
or the plasma IgM, the percentage of B cells
and the plasma IgM correlated with each other
( p < 0.001). When the patients with amino acid
substitutions were divided into those whose
monocytes were positive for Btk and those
whose monocytes were negative, the Btk+
patients were slightly older at diagnosis and
had slightly higher mean plasma IgM than the
patients who were Btk− , but both groups differed from the patients with severe mutations.
Amino acid substitutions resulting in unstable
proteins may have some residual function.
Similar ﬁndings have been described by others. Plebani et al. (3) noted that certain amino
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acid substitutions in Btk were associated with
higher concentrations of serum immunoglobulins at the time of diagnosis. Lopez-Granados
et al. (4) analyzed 54 patients with proven mutations in Btk, from 40 unrelated families, using a system similar to ours to classify severe
versus mild mutations. The age at diagnosis,
the concentrations of serum immunoglobulins
at diagnosis, and the percentage of CD19+ B
cells all correlated with the severity of mutation.
However, the speciﬁc mutation in Btk clearly is
not the only factor that inﬂuences the severity
of disease. Environmental factors may play a
role, but modifying genetic factors likely wield
a stronger inﬂuence.
When considering modifying genetic factors, one can see that polymorphic variants in
components of the BCR signal transduction
pathway are obvious candidates. Both IgM and
λ5 are highly polymorphic (112, 113). However, it is not clear which components of this
pathway act as limiting factors. One might expect that polymorphic variants in the Btk family member Tec might inﬂuence the severity of
disease. Mice that are mutant in Tec as well as
Btk have a more severe phenotype than mice
that are deﬁcient in Btk alone (114), indicating that Tec, which is activated by many of the
same signals as Btk (115), may compensate for
Btk when the latter is mutant. However, we did
not ﬁnd polymorphic variants in Tec that could
explain clinical or laboratory variability (5).
Polymorphic variants in molecules that enhance signaling through the BCR, such as
CD19, or dampen signaling, such as CD22,
might impact the number of B cells or the concentration of IgM. Furthermore, some modifying genetic factors may depend on the
speciﬁc type of mutation. For example, polymorphic variants in the splicing apparatus
might be expected to affect splice defects but
not amino acid substitutions.
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Autosomal Recessive
Agammaglobulinemia
Starting in the 1970s, several reports described
females with a clinical disorder that was indis208
Conley et al.
tinguishable from XLA (116–118). The affected
girls had an early onset of disease, profound
hypogammaglobulinemia, and less than 1% of
the normal number of B cells in the peripheral circulation. This suggested that there were
autosomal recessive forms of the disease. The
identiﬁcation of Btk as the gene responsible for
XLA made it possible to exclude this diagnosis in some families and spurred a search for
the genes that might cause autosomal recessive
agammaglobulinemia.
Defects in μ Heavy Chain
If the most important role for Btk is its involvement in signaling through the pre-BCR and
BCR, then other genes required for this pathway would be strong candidates for unidentiﬁed
forms of agammaglobulinemia. Using a combination of homozygosity mapping and candidate
gene analysis, in 1996 we showed that mutations in μ heavy chain (IGHM ) cause agammaglobulinemia and a clinical picture that is similar to that seen in XLA (9). Twenty-six families
with mutations in μ heavy chain have been reported to date (9, 29, 30, 112, 119). All the reported mutations result in the complete absence
of CD19+ B cells in the peripheral circulation,
with a detection threshold of 0.01%.
Although there is considerable overlap, the
patients with mutations in μ heavy chain tend
to have a more severe phenotype than that seen
in patients with mutations in Btk (112). They
are recognized to have immunodeﬁciency at a
mean age of 11 months rather than 35 months in
patients with XLA, and they have a higher incidence of enteroviral infection and pseudomonas
sepsis with neutropenia. These ﬁndings indicate that the small amount of immunoglobulin
produced by patients with XLA has some protective value. These ﬁndings also imply that the
enteroviral infections and neutropenia in patients with XLA result from hypogammaglobulinemia rather than requirements for Btk in
myeloid cells.
The spectrum of mutations seen in patients
with defects in μ heavy chain is quite different
from that seen in patients with XLA. Between
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30% and 50% of mutations are large deletions
that remove between 70 and 700 kb of DNA,
including JH and DH regions, as well as all μ
constant region exons (30, 112). Some deletions
also result in the loss of some VH segments
and/or heavy chain constant segments. In the 17
families in which we have identiﬁed mutations
in μ heavy chain, two mutations have been seen
in several unrelated families with agammaglobulinemia. One mutation, a two base pair deletion at codon 168 in exon 2, has been seen in
four unrelated families, two from Spain and two
from Mexico (112). In all these families, the mutation is on the same uncommon μ heavy chain
haplotype, indicating that the patients share a
common ancestor. By contrast, the other mutation, a single base pair substitution in codon
433, at the −1 position of the alternative splice
site, has been seen on three different haplotypes
in six unrelated families, indicating that it is a
recurrent mutation (112).
The guanine to adenine substitution at the
−1 position of the alternative splice site has
three effects. First, it changes the amino acid
sequence of the secretory form of μ heavy chain
from glycine to serine at codon 433; second, it
replaces the negatively charged glutamic acid
with the positively charged lysine at the same
site in the membrane form of μ heavy chain;
and, ﬁnally, because the base pair substitution
is at a site that is conserved but not invariant within the splice consensus sequence, it is
predicted to markedly impair but not ablate
the production of transcripts for the membrane
form of μ heavy chain.
The effects of the base pair substitution at
codon 433 on B cell development were evaluated in bone marrow samples from two brothers
with this mutation. Studies from two patients
with other mutations in μ heavy chain were analyzed for comparison. One of these patients
had the codon 168 frameshift mutation on one
allele and a large deletion on the other allele; the
other patient had an amino acid substitution at
an essential cysteine (codon 412) in exon 4 on
one allele and a large deletion on the other allele (9). In both teenagers with the codon 433
mutation, 65–83% of the CD19+ cells in the
bone marrow were pro-B cells (Figure 3). The
stalled pro-B cells, cytoplasmic μ+ /TdT+ cells,
which have been identiﬁed in patients with mutations in Btk, were not seen. Between 15% and
30% of the CD19+ cells had a pre-B cell phenotype manifested by the low-intensity expression
of cytoplasmic μ heavy chain and the absence of
CD34 or TdT. Mature, surface Ig+ cells were
not seen. The other two patients with defects
in μ heavy chain also had a small percentage
of CD19+ /TdT− /CD34− cells; however, the
percentage was lower (5–10% of the CD19+
cells). Schiff et al. (29) also noted that a patient with a homozygous frameshift mutation
in exon 1 of μ heavy chain had a small number of CD19+ /CD34− /TdT− cells in the bone
marrow.
The identity of the CD19+ /CD34− /TdT−
cells in all the patients with defects in μ
heavy chain is not clear. The two patients
with frameshift mutations in the amino terminal portion of μ heavy chain should not
be able to make any cytoplasmic or surface
pre-BCRs. Expression of a pre-BCR is considered essential for B cells to progress beyond the pro-B cell stage of differentiation.
In our patient with a frameshift mutation, the
CD19+ /CD34− /TdT− cells were characterized in more detail. These cells were positive
for CD22 but negative for CD20, CD21, and
CD37. The TdT− cells from one of the patients
with the alternative splice defect were positive
for cytoplasmic Vpre-B and Igα and negative
for CD117.
The observation that the patients with the
alternative splice site defect had a few more of
these pre-B-like cells, compared with other patients with mutations in Btk or μ heavy chain,
made us question if some μ heavy chain was
being produced. We therefore analyzed the
cDNA from the bone marrow of the two brothers with the codon 433 mutation. PCR (polymerase chain reaction) primers expected to amplify transcripts for the membrane form of μ
heavy chain were used to amplify cDNA from
both patients. The results demonstrated three
products (Figure 4). The sequencing of these
products indicated that the largest could be
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209
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a
b
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1
2
3
4
1
Mem μ
Mem μ
Sec μ
GADPH
2
3
4
5
6
Figure 4
Transcripts for the membrane form of μ heavy chain in a patient with a defect at the alternative splice site.
(a) A RT PCR was used to amplify cDNA from the Daudi B cell line (column 1), Jurkat T cells (column 2),
control peripheral blood lymphocytes (column 3), or from the bone marrow of a patient with the alternative
splice site defect (column 4 ). Transcripts for membrane μ (top panel ) and secretory μ (bottom panel ) are shown.
(b) A semiquantitative PCR was conducted to estimate the amount of correctly spliced membrane μ
transcripts in the patient with the splice defect. Transcripts from the bone marrow of a normal control
(column 1), two patients with mutations in Btk (columns 2 and 3), and a patient with the alternative splice
defect (column 4 ) are shown. The cDNA from the normal control was diluted 1:10 (column 5 ) and 1:100
(column 6 ) to allow comparison. The amount of correctly spliced message in the sample from the patient
with the alternative splice defect was approximately 1% of the control.
attributed to the use of a cryptic splice site
(GTGAG) 136 base pairs downstream of the
authentic alternative splice site and 75 base pairs
downstream of the stop codon for the secretory
form of μ heavy chain. This transcript encodes
the secretory form of μ heavy chain with an
amino acid substitution, glycine to serine, at
codon 433 (at the alternative splice site position). Ferrari et al. (119) studied a different patient with the alternative splice defect and identiﬁed this transcript but not the other two.
The smallest PCR product showed the use
of a cryptic splice site (GTATG) 173 base pairs
upstream of the authentic splice site. This alteration would result in a frameshift mutation and
a premature stop codon four amino acids downstream of the cryptic splice site. The protein
encoded by this transcript would lack a transmembrane domain. The third product represented a correctly spliced message encoding
the membrane form of μ heavy chain with the
substitution of lysine for the wild-type glutamic
acid at codon 433. The wild-type glutamic acid
at this site is conserved in mice, rabbits, and
210
Conley et al.
camels, and an aspartic acid is seen at a homologous position of the membrane form of μ heavy
chain in ducks and sharks. The site of the amino
acid substitution is 13 amino acids proximal to
the transmembrane domain. It forms part of the
conserved extracellular stalk that permits the
dimerization of μ heavy chain and binding to
the signal transduction molecules Igα and Igβ.
The substitution of the highly conserved,
negatively charged glutamic acid at codon 433
of the membrane form of μ heavy chain with
the positively charged lysine might be expected
to inﬂuence cell surface expression of μ heavy
chain or signaling through the BCR. We tested
this possibility by recreating normal or mutant BCRs in Jurkat T cell lines. Two retroviral
vectors—one containing GFP (green ﬂuorescence protein), λ light chain, and either normal or codon 433 mutant μ heavy chain and
the other containing YFP (yellow ﬂuorescence
protein), Igα, and Igβ—were used to transduce
Jurkat cells. Six to 10 days after transduction,
GFP+ /YFP+ cells were sorted and placed back
into culture. The cultured cells were stained for
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Empty vector
Wild-type
AS mutant
Wild-type
AS mutant
YFP
GFP
b
200
IL-2 (pg/ml)
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slgM
Anti-CD3
Isotype control
Anti-IGM
150
100
50
0
Control
Empty vector
Figure 5
Expression of a wild-type or mutant BCR in Jurkat T cells. Jurkat cells were transduced with two retroviral
vectors, one expressing YFP, Igα, and Igβ and the other expressing GFP, λ light chain, and either wild-type
membrane μ heavy chain or μ heavy chain with the alternative splice (AS) site mutation (E433K). Empty
vectors were used as a control. (a) Cells transduced with empty vectors, wild-type vectors, or vectors
expressing mutant BCR were sorted to obtain populations with equal amounts of YFP and GFP. These cells
demonstrated equal amounts of surface IgM, indicating that the amino acid substitution did not impair
membrane expression of μ heavy chain. (b) The cells shown in panel a were cultured with anti-CD3 or
anti-IgM. Cells expressing the wild-type or mutant BCR secreted approximately equal amounts of IL-2,
suggesting that the mutation did not impair signal transduction.
surface expression of IgM 8 to 30 days after the
sort. When we gated on cells that were equally
positive for GFP and YFP, the cells bearing the
normal and mutant BCR expressed comparable
amounts of surface IgM (Figure 5), indicating
that the mutation did not impair cell surface
expression of μ heavy chain. The ability of the
mutant BCR to signal was tested by culturing
the Jurkat cells bearing the normal or mutant
BCR for 24 h with anti-CD3 or anti-IgM and
measuring IL-2 released into the supernatant.
Approximately equal amounts of IL-2 were produced by cells bearing the normal or mutant
BCR. These ﬁndings indicate that the small
amount of membrane μ heavy chain produced
in the patients with the alternative splice defects enhanced the transition of pro-B cells to
the pre-B cell stage of differentiation, but it was
insufﬁcient to support the expansion or further
differentiation of pre-B cells.
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Meffre et al. (120) examined VDJ rearrangements in a patient with a frameshift mutation
in exon 1 of μ heavy chain and found that the
CDR3 regions were longer than those seen in
controls, indicating that expression of a preBCR inﬂuences the immunoglobulin repertoire. Furthermore, light chain rearrangement
could be detected in the μ heavy chain–deﬁcient
patients, and the kappa repertoire was skewed
toward 5 Vks and 3 Jks, suggesting that in
the absence of an effective pre-BCR, continued
light chain rearrangement occurs (120).
Defects in λ5, Igα, Igβ, and BLNK
A small number of patients with defects in
λ5 (IGLL1), Igα (CD79A ), Igβ (CD79B ), or
BLNK have been reported (31–36). These patients generally have clinical ﬁndings that are
indistinguishable from those seen in patients
with mutations in Btk. Similar to patients with
defects in μ heavy chain, patients with other
forms of autosomal recessive agammaglobulinemia tend to have the onset of severe infections within the ﬁrst year of life. However, there
are exceptions. One of the two patients studied with defects in λ5 was recognized to have
immunodeﬁciency after his second hospitalization for pneumococcal pneumonia at 29 years of
age (M.E. Conley, D.M. Farmer, A.K. Dobbs,
and K. Paris, unpublished observations). Significant enteroviral infections and pseudomonas
sepsis with neutropenia were seen in patients
with Igα or BLNK deﬁciency. One child
with Igα deﬁciency had wild-type or vaccineassociated polio at 12 months of age (M.E.
Conley and V. Howard, unpublished observations). A second child with Igα deﬁciency had
progressive weakness and a dermatomyositislike syndrome, ﬁndings typical of enteroviral
infection (32). The older brother of one of the
patients with BLNK deﬁciency died of pseudomonas sepsis and neutropenia at 16 months
of age (36). It is likely that he also had BLNK
deﬁciency.
We have analyzed B cell number and phenotype in two patients with λ5 deﬁciency. One
patient, who has a premature stop codon on one
212
Conley et al.
allele and a proline to leucine amino acid substitution at codon 142 on the other allele, has been
studied several times between 4 and 15 years of
age. He has never had more than 0.06% circulating CD19+ cells, and in recent years he has
had less than 0.02% CD19+ cells (35). These
cells have surface IgM and CD19 expression
that is similar to that seen in healthy individuals. The other patient, who has a single base
pair deletion, a guanine deletion in codon 85,
was ﬁrst analyzed at 35 years of age and had less
than 0.01% CD19+ cells (M.E. Conley, D.M.
Farmer, K.A. Dobbs, K. Paris, unpublished
observations).
The B cell phenotype was evaluated in two
patients with mutations in BLNK, an 8-year-old
girl with a homozygous premature stop codon
in exon 123 (M.E. Conley and S. Kilic, unpublished observations) and a 20-year-old man with
a homozygous splice defect. The girl had 0.01%
CD19+ cells in the peripheral circulation, and,
by analyzing nearly 500,000 events, we showed
that the small number of B cells had a phenotype that was similar to that seen in patients with
mutations in Btk. The cells expressed variable
and slightly dimmer CD19, but also expressed
high levels of surface IgM. Bone marrow from
both patients showed a cell distribution that was
similar to that seen in patients with mutations
in Btk; both patients showed an easily identiﬁed population of stalled pro-B cells. Two additional patients with mutations in BLNK have
been noted, but the precise mutations and phenotypic characteristics of these patients have
not been reported (30).
Our laboratory has evaluated three females
with homozygous null mutations in Igα (31).
The ﬁrst had an adenine to guanine base pair
substitution at the invariant −2 position of the
acceptor splice site for intron 2; the second had
a guanine to thymine base pair substitution at
codon 48, leading to the replacement of the
wild-type glutamic acid with a premature stop
codon; and the third had a guanine-cytosine
deletion that spanned codons 68 and 69. All
these mutations occurred upstream of the transmembrane domain. Blood and bone marrow
studies done on the ﬁrst two patients, who were
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both small children at the time, showed less
than 0.01% CD19+ cells in the peripheral circulation and a block at the pro-B to pre-B cell
transition that was indistinguishable from that
seen in patients with null mutations in μ heavy
chain. Blood and bone marrow samples were
not available from the third patient. Wang et al.
(32) reported a fourth patient with a null mutation in Igα, a splice defect in the donor site for
intron 2, but no details were available about the
laboratory phenotype.
Ferrari et al. (34) recently described a boy
with a base pair substitution in codon 80 of Igβ,
resulting in a premature stop codon (Q80X).
This alteration, which is upstream of the transmembrane domain, is a null mutation, and the
affected patient was reported to have less than
1% CD19+ cells in the blood and a complete
block at the pro-B cell to pre-B cell stage of differentiation. We also identiﬁed a patient with a
defect in Igβ, a 15-year-old girl who had a homozygous amino acid substitution at codon 137
(33). The alteration at this site, which is immediately downstream of the cysteine that forms
the disulﬁde bridge with Igα, is the replacement of the wild-type glycine with serine. This
glycine is conserved not only in Igβ, but also in
Igα, from humans, mice, dogs, and cattle.
The patient with the G137S mutation in Igβ
had a small number of B cells in the peripheral
circulation (0.08% CD19+ cells) (33). These
B cells showed striking similarities and differences when compared with those seen in patients with mutations in Btk (Figure 2). B cells
from both demonstrated variable intensity of
CD19 expression, had increased expression of
CD38, and had decreased expression of CD21.
However, the B cells from the patient with the
Igβ mutation showed decreased or absent expression of surface IgM, whereas those from
patients with mutations in Btk show increased
expression of surface IgM. These ﬁndings suggest that the alteration in Igβ inﬂuenced the
ability of the BCR to reach the cell surface.
They also support the hypothesis that the phenotype of the B cells in patients with XLA could
be attributed to defective signaling through the
BCR.
To examine the ability of the G137S mutant Igβ to bring the BCR to the cell surface,
we transfected Jurkat T cells to produce a wildtype or mutant BCR. With transient transfection, there was no difference in the intensity
of surface IgM in the cells that had either the
wild-type or mutant Igβ. By contrast, with stable transduction (using the retroviral viral vectors described above), there was consistently
less surface IgM in cells that contained the mutant Igβ (33). This study provides another example of the severe consequences of subtle decreases in the BCR signal transduction pathway.
HYPER-IgM SYNDROMES
(CLASS SWITCH
RECOMBINATION DEFECTS)
In the early 1960s, several groups described patients with recurrent infections and elevated β2
macroglobulin (121, 122) (the term IgM did
not come into use until the mid-1960s) but decreased serum gammaglobulin. These patients
were said to have dysgammaglobulinemia, and
many, but not all, were boys with neutropenia
and the early onset of disease. The term hyperIgM syndrome was ﬁrst used to describe this
group of patients in 1974 (123). It is now obvious that not all patients with the genetic disorders that come under this category have elevated IgM. Instead, the most consistent feature
of these disorders is a defect in class switch recombination, and Durandy et al. (25) proposed
the term class switch recombination defects to
describe them. Patients with recurrent bacterial infections and normal or elevated serum
IgM but low serum IgG, IgA, and IgE are considered to have hyper-IgM syndrome or class
switch recombination defects.
Patients with mutations in CD40 ligand
(also called CD154, gene symbol CD40LG ) account for approximately 65% of patients with
defects in class switch recombination (10, 124–
127). As a group, these patients are sicker than
those with early defects in B cell development.
Median age at diagnosis is less than 12 months,
and more than half the patients have opportunistic infections and/or neutropenia (20, 23).
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The opportunistic infections (which include
pneumocystis pneumonia and infections with
cytomegalovirus or cryptosporidium) are generally attributed to the failure to initiate the normal cross talk between CD40 ligand–expressing
T cells and CD40-expressing macrophages and
dendritic cells. Interestingly, affected patients
may have recurrent episodes of pneumocystis
pneumonia (23), indicating that the patients
have a defect in the memory T cell response,
as well as the primary response. European patients with CD40 ligand deﬁciency have a high
incidence of sclerosing cholangitis owing to
infection with cryptosporidium (19.6%) (20).
This complication occurs in North American
patients, but it is less common (6%) (23).
Four patients with null mutations in CD40
have been reported (24, 128). These patients
had a clinical phenotype that was indistinguishable from that seen in those with defects in
CD40 ligand. This indicates that neither CD40
nor CD40 ligand has additional ligands or
receptors.
Approximately 10–15% of patients with
defects in class switch recombination have
autosomal recessive mutations in AICDA,
which encodes the B cell–speciﬁc enzyme AID
(activation-induced cytosine deaminase) (129–
131). AID is transiently and selectively expressed in germinal center B cells in response to
stimulation through CD40 and cytokines (132,
133). It initiates both class switch recombination and somatic hypermutation by deaminating cytosine residues in VH regions and switch
regions in actively transcribed immunoglobulin
genes (134, 135). The resulting uracil residues
are then deglycosylated and removed by an
enzyme called uracil-DNA glycosylase (UNG )
(25, 136–138). The nicks in DNA are then converted to double-strand breaks, which are processed by mismatch repair proteins and proteins
involved in nonhomologous end joining (133).
Patients with AID mutations may be recognized as having immunodeﬁciency in the ﬁrst
5 years of life, but more than half are older at
the time of diagnosis and the initiation of therapy (129, 130). In addition to problems with
infections (which may be quite severe), these
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patients have enlarged lymph nodes and a high
incidence of autoimmune disorders (139). Notably, markedly enlarged lymph nodes are not
as common in CD40 ligand deﬁciencies.
The speciﬁc mutation in AICDA does inﬂuence the phenotype. Patients with mutations
in the 3 part of the gene, the part encoding
the nuclear localization signal, have impaired
class switch recombination but not somatic hypermutation (140). A small number of patients
with heterozygous premature stop codons at
residues 186 or 190 in the 3 part of AICDA
have been identiﬁed (141). These patients have
a milder disease. They are usually not evaluated for immunodeﬁciency until they are
adolescents or adults, and they may have asymptomatic relatives who share the same heterozygous mutation. Their serum IgM is usually
mildly increased, IgG is low, IgA is variable,
and serum IgE is absent. Somatic hypermutation is normal in these patients. The normal somatic hypermutation combined with defective
class switch recombination in patients with mutations in the carboxy-terminal region of AID
suggests that this portion of the molecule has a
function that is speciﬁc to class switch recombination. The difference between the autosomal
recessive and autosomal dominant forms may
reﬂect the amount of stable protein that is produced. Because AID functions as a tetramer, a
stable truncated form of the protein may have
a dominant negative function.
Imai et al. (137) described three unrelated
patients with autosomal recessive defects in
UNG. These patients were clinically similar
to those who had mutations in AICDA; two
had lymphadenopathy, and one had autoimmune disease. Laboratory studies showed a severe defect in class switch recombination and a
skewed pattern of somatic hypermutation. Almost all the mutations were transitions (guanine
to adenine or cytosine to thymine), whereas
in controls transitions composed only 65% of
mutations.
It is highly likely that there is at least one additional single-gene defect causing autosomal
recessive hyper-IgM syndrome. Peron et al.
(142) described a group of patients with
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recurrent respiratory infections and normal or
elevated serum IgM, but low serum IgG, IgA,
and IgE. Detailed studies in a subset of these
patients, including two brothers and the child
of consanguineous parents, showed normal
activation of AID and normal production of
AID-initiated double-strand DNA breaks.
Fibroblast cell lines from the affected patients
demonstrated increased radiation sensitivity,
suggesting a defect in DNA repair. It is not clear
that all the children with recurrent infections,
normal or elevated serum IgM, and low IgG,
IgA, and IgE will have single-gene defects of the
immune system. This phenotype is common in
adults who are given the diagnosis of CVID.
COMMON VARIABLE
IMMUNODEFICIENCY (CVID)
All clinical immunologists would agree that the
term CVID includes a heterogeneous group of
disorders (13, 26, 27). Typically, affected patients have the onset of recurrent infections after the ﬁrst 10 years of life; they have normal
or low serum IgM and low IgG and IgA with
poor production of antibody to vaccine antigens
(13, 16, 26, 48). Autoimmune manifestations
are common and may be more difﬁcult to control than the immunodeﬁciency. The number
of B cells in the peripheral circulation is usually within the normal range but may be very
low. Most patients have very low numbers of
CD27+ switched memory B cells (143). However, there are exceptions to each of these features. CVID should be considered a diagnosis
of exclusion (144). Malignancies, congenital infections, drug reactions, and single-gene defects
of the immune system (145–147) can all masquerade as CVID.
Most patients with what are considered
single-gene defects of the immune system are
evaluated for immunodeﬁciency in the ﬁrst
5 years of life because of recurrent or persistent
infections (14, 20). By contrast, patients with
CVID, which is generally thought to be multifactorial in etiology, are more likely to have
the onset of disease in adulthood (13, 16, 26). It
is not clear why patients with CVID have a de-
layed onset of vulnerability. It may be that some
of them have had problems with infections from
early childhood, but the problems were not
severe enough to arouse concern. However,
other patients adamantly deny having had excessive infections as children. Did these patients
lose their immunity? Have they acquired inappropriate suppression of antibody production?
Do they have an accelerated exhaustion of the
immune system? Over the years, studies evaluating the clinical and laboratory ﬁndings in
patients with CVID have suggested many different answers to these questions (143, 148–
151), but thus far the answers have not proven
to be satisfying, and there are no animal models
that clearly replicate the ﬁndings in CVID.
Approximately 10–20% of patients with
CVID have a family history of autoimmunity
or disorders of antibody production (152, 153).
Both autosomal dominant and autosomal recessive patterns of inheritance have been reported
(11, 154–156). In some family members, the
serum IgM, IgG, or IgA is elevated rather than
decreased. IgA deﬁciency is particularly common in relatives of patients with CVID. Early
attempts to identify the genetic variations that
contribute to CVID demonstrated that certain
HLA haplotypes were more common in both
CVID and IgA deﬁciency (157–162). Because
the HLA locus is complex (including genes for
complement factors C2 and C4, TNF-α, and
mismatch repair genes, as well as genes for histocompatibility antigens), it has been difﬁcult
to pin down the speciﬁc genetic changes that
confer vulnerability.
Recent studies have shown that there are
polymorphic variants in the mismatch repair
gene Msh5 (MSH5 ), which is encoded in the
central MHC class III region (163). Msh5
and its heterodimeric partner, Msh4, help resolve the DNA breaks that occur as part of
class switch recombination. CVID patients with
these polymorphic variants show extended microhomology regions at switch joints (163).
However, these polymorphic variants are not
more common in CVID patients compared
with controls, making their role in the pathogenesis of CVID uncertain.
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Defects in ICOS and CD19
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Homozygous mutations in ICOS or CD19
are clearly the cause of disease. In 2003,
Grimbacher et al. (11) identiﬁed four patients,
two sibling pairs, whose T cells failed to express ICOS after activation. Genomic studies
revealed a 1.8-kb deletion that removed exons
2 and 3 of ICOS in all the patients. Later studies described ﬁve additional patients with the
same mutation on the same haplotype, indicating that all nine patients shared a common
ancestor (164).
ICOS, a member of the CD28 CTLA4 family, is transiently expressed on activated
T cells and acts as a positive costimulatory
molecule (165, 166). Its ligand, B7RP-1, is a
member of the B7 family; it is expressed constitutively on B cells and in response to stimulation on antigen-presenting cells (167, 168).
Knockout mice that fail to express ICOS have
decreased serum IgG1, IgG2, and IgE but normal or elevated serum IgM and IgG3 (169–
171). Failure to produce IgG1 in these mice
could be overcome by CD40 stimulation (169).
Although seven of the nine patients with
mutations in ICOS had the onset of recurrent
infections at 15–28 years of age (which is typical
of CVID), the remaining two were less than 5
years old at the time of diagnosis (164). These
two patients had an older sibling with the ICOS
mutation, which probably prompted an early
evaluation of recurrent infections. None of the
patients has been reported to have autoimmune
disease. Four of the nine patients had serum
IgM concentrations that were within the normal range, and one had normal serum IgA. B
cell numbers were low or borderline low in all
except the two youngest patients. Long-term
follow up of these patients will indicate whether
B cell numbers and immunoglobulin concentrations decline with age.
Mutations in CD19 also result in an autosomal recessive form of hypogammaglobulinemia with similarities to CVID. Six patients
from four unrelated families have been identiﬁed (172, 173; M.E. Conley, A.K. Dobbs,
D.M. Farmer, J-L. Casanova, unpublished re-
216
Conley et al.
sults). One patient had a splice defect on one
allele and a large deletion on the other (173).
The remaining ﬁve patients had three different
homozygous frameshift mutations within the
cytoplasmic domain of CD19. All the mutations resulted in normal numbers of circulating
B cells, as identiﬁed by expression of CD20;
however, there was minimal or no CD19 identiﬁed on the B cell surface.
CD19 is normally expressed throughout B
cell differentiation as part of a signaling complex that includes CD21, CD81, and CD225
(174). Studies done in CD19 knockout and
transgenic mice indicate that CD19 regulates
basal signal transduction thresholds in resting
B cells (175). It does this by amplifying src family activation following BCR ligation. Elevated
CD19 expression is associated with autoantibody production (175). These ﬁndings raise
questions about the effects of decreased CD19
expression on B cells from patients with mutations in Btk.
The six patients described above include
three siblings with a frameshift mutation who
were not recognized to have immunodeﬁciency
until they were 35–49 years old. However, all
three had a history of frequent infections starting in childhood (172). The remaining three
patients were found to have hypogammaglobulinemia at 5–12 years of age. All the patients
had low serum IgG, and most, but not all,
had low IgM and IgA. No autoimmunity has
been reported. Van Zelm et al. (172) examined four of the patients with CD19 defects
in great detail. They found normal amounts of
CD19 transcripts in the B cells from the patients
with frameshift mutations but detected minimal amounts of intracellular protein, suggesting that the frameshift mutations did not result
in nonsense-mediated decay of the message, but
instead decreased translation or survival of the
protein. Surface expression of CD21 on the B
cells was decreased, but CD81 and CD225 expression was normal. Other cell surface markers
(including IgM, IgD, CD22, CD38, and CD40)
were normally expressed. CD27+ memory B
cells were present, but in reduced numbers
(1–6% of B cells compared with 17–28% in
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controls). Analysis of the switch memory B cells
showed normal somatic hypermutation. B cells
from the four patients showed decreased calcium ﬂux after cross-linking of the BCR. The
primary IgG response to rabies immunization
was at the low end of the normal range, whereas
the secondary response was clearly below
normal.
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Alterations in TACI
Heterozygous mutations in the TNF receptor family member TACI (transmembrane
activator and calcium-modulating cyclophilin
ligand interactor) can be found in up to 10%
of patients with CVID (156, 176–179). However, the relationship between TACI and CVID
is complex. Large population studies indicate
that approximately 1–2% of healthy controls
have one of the amino acid substitutions found
in patients with CVID (178, 179). On the basis
of Hardy-Weinberg law (180, p. 147), we may
reasonably assume that 1/10,000 individuals are
homozygous for these amino acid substitutions
(0.01 × 0.01). The prevalence of CVID in the
population has been estimated to be 1/25,000
(156). Taken together, these ﬁgures indicate
that over 90% of people who are heterozygous
or homozygous for one of the amino acid substitutions associated with CVID do not have
infections severe enough to elicit an evaluation
for immunodeﬁciency.
In almost all the patients with CVID and
heterozygous alterations in TACI, the alteration is an amino acid substitution. Premature
stop codons and frameshift mutations have been
seen in individuals who were compound heterozygotes and had an amino acid substitution on the other allele; however, only a single
patient with a premature stop codon on a single allele has been reported (164). These ﬁndings suggest that the amino acid substitutions
in TACI function as dominant-negative mutations. This can be explained by the fact that
TACI forms trimers prior to ligand interaction. Using transfection of 293T cells, Garibyan
et al. (181) demonstrated that proteins bearing the amino acid substitution seen most fre-
quently in CVID, C104R, can assemble with
wild-type TACI, but they are unable to signal
appropriately.
The serum IgG concentration in patients
with TACI abnormalities is often borderline
low, and the serum IgM may be within normal
range (176, 177). However, autoimmunity, particularly thrombocytopenia and splenomegaly,
is more common in this group of patients (156,
177).
It is not clear why some individuals with particular heterozygous alterations in TACI have
disease and others do not. Salzer et al. (156) and
Waldrup et al. (182) examined HLA haplotypes
in patients with TACI alterations to determine
if these patients were more likely to have HLA
haplotypes previously associated with disease.
Although the numbers are small, the two susceptibility factors do not appear to cosegregate.
The functional data using the C104R mutation and the higher prevalence of TACI amino
acid substitutions in CVID patients compared
with controls indicate that alterations in TACI
can function as susceptibility genes; however,
the relatively high prevalence of these amino
acid substitutions in healthy donors demonstrates that these alterations are not diseasecausing mutations.
CONCLUDING REMARKS
Tremendous progress has been made in the
identiﬁcation and characterization of genes responsible for immunodeﬁciencies in the past
15 years. For some of the classic X-linked immunodeﬁciencies, such as XLA and X-linked
hyper-IgM syndrome, hundreds of different
mutations have been described in the causative
genes. Careful analysis of the functional consequences of some of these mutations can provide new insight into the requirements for
normal B cell development. Further areas of
investigation will include a better understanding of susceptibility genes and modifying genetic factors, as well as the identiﬁcation of the
mutant genes in patients who do not appear to
have defects in the genes already associated with
immunodeﬁciency.
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SUMMARY POINTS
1. Mutations in Btk, the gene responsible for XLA, account for approximately 85% of
patients with early onset of infection, profound hypogammaglobulinemia, and markedly
reduced or absent B cells.
2. XLA is a leaky defect in B cell development. Most patients do have a small number of B
cells in the peripheral circulation. Those B cells have a distinctive phenotype.
3. The speciﬁc mutation in Btk is only one factor that inﬂuences the severity of disease in
XLA.
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4. Mutations in μ heavy chain account for approximately 5% of patients with defects in early
B cell development. All the reported mutations have been associated with the complete
absence of B cells in the peripheral circulation.
5. A small number of mutations in other components of the pre-BCR or the scaffold protein
BLNK have been identiﬁed. All the known mutations in Igα have been null mutations
resulting in the complete absence of B cells in the blood. Some mutations in λ5, Igβ,
and BLNK have been associated with a very small number of B cells in the blood. The B
cells seen in BLNK deﬁciency and in a patient with a hypomorphic Igβ mutation have
a phenotype similar to that seen in patients with mutations in Btk.
6. Patients with hyper-IgM syndrome or defects in class switch recombination may have
mutations in CD40 ligand (65% of patients), CD40 (<1%), AID (20%), or UNG (<1%).
Mutations in AID can cause an autosomal recessive or a milder autosomal dominant form
of disease.
7. The predisposing genetic factors that are associated with CVID are unknown in the
majority of affected patients. A very small number of patients have homozygous defects
in ICOS or CD19.
8. Some heterozygous amino acid substitutions in TACI act as susceptibility genes for
CVID. These polymorphisms are seen in healthy controls, but they are more common
in patients with CVID, occurring in up to 10% of patients.
FUTURE ISSUES
1. Although most genes responsible for defects in early B cell development or hyper-IgM
syndrome have been identiﬁed, there are still some patients with these clinical disorders who do not have defects in the described genes. What are the best approaches for
determining the nature of the defect in these patients?
2. Knowing the genetic etiology of a particular immunodeﬁciency allows more informed
genetic counseling and lays the groundwork for gene therapy. Are there other ways in
which this information can beneﬁt the patient? Can we ﬁnd ways to compensate for the
genetic defect?
3. Are there modifying genetic factors that inﬂuence the severity of all primary B cell
immunodeﬁciencies, or are there disease-speciﬁc modifying factors?
218
Conley et al.
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4. Large cooperative studies may make it possible to determine if there are one or many
modifying genetic factors that dictate whether an individual with a heterozygous alteration in TACI will have immunodeﬁciency.
DISCLOSURE STATEMENT
Annu. Rev. Immunol. 2009.27:199-227. Downloaded from arjournals.annualreviews.org
by Rutgers University Libraries on 05/24/09. For personal use only.
The authors are not aware of any afﬁliations, memberships, funding, or ﬁnancial holdings that
might be perceived as affecting the objectivity of this review.
ACKNOWLEDGMENTS
The work described in this article was supported by grants from the National Institutes of Health
(AI25129), National Cancer Institute (P30 CA21765), and American Lebanese Syrian Associated
Charities and by funds from the Federal Express Chair of Excellence.
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Contents
Volume 27, 2009
Frontispiece
Marc Feldmann p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p x
Translating Molecular Insights in Autoimmunity into Effective
Therapy
Marc Feldmann p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p1
Structural Biology of Shared Cytokine Receptors
Xinquan Wang, Patrick Lupardus, Sherry L. LaPorte,
and K. Christopher Garcia p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 29
Immunity to Respiratory Viruses
Jacob E. Kohlmeier and David L. Woodland p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 61
Immune Therapy for Cancer
Michael Dougan and Glenn Dranoff p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 83
Microglial Physiology: Unique Stimuli, Specialized Responses
Richard M. Ransohoff and V. Hugh Perry p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p119
The Liver as a Lymphoid Organ
Ian Nicholas Crispe p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p147
Immune and Inﬂammatory Mechanisms of Atherosclerosis
Elena Galkina and Klaus Ley p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p165
Primary B Cell Immunodeﬁciencies: Comparisons and Contrasts
Mary Ellen Conley, A. Kerry Dobbs, Dana M. Farmer, Sebnem Kilic,
Kenneth Paris, Soﬁa Grigoriadou, Elaine Coustan-Smith, Vanessa Howard,
and Dario Campana p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p199
The Inﬂammasomes: Guardians of the Body
Fabio Martinon, Annick Mayor, and Jürg Tschopp p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p229
Human Marginal Zone B Cells
Jean-Claude Weill, Sandra Weller, and Claude-Agnès Reynaud p p p p p p p p p p p p p p p p p p p p p p267
v
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ARI
16 February 2009
15:37
Aire
Diane Mathis and Christophe Benoist p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p287
Regulatory Lymphocytes and Intestinal Inﬂammation
Ana Izcue, Janine L. Coombes, and Fiona Powrie p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p313
The Ins and Outs of Leukocyte Integrin Signaling
Clare L. Abram and Clifford A. Lowell p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p339
Annu. Rev. Immunol. 2009.27:199-227. Downloaded from arjournals.annualreviews.org
by Rutgers University Libraries on 05/24/09. For personal use only.
Recent Advances in the Genetics of Autoimmune Disease
Peter K. Gregersen and Lina M. Olsson p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p363
Cell-Mediated Immune Responses in Tuberculosis
Andrea M. Cooper p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p393
Enhancing Immunity Through Autophagy
Christian Münz p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p423
Alternative Activation of Macrophages: An Immunologic Functional
Perspective
Fernando O. Martinez, Laura Helming, and Siamon Gordon p p p p p p p p p p p p p p p p p p p p p p p p451
IL-17 and Th17 Cells
Thomas Korn, Estelle Bettelli, Mohamed Oukka, and Vijay K. Kuchroo p p p p p p p p p p p p p p485
Immunological and Inﬂammatory Functions of the Interleukin-1
Family
Charles A. Dinarello p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p519
Regulatory T Cells in the Control of Host-Microorganism Interactions
Yasmine Belkaid and Kristin Tarbell p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p551
T Cell Activation
Jennifer E. Smith-Garvin, Gary A. Koretzky, and Martha S. Jordan p p p p p p p p p p p p p p p591
Horror Autoinﬂammaticus: The Molecular Pathophysiology of
Autoinﬂammatory Disease
Seth L. Masters, Anna Simon, Ivona Aksentijevich, and Daniel L. Kastner p p p p p p p p p621
Blood Monocytes: Development, Heterogeneity, and Relationship
with Dendritic Cells
Cedric Auffray, Michael H. Sieweke, and Frederic Geissmann p p p p p p p p p p p p p p p p p p p p p p p p669
Regulation and Function of NF-κB Transcription Factors in the
Immune System
Sivakumar Vallabhapurapu and Michael Karin p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p693
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