Deconstructing common variable immunodeficiency bygenetic analysisAlejandro A Schaffer1, Ulrich Salzer2, Lennart Hammarstrom3 andBodo Grimbacher4

Common variable immunodeficiency (CVID) is the most

common symptomatic primary immunodeficiency. Patients

have recurrent bacterial infections and an increased risk of

developing autoimmune diseases, lung damage, and selected

cancers. Since 2003, four genes have been shown to be

mutated in CVID patients: ICOS, TNFRSF13B (encoding TACI),

TNFRSF13C (encoding BAFF-R) and CD19. Heterozygous

mutations in TNFRSF13B are also associated with CVID,

whereas the other three genes are purely recessive. Recent

genetic linkage studies have also identified possible loci for

dominant CVID genes on chromosomes 4q, 5p and 16q. These

findings markedly improved the genetic diagnosis of CVID and

point towards new strategies for future genetic studies. In

addition, some CVID genes might be relevant to more common

diseases such as asthma and stroke.

Addresses1 National Center for Biotechnology Information, National Library of

Medicine, National Institutes of Health, Department of Heath and Human

Services, 8600 Rockvile Pike, Bethesda, MD 20894, USA2 Division of Rheumatology and Clinical Immunology, Medical Center,

University of Freiburg, Hugstetterstraße 55, 79106 Freiburg, Germany3 Division of Clinical Immunology, Karoliska Institutet at Karolisnka

University Hospital Huddinge, SE-141 86 Stockholm, Sweden4 Department of Immunology and Molecular Pathology, Royal Free

Hospital, University College London, Pond Street, London, NW3 2QG,

UK

Corresponding author: Grimbacher, Bodo

(b.grimbacher@medsch.ucl.ac.uk)

Current Opinion in Genetics & Development 2007, 17:201–212

This review comes from a themed issue on

Genetics of disease

Edited by Robert Nussbaum and Leena Peltonen

Available online 27th April 2007

0959-437X/$ – see front matter

# 2007 Elsevier Ltd. All rights reserved.

DOI 10.1016/j.gde.2007.04.002

IntroductionThe major achievement in the evolution of the adaptive

immune system is its capability to generate specific

antibodies directed against invading pathogens, and to

memorize this immune response. These antibodies,

generated as various immunoglobulin (Ig) isotypes (i.e.

IgM, IgG, IgA and IgE), represent an important com-

ponent of the humoral immune system and are thus kept

at a constant concentration in blood. Disorders affecting

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immunoglobulin production or turnover frequently lead

to hypogammaglobulinemia, rendering patients suscep-

tible to recurrent infection, especially by encapsulated

bacteria. The severity of this hypogammaglobulinemic

state can range from IgG subclass deficiencies in combi-

nation with IgA deficiency to complete absence of all

three major Ig isotypes (IgA, IgG and IgM), which is

termed ‘agammaglobulinemia’.

The diagnosis of common variable immunodeficiency

(CVID) is typically made in patients with a history of

recurrent bacterial infections and substantially lowered

serum levels of immunoglobulins. In particular, CVID

patients almost always have low IgG and IgA serum

levels, and about 85% also show a reduction of IgM in

serum [1]. The clinical course in CVID patients includes

an elevated risk of autoimmune diseases, lung compli-

cations and several types of cancer.

CVID is the most common primary immunodeficiency

that necessitates clinical attention, with an incidence

estimated at 1:10 000 to 1:50 000 [2]. Isolated IgA

deficiency is much more common in Caucasians, with

an incidence estimated at 1:700, but the vast majority of

cases are clinically unapparent. Several individuals have

been shown to gradually progress from IgA deficiency to

full-blown CVID [3–6]. How often this deterioration

occurs and over what time frame is hard to estimate,

because isolated IgA deficiency is often asymptomatic

and thus underdiagnosed.

In a large CVID patient cohort, Cunningham-Rundles

and Bodian [1] estimated that the difference between the

median age at the onset of initial symptoms and the

median age at diagnosis is five to six years. In the current

European database for CVID, this diagnostic delay was

shown to be four years [7]. Once patients are diagnosed

with CVID, immunoglobulin substitution is an effective

treatment in the majority of patients [8]. Immunoglobulin

administration is not a curative treatment, but a lifelong

replacement therapy that has to be applied either on a

monthly basis if given by the intravenous route or weekly

if subcutaneous immunoglobulin replacement therapy is

chosen. The safety and reliability of Ig replacement

therapy are overshadowed by various factors: possible

deleterious effects over decades of treatment [8,9];

economic constraints, because Ig therapy is expensive;

and the resources for the production of Ig for clinical

application are limited by the availability of eligible

Current Opinion in Genetics & Development 2007, 17:201–212

202 Genetics of disease

plasma donors. Therefore, the identification of genetic

factors that are involved in the etiology of CVID will

enable not only new diagnostics but also new leads for

possibly curative, therapeutic interventions.

It was recognized decades ago that CVID has a genetic

component [10]. The progression from IgA deficiency to

CVID mentioned above is most frequently observed in

families in which at least one immunodeficient individual

is diagnosed with CVID and in which the immunoglo-

bulin levels of available relatives are measured. Both by

this strategy and by strategies of ascertaining IgA-

deficient probands, Vorechovsky et al. [11] estimated that

approximately 20% of cases of IgA deficiency are familial,

whereby IgAD and CVID can cluster within single

families. For CVID alone we, and others, estimate the

frequency of familial occurrence to be about 10% [1].

There have been surprisingly few genetic studies of

CVID until the past few years. Early studies using genetic

linkage and association established that there is at least

one susceptibility locus in the HLA region on chromo-

some arm 6p. However, as with so many other HLA-

linked immune related diseases [12], pinning down the

CVID susceptibility genes and mutations on 6p has been

a quixotic challenge.

Both dominant and recessive inheritance have been

documented in CVID–IgAD families, with dominant

inheritance being far more common [11]. For recessive

inheritance, numerous CVID candidate genes have been

suggested on the basis of studies of single-gene knockout

mice that have low immunoglobulin levels and are suscept-

ible to infections. Within the past five years, studies of such

candidate genes outside 6p, and genome-wide linkage

studies of CVID have identified several causative or

associated genetic factors: three genes mutated in a small

number of recessive cases; one gene that is mutated in as

many as 10% of CVID cases; and some possible regions of

genetic linkage between polymorphic markers and the

CVID–IgAD phenotype.

In the central sections of this article, we review these

recent genetic findings. To put these findings into a

broader genetic context, we first describe some examples

of genetically defined differential diagnoses of CVID,

several of which have been made possible by the identi-

fication of other genes mutated in immunodeficiencies

that can mimic the clinical picture of CVID. In the later

sections, we speculate on the prospects for future genetic

studies of CVID and we discuss the possible relevance of

CVID-causing genes to two more common diseases,

asthma and stroke.

CVID is a diagnosis of exclusionMany conditions can manifest with the symptoms of

hypogammaglobulinemia and subsequent recurrent bac-

Current Opinion in Genetics & Development 2007, 17:201–212

terial infections. Still today, the diagnosis of CVID is

usually made when a variety of tests for other conditions

are negative. Only the discovery of some CVID-causing

genes, as described below, enabled us to make a definite,

genetically based diagnosis of CVID (i.e. by identification

of a mutation) in a small percentage of patients.

In Table 1, we highlight some monogenic immune dis-

eases that can mimic the clinical phenotype of CVID and

as such constitute important differential diagnoses.

Incomplete or abortive clinical courses of some multi-

system monogenic disorders such as ataxia telangiectasia

and myotonic dystrophy can also manifest with a CVID-

like phenotype. Additionally, exposure to non-genetic

factors such as drugs (e.g. gold salts) and viral infections

(e.g. Epstein-Barr virus [EBV]) can also result in states of

hypogammaglobulinemia.

In male CVID patients, especially when there is a family

history compatible with X-linked inheritance, two well-

known other immunodeficiency disorders need to be

excluded: in X-linked agammaglobulinemia (XLA),

B-cell development is blocked at the pre-B-cell stage,

resulting in severe peripheral B-cell lymphopenia and

usually very low immunoglobulin levels; in X-linked

lymphoproliferative syndrome (XLP) the clinical picture

contains the triad of an often fatal infection with EBV

associated with the development of lymphoma and hypo-

gammaglobulinemia [13].

A crucial distinction between XLA and XLP and CVID is

that the onset of XLA and XLP is usually shortly after

birth, whereas the diagnosis of CVID is usually reserved

for patients whose onset is above age 2. However, several

papers cited in Table 1 document XLA and XLP cases

with hypomorphic mutations that led to later age of onset

and misdiagnosis as CVID. XLA can be distinguished

from CVID by the nearly complete lack of B cells (<1% of

lymphocytes), whereas a distinguishing characteristic of

XLP is a very low number of natural killer T-cells [14��]and a proven history of a usually severe course of EBV-

induced infectious mononucleosis.

Hyper-IgM syndromes seem to be closely related to

CVID from a mechanistic point of view because they

also lack switched isotypes, which is one of the clinical

hallmarks of CVID. The observation of abnormally high

levels of IgM with concomitant reduction of switched

isotypes in some patients led to the name for these

disease entities. However, recent consensus statements

suggest that the hyper-IgM syndromes should rather be

called ‘class-switch recombination’ (CSR) defects to bet-

ter define the underlying pathomechanism in these

groups of patients. Consequently, many patients diag-

nosed with a CSR defect have serum IgM levels in the

normal range for their age, making it difficult to dis-

tinguish them from those with the CVID phenotype.

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Deconstructing common variable immunodeficiency by genetic analysis Schaffer, Salzer, Hammarstrom and Grimbacher 203

Table 1

Some monogenic disorders that are differential diagnoses for CVID.

Disease Inheritance Gene(s) involved References

X-linked agammaglobulinemia (Bruton’s disease) X-linked BTK [68–70]

Autosomal agammaglobulinemia due to m-heavy

chain deficiency

AR IGHM [71–73]

Rare autosomal agammaglobulinemias AR CD79A (Iga) [74–77]

IGLL1 (l5/14.1)

BLNK/SLP65

LRRC8 (translocation)

X-linked Hyper-IgM syndrome X-linked CD40L [78,79]

Autosomal Hyper-IgM syndromes Usually AR;

Mutations in AID can be AD

AID, CD40, UNG [80–83]

X-linked lymphoproliferative syndromes X-linked SH2D1A, XIAP (also known as BIRC4) [84,85,86��]

X-linked severe combined immunodeficiency

(SCID)

X-linked IL2RG [86��]

Autosomal SCID AR ADA, DCLRE1C, RAG1, RAG2, IL7R, CD45,

CD3D, CD3E

[87]

WHIM syndrome AD CXCR4 [88]

IgG subclass deficiencies AR Deletions involving the Ig heavy chain region

on chromosome 14

[89]

CVID is diagnosed by exclusion. For example, several rarer genetic disorders might mimic the symptoms and sometimes need to be excluded by

gene sequencing to substantiate the diagnosis of CVID. This table lists rare, but genetically defined, differential diagnoses of CVID, their mode

of inheritance and the respective mutated gene(s). Abbreviations: AID, activation-induced cytidine deaminase; AR, autosomal recessive;

AD, autosomal dominant; WHIM, warts, hypogammaglobulinemia, infections and myelokathexis.

CSR defects can be diagnosed most easily and reliably by

sequencing genes listed in Table 1; the CSR process itself

involves multiple steps, any one of which can be defec-

tive.

Candidate genes implicated in recent CVIDstudiesSince 2003, four genes have been found to have both

alleles mutated in at least one CVID patient (Table 2). All

four genes were considered as candidates on the basis of

the combined knowledge about B-cell biology and pub-

lished phenotypes of single-gene knockout mice. These

criteria could be used to justify the candidacy of dozens of

genes, and the majority of the genes we have tested have

no patently deleterious sequence changes in cohorts of

dozens of CVID patients. The rarity of mutations in ICOS(inducible co-stimulator), TNFRSF13C (tumor necrosis

factor superfamily member 13C) and CD19 (B-lympho-

cyte antigen CD19) demonstrates that by sequencing

Table 2

Four genes in which double mutations cause either CVID or IgAD (sin

and IgAD).

Gene Mutations Patients with 2 alleles mutated Pa

ICOS 1 9 0

TNFRSF13C 1 1 0

TNFRSF13B 17 20 38

CD19 2 4 0

In the past five years, four genes have been identified that have both allel

mutations in TNFRSF13B are associated with CVID, whereas heterozygot

gene names, the number of different mutations that have been described

one or two mutated alleles of the respective gene.

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alone it is impossible to exclude rare mutations in any

gene. We now present short reviews of the proteins

encoded by the four genes known to cause CVID.

ICOS is expressed exclusively on T cells after their

activation [15]. ICOS is a T-cell co-stimulatory molecule

that interacts with ICOS-L, which is expressed on the

surface of B cells and specialized antigen-presenting cells,

thereby supporting the collaboration among B, T and

dendritic cells in an ongoing immune response. Ligation

of ICOS-L to ICOS leads to a release of interleukin 10 from

germinal center T-cells, enabling B cells to undergo CSR

(see Figure 1). Furthermore, the ICOS–ICOS-L signaling

in germinal centers is crucial for the development and

function of the highly specialized subpopulation of

CXCR5+ follicular T-helper cells [16�]. The loss of ICOS

expression leads to absence of this special cell population,

consecutive failure to develop functional germinal centers

and, ultimately, impaired terminal B-cell differentiation

gle mutations in TNFRSF13B are also associated with CVID

tients with 1 allele mutated References

[29,90��]

[91]

[61��,92��] (Salzer et al., unpublished)

[18��]

es mutated in at least one CVID patient. Single, heterozygous

es for the other genes have no apparent phenotype. The table lists

for each of the four genes, and the numbers of patients carrying either

Current Opinion in Genetics & Development 2007, 17:201–212

204 Genetics of disease

Figure 2

The B cell receptor signaling complex. The B cell receptor (BCR) itself

has quite a weak capability of signaling into B cells. The BCR signal is

thus amplified by a transmembrane signaling complex consisting of

CD19, CD21 (also termed complement receptor (CR) 2), CD81 and

CD225 (also termed Leu-13). Not only does Antigen, opsonised by C3d,

bind the BCR but the C3d also binds to CD21. CD21 in turn is linked to

CD19, which has a long intracytoplasmatic signaling domain with at

least three important phosphorylation sites, well capable of amplifying

the BCR signal into the B cells.

Figure 1

T–B cell cooperation. After TCR engagement, the activation status of T

cells is fine-tuned by co-stimulatory signals. Ligation of CD80 or CD86

on antigen presenting cells (e.g. B cells) to CD28, which is constitutively

expressed on T cells, and ligation of ICOS-L to the inducible co-

stimulator (ICOS) of T cells, upregulates the T cell’s activation status. On

the contrary, engagement of CTLA-4 with CD80 or CD86, for example,

serves as a downregulatory mechanism. Ligation of ICOS-L and ICOS

lead to the secretion of a wide array of cytokines such as interleukin (IL)

10, IL-17, IL-21 and IL-23, with IL-10 being the most abundant one. If T

cells are missing this co-stimulatory signal, they are unable to provide B

cells with sufficient T cell help (cytokines) to perform a proper germinal

center formation and class-switch recombination.

and hypogammaglobulinemia [16�,17�]. Some of the

patients with ICOS mutations had normal levels of IgM

or showed a transient increase of antigen-specific IgM in

episodes with acute infection, but they had low levels of

IgG and IgA. ICOS deficiency is currently classified as a

cause of CVID rather than a CSR defect because of

historical reasons and the fact that, unlike the CSR-defect

genes in Table 1, the known functional connection be-

tween ICOS activity and CSR is quite indirect.

CD19, in contrast to ICOS, is expressed exclusively on B

cells. Indeed, surface expression of CD19 is often used in

flow cytometry to identify B cells. van Zelm et al. [18��]reported that B cells from four patients had severely

reduced CD19 expression, but had normal numbers of

B cells, as detected by the existence of other surface

markers such as CD20. The likely reason that CD19

deficiency is deleterious is that CD19 is part of a four-

protein complex, together with CD21, CD81 and CD225,

that helps receive and process the B-cell receptor–antigen

signal (see Figure 2). The impaired antigen-dependent

signaling of the B-cell receptor complex in CD19-

deficient humans, as evidenced by the reduced Ca2+

influx, results in inadequate numbers of mature B-cells,

which produce insufficient amounts of antibodies when

challenged with antigen — either by vaccination or by

recurrent infections.

Current Opinion in Genetics & Development 2007, 17:201–212

Both reported mutations in CD19 code for putative

proteins that have a premature truncation. The patients

were shown to have normal levels of CD19 mRNA, and

thus the truncated proteins might perform some function

in vivo. This differs from the scenario in ICOS deficiency,

in which the only known mutation causes a complete

protein knockout. CD19 mutations that affect surface

expression are likely to be rare because they should be

noticed accidentally in flow cytometry. However, CD19sequence changes with retained CD19 expression (e.g. at

phosphorylation sites in the CD19 intracellular domain)

might exist and could lead to a CVID phenotype when

both alleles are affected.

The other two proteins, BAFF-R (B-cell-activating fac-

tor receptor) and TACI (transmembrane activator and

calcium-modulating cyclophilin ligand interactor), are

receptors expressed at the surface of B cells and partici-

pate in a complex signaling network; the five most

studied proteins in this network are depicted in

Figure 3. BAFF-R receives signals from BAFF that

are essential for the survival of peripheral B-cells [19].

By contrast, BCMA (B-cell maturation antigen) expres-

sion is highly restricted to end stages of B-cell differen-

tiation and seems to be essential for the survival of

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Deconstructing common variable immunodeficiency by genetic analysis Schaffer, Salzer, Hammarstrom and Grimbacher 205

Figure 3

The APRIL–BAFF network: BAFF-R, TACI and BCMA are TNF-like receptors expressed in various stages of the B-cell development. Whereas

BAFF-R is more universally expressed and can be found on transitional and naıve B-cells, the expression of TACI is dependent on B-cell activation

and is mostly confined to the germinal center of the lymphoid organs. The expression of BCMA is mostly restricted to terminally differentiated

plasma blasts and plasma cells. BAFF binds all three receptors, but APRIL only binds to TACI and BCMA. BAFF binding to TACI seems to

downregulate the B cell’s activation status, but APRIL binding to TACI seems to induce class switch recombination to IgG and especially IgA.

long-lived bone marrow plasma cells [20]. The interaction

of APRIL (A proliferation-inducing ligand) with TACI

and with proteoglycans promotes IgA and IgG production

in a T cell-independent fashion [21,22�], whereas the

BAFF–TACI interaction keeps it in check [23�].

Based on knockout mouse models, any of the five genes in

Figure 3 could have been a plausible candidate for double

mutations in CVID patients. It is somewhat surprising

that, among the five, only TNFRSF13B has recurrent

double mutations. It is even more surprising that hetero-

zygosity for at least some mutations in TNFRSF13B was

reported to be associated with susceptibility to CVID and

possibly IgAD, since heterozygous TNFRSF13B+/� mice

are healthy and do not show signs of antibody deficiency

[24]. More recent data, however, suggests that mutations

in TNFRSF13B are not associated with sporadic selective

IgAD [25].

Because heterozygous TNFRSF13B mutations are seen in

approximately 10% of CVID patients, a major current

challenge is to understand which mutations are deleter-

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ious, by how much they increase the risk of developing an

antibody deficiency, and by what mechanism. The prin-

ciple that heterozygous mutations in TNF receptor

superfamily genes can increase susceptibility to human

disease was previously established through two other

immunological diseases: mutations in TNFRSF6, which

encodes Fas, are associated with autoimmune lympho-

proliferative syndrome (ALPS) [26]; and mutations in

TNFRSF1A, which encodes TNFR1, are associated with

TNFR1-associated periodic syndrome (TRAPS) [27]. For

CVID, ALPS and TRAPS, heterozygous mutations in the

TNF receptor superfamily member gene have variable

penetrance, even within families (for example [28]). It is

not known whether the variable penetrance is primarily

due to the effects of modifier genes, the effects of

environmental factors such as the infecting microbes,

or stochastic behavior of the TNF receptor proteins,

which naturally form homotrimers.

The discovery of four genes mutated in monogenic forms

of CVID–IgAD gives hope that more such genes can be

discovered by a candidate gene approach. The contrast

Current Opinion in Genetics & Development 2007, 17:201–212

206 Genetics of disease

between the B-cell-specific cellular function of TACI and

the T-cell specific expression of ICOS exemplifies the

extreme heterogeneity in the etiology of CVID. To date,

other genes encoding proteins that interact with the four

genes in Table 2 have not been found to have mutations

in any CVID patient (for example [29,30]). Given that the

candidate gene approach to identifying CVID genes

might be incomplete because so many immune-related

proteins have an incomplete functional annotation, we

have hedged our bets by also trying a positional approach

described in the next section.

Genetic linkage studiesThe genes described in the previous section were identi-

fied as being mutated in CVID patients, with minimal

usage of positional reasoning such as genetic linkage

analysis. There are dozens more genes that could be

functional candidates for CVID, and we are gradually

sequencing these for mutations [30] (Salzer et al., unpub-

lished). Nevertheless, we have some hope that genetic

linkage analysis could either lead to the identification of

some non-obvious CVID genes or help prioritize among

functional candidates. Especially for families with domi-

nant inheritance, candidate genes suggested by knockout

mouse models might be of limited relevance. Therefore,

we have undertaken genetic linkage studies in some

CVID families.

Many linkage or association studies in the 1990s focused

on the HLA region on chromosome 6p and suggested

that there is at least one susceptibility locus [31–37].

Whether there is one or two loci is still unresolved

[38]. The largest family collection grew to 101 multiplex

IgAD families, of which 43 have at least one patient with

CVID. Analysis of this dataset by model-free methods

defined the locus IGAD1 on chromosomes 6p but

suggested that it is a locus for IgAD only [37,39,40�].The last paper studying those families [40�] also gave

Table 3

Possible genetic linkages for CVID or IgAD, outside the HLA region.

Region(s) Type(s) of analysis Families

4p,12p,14q Model-free 101 with IgAD of which

43 had a CVID case

5p Model-based

(LOD scores)

1 large, 2 small

16q Model-based and

model-free

40 small families with a CVID

case from first study; 32

available for fine mapping

4q Model-based and

model-free

1 large family from Nijenhuis

et al. 2001

Besides the genes listed in Table 2, several regions have evidence of gen

found in these regions. In this table, the chromosomal region of each CVI

for the interpretation of the linkage data in the respective study, the numb

replicated in follow-up studies, and which candidate genes in the linked re

Current Opinion in Genetics & Development 2007, 17:201–212

some weaker evidence for IgAD loci on chromosomes 4p,

12p and 14q (Table 3).

We have carried out model-based and model-free analysis

on some larger families, as well as a subset of families from

the [40�] set that have at least one CVID case and no

mutations in TNFRSF13B. These results are summarized

in Table 3. Sequencing of a few plausible candidate genes

in the 4q, 5p and 16q regions yielded no mutations in the

coding regions. The 4q result looks most promising

because it was found in a large family, in which it was

possible to define a disease-associated haplotype, and

then replicated in the existing set of small families.

Strategies that might help identify more large, multiplex

families suitable for genetic linkage analysis are discussed

in the next section.

Can CVID patients be classified in agenetically useful way?A successful immune response to recurrent bacterial

infections is the result of a cooperation of many cell types

both of the innate and the adaptive immune system.

Phenotypic analyses of lymphocyte subpopulations in

CVID patients have focused on B cells because the

defining characteristic of hypogammaglobulinemia is

most probably a disturbance of memory B-cells and

plasma cells. These B-cell defects and the resultant

hypogammaglobulinemia might be due to various factors:

for example, B-cell lymphopenia; maturation defects of B

cells; defective production or secretion of antibodies; or

increased Ig catabolism. Indeed, the finding of numerous

mutations in TNFRSF13B, a few mutations in CD19, and

one mutation in TNFRSF13C (BAFF-R) in CVID

patients supports the B-cell-centric point of view. A brief

sketch of human B-cell development is given in Figure 4.

Even before any CVID genes had been found, this

general concept led to several proposals to classify CVID

Replication Candidate gene(s)

sequenced

Reference

No None [40�]

No PDCD6 [93]

No WWOX [94]

Yes, using 32 CVID

families from [38]

DAPP1, BANK1, NFkB,

SCYE1, CASP6

[95�]

etic linkage to CVID, although no mutated genes have yet been

D-linked locus is given, followed by the model of analysis used

er and types of CVID families analyzed, if this locus has been

gion have been excluded by sequencing.

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Deconstructing common variable immunodeficiency by genetic analysis Schaffer, Salzer, Hammarstrom and Grimbacher 207

Figure 4

A brief sketch of human B cell development. After leaving the bone marrow as transitional B-cells, B cells circulate in the peripheral blood and

become naıve B-cells, most probably with help of the splenic environment. At that stage they need BAFF as a survival signal to prevent

apoptosis. Once engaged in a germinal center reaction in secondary lymphoid organs, B cells receive T cell help by providing the correct set

of co-stimulatory molecules such as CD28 and ICOS to select the B cells with the correct BCR, and provide help to form a germinal center

where B cells proliferate, undergo class switch and somatic hypermutation. From there, B cells either become plasma blasts and plasma

cells and home back to the bone marrow to secrete immunoglobulin or become memory B cells, which circulate in the blood and engage

in the secondary immune response to provide an immunological memory to infections and vaccinations. Plasma cells have been shown to

depend on the survival factor provided by APRIL signaling through BCMA.

patients on the basis of flow cytometric analyses of their

B-cell subpopulations (for example [41,42]). A consistent

finding in these classification approaches is that about

75% of CVID patients have substantially fewer switched

memory (defined as IgD�CD27+) B cells as compared

with those of healthy controls. These classifications are

now used to correlate the disturbed B-cell phenotype

with the disease course [43,44]. Additionally, recent stu-

dies identified a subgroup of patients who have reduced

numbers of nonswitched memory B-cells (IgD+CD27+)

and who suffer from an increased rate of pulmonary

infections and respiratory disease [45]. Once again, the

absence of switched memory cells in most of the CVID

patients, mirroring the lack of switched isotypes in serum,

suggests a close relationship between CVID and defects

of class switch recombination. It still has to be determined

if these classification models or other possibilities for

classification discussed below show concordance among

affected relatives.

Some recent findings suggest that a more global view of

the defective immune response in CVID could help

identify other genes that are mutated or dysregulated.

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The finding of CVID patients with a homozygous

mutation in ICOS, which is expressed exclusively in

T cells [15], gave molecular proof for the longstanding

hypothesis (for example [46]) that T-cell defects can be a

primary cause of CVID.

More recent studies have moved further upstream from the

T–B interaction to consider antigen-presenting dendritic

cells. Bayry et al. [47�] and Viallard et al. [48] have shown

association between CVID and low numbers of mature

dendritic cells, especially plasmocytoid (CD11cneg)

dendritic cells. One effect of diminished dendritic cell

function in presenting antigens is that CVID patient cells

tend to secrete subnormal levels of the cytokine IL-12 [49].

Another possibility is that defective plasmocytoid dendri-

tic cells could directly inhibit the development of long-

lived memory B-cells [50].

Another important aspect of terminal B-cell differen-

tiation that has been found to be impaired in CVID is

the process of somatic hypermutation. Somatic hypermu-

tation diversifies the transcripts that comprise both the

heavy chains and the light chains of immunoglobulins, so

Current Opinion in Genetics & Development 2007, 17:201–212

208 Genetics of disease

that different Ig molecules have enhanced affinity to

different antigens at the surface of B cells, thus support-

ing a stronger and more selective immune response.

Defective somatic hypermutation in an IgG heavy chain

gene was first reported by Levy et al. [51] in a cohort of

eight CVID patients. Schejbel et al. [52] recently

strengthened and extended this observation by using a

larger cohort of patients, and by showing that defective

somatic hypermutation is a better predictor of disease

severity than the B-cell-based classifications. Andersen

et al. [53] showed that defective somatic hypermutation

occurs also in IgG light chain genes and that this measure-

ment is also associated with the severity of respiratory

tract infections.

The process of somatic hypermutation also involves

proteins with distinct roles in DNA mismatch repair

[54] and several immunodeficiency diseases have been

shown to be caused by defects in DNA repair proteins [55].

Given these facts, one could speculate that the increased

rate of certain types of cancer in CVID and the defect in

somatic hypermutation might be related to a possible

mismatch repair defect. Predisposing mutations in such

genes could exist in CVID patients analogous to numerous

cancer susceptibility genes in which germline mutations,

present at birth, can lead to disease in adulthood, when

combined with deleterious somatic mutation events.

Especially interesting in this regard are genes such as

MLH1 [56] and BRCA1 [57] in which the same germline

mutation in relatives can lead to tumors in different tissues

and at rather different ages. These tumor suppressor genes

serve as counterpoints to the suggestion that CVID

is rarely associated with germline mutation because of

the following reasons: only a small percentage of cases are

familial; there are few large multiplex families; and most

patients have disease onset in adulthood.

One tool that has proven quite successful in cancer studies,

especially classification, is microarrays (for example

[58,59]). One might hope that a similar application of

microarrays to CVID patients will lead to the identification

of more homogenous subsets of patients as well as specific

genes that are dysregulated. However, we are aware of

only one published study that carried out a microarray

experiment on a CVID patient sample [60].

CVID genes and susceptibility to morecommon diseasesThe genes encoding a healthy immune system must

achieve a delicate balance to avoid both under-reaction

(e.g. immunodeficiency) and overreaction (e.g. autoim-

munity, allergy and excessive inflammation) to foreign

antigens. CVID is categorized as an immunodeficiencybecause all patients are unable to mount an adequate

antibody response to bacterial pathogens. However,

approximately 25% of all CVID patients have at least

one autoimmune disease [1], and a similar proportion has

Current Opinion in Genetics & Development 2007, 17:201–212

been documented within the subpopulation of CVID

patients carrying at least one mutation in TNFRSF13B[61��]. Thus, one might predict that genes mutated in

CVID patients might also be involved in susceptibility to

other immunological diseases.

In the case of ICOS, this possibility has been implicitly

considered since even before ICOS was discovered [15],

because the better known genes CD28 and CTLA4 are

adjacent to ICOS on human chromosome 2q. A variety of

studies have suggested that polymorphisms in this region

are associated with several autoimmune diseases (for

example [62] and references therein). However, almost

none of these studies have either specifically implicated

or specifically ruled out variants inside or close to ICOS.

One notable exception is the recent study by Shilling et al.[63�] showing that two polymorphisms at positions �691

and �1413 in the ICOS promoter region are associated

with allergy as measured by positive skin-prick tests

and elevated IgE. These results fit the over-reaction–

underreaction paradigm. Although Icos knockout mice do

not perfectly model human ICOS deficiency, these mice

do have low levels of IgE [64]. Thus, it mirrors previous

data that promoter polymorphisms leading to higher ICOSexpression also lead to elevated IgE and an over-reaction

to allergens.

The second recent example we highlight is more puz-

zling. Inoue et al. [65�] showed, using both multiplex

families and a case-control design, that a variety of het-

erozygous changes in TNFRSF13B are associated with

intracranial aneurysm and subsequent stroke. However,

no measurements of immunoglobulin levels were

reported. Conversely, we know of no evidence that

TACI-deficient CVID patients have an elevated risk of

stroke. Many studies have proposed that microbial infec-

tions are a risk factor of stroke [66]. TNFRSF13B hetero-

zygotes might be compromised in clearing infections that

possibly could cause damage to cerebral arteries, thereby

promoting the formation of aneurysms. An alternative

hypothesis is that the TACI protein, encoded by

TNFRSF13B, has a second, unknown function (e.g.

specific to the vascular endothelium of cerebral arteries).

ConclusionsGenetic studies of CVID–IgAD have identified

mutations explaining recessive inheritance in ICOS,

TNFRSF13B, CD19 and TNFRSF13C (BAFF-R). Hetero-

zygous missense mutations in TNFRSF13B also appear to

increase the risk of CVID, but which missense mutations

are deleterious and how much they increase risk requires

further investigation. Identifying other genes with het-

erozygous mutations and dominant inheritance has been

difficult because of the lack of mouse models and the lack

of large multiplex families. So far as we know, the most

www.sciencedirect.com

Deconstructing common variable immunodeficiency by genetic analysis Schaffer, Salzer, Hammarstrom and Grimbacher 209

CVID cases seen in a single published family is only six

[67�].

The diverse functions of the ICOS, TACI and CD19

proteins in the process of antibody production are con-

sistent with the repeatedly documented heterogeneity in

the clinical and laboratory measurements in CVID

patients. Future genetic studies of CVID will benefit

from new assays that can identify more homogeneous

subsets of patients. Microarray analysis, quantifications of

somatic hypermutation potential, and measurement of

dendritic cell subpopulations are three recently proposed

approaches to address the problem of CVID heterogen-

eity.

In summary, recent genetic research in CVID has made

some steps toward the ultimate goal of replacing the

existing and all-too-common diagnosis of exclusion with

numerous rare diagnoses of inclusion such as ‘ICOS

deficiency’, ‘CD19 deficiency’, ‘BAFF-R deficiency’

and ‘TACI deficiency’. However, these four genes can

be disease causing in at most 10% of CVID–IgAD

patients, and the recent results of genetic linkage studies

suggest that more CVID susceptibility genes can be

found through genetic studies.

AcknowledgementsOur research on CVID has been supported by the Intramural ResearchProgram at the National Institutes of Health, by grant SFB620-C2 fromthe Deutsche Forschungsgemeinschaft, by a grant from the Swedishresearch council, and by EU-Project QLRT-2001-01536 (IMPAD).

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This paper describes the first gene found to be mutated in CVID. It showshow a T-cell defect can lead to CVID.

91. Warnatz K, Salzer U, Gutenberger S, Taubenheim N, Theil K,Schlesier M, Grimbacher B, Eibel H, Peter HH: Finally found:human BAFF-R deficiency causes CVID. In: XIth Meeting of theEuropean Society for Immunodeficiencies 21–24 October 2004;Versailles [Abstract #B. 72].

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Castigli E, Wilson SA, Garibyan L, Raschid R, Bonilla F,Schneider L, Geha RS: TACI is mutant in common variableimmunodeficiency and IgA deficiency. Nat Genet 2005,37:829-834.

Identifies the first commonly mutated gene in CVID and shows thatmutations can be heterozygous as well as homozygous.

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94. Schaffer AA, Pfannstiel J, Webster ADB, Plebani A,Hammarstrom L, Grimbacher B: Analysis of families withcommon variable immunodeficiency (CVID) and IgA deficiencysuggests linkage of CVID to chromosome 16q. Hum Genet2006, 118:725-729.

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Finck A, Van der Meer JWM, Schaffer AA, Pfannstiel J, Fieschi C,Plebani A, Webster ADB, Hammarstrom L, Grimbacher B: Linkageof autosomal-dominant common variable immunodeficiencyto chromosome 4q. Eur J Hum Genet 2006, 14:867-875.

The first replicated linkage for autosomal dominant CVID outside the HLAregion on chromosome 6p. See also study by Nijenhuis et al. [67�].

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