Download molecular defects in t and b cell primary immunodeficiency diseases

REVIEWS
MOLECULAR DEFECTS IN
T AND BCELL PRIMARY
IMMUNODEFICIENCY DISEASES
Charlotte Cunningham-Rundles and Prashant P. Ponda
Abstract | More than 120 inherited primary immunodeficiency diseases have been discovered
in the past five decades, and the precise genetic defect in many of these diseases has now
been identified. Increasing understanding of these molecular defects has considerably
influenced both basic and translational research, and this has extended to many branches of
medicine. Recent advances in both diagnosis and therapeutic modalities have allowed these
defects to be identified earlier and to be more precisely defined, and they have also resulted in
more promising long-term outcomes. The prospect of gene therapy continues to be included
in the armamentarium of treatment considerations, because these conditions could be among
the first to benefit from gene-therapy trials in humans.
Division of Clinical
Immunology, Mount Sinai
School of Medicine,
1425 Madison Avenue,
Box 1089, New York,
New York 10029, USA.
Correspondence to C.C.R.
e-mail: charlotte.
[email protected]
doi:10.1038/nri1713
880 | NOVEMBER 2005
The human immune system is confronted with the challenge of host defence. This is accomplished through various innate immune responses (which are non-specific)
and adaptive immune responses (which are specific)
that work synergistically to achieve this goal. Cells of
the adaptive immune system include T and B cells,
which are derived from a common multipotent haematopoietic stem cell. Defects involving T and B cells have
been described with respect to their development, effector function and roles in immunoregulation1. Although
defined primary natural killer (NK)-cell deficiencies
are rare among primary immunodeficiency diseases,
other cells of the innate immune system, which were
previously thought to function independently of adaptive immune responses, are now seen as important
partners in the development of adaptive immunity.
The clinical presentation of patients with a primary
immunodeficiency reflects the complex underpinnings
of the immune system and depends on the underlying
genetic defect. Patients with severe combined immunodeficiency (SCID) generally present with opportunistic
infections and fail to thrive within a few months of
life. Recurrent bacterial infections are the hallmark
of disease in patients with defects in B cells, phagocytic
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cells or complement, whereas opportunistic infections
with viruses or fungi are particularly common in
patients with T-cell deficiencies. A subset of primary
immunodeficiencies is associated with inflammatory
or autoimmune manifestations, and certain subgroups
of patients are susceptible to developing malignancies.
This Review focuses on the recent advances in the
field, with an emphasis on newly identified genetic
deficiencies and therapeutic options for patients.
SCID — an immunodeficiency that is characterized by severely reduced numbers or an absence of
functional T cells, which in turn results in the absence
of an adaptive immune response — is a consequence of
a mutation in any one of ten distinct genes that are
inherited in an autosomal recessive or an X-linked
manner 2–10. Four lymphocyte phenotypes are possible
on the basis of the influence of the defective gene on
B-cell and NK-cell development TABLE 1. A diagnosis is possible at birth, with most affected infants
having lymphopaenia (less than 2,000 lymphocytes
per mm3 of blood) and their lymphocytes showing
decreased proliferation in vitro after stimulation with
mitogen, antigen or allogeneic cells11. Although these
infants have a severely reduced amount of thymic
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TCELLRECEPTOR EXCISION
CIRCLES
(TRECs). DNA episomes
that are normally produced
during the thymic maturation
of T cells, specifically during
recombination of the T-cellreceptor genes.
XLINKED
LYMPHOPROLIFERATIVE
SYNDROME
(XLP). A rare, often fatal,
primary immunodeficiency
disease that is characterized
by an inability to mount an
effective immune response
to Epstein–Barr virus. This
can lead to lymphoma or
hypogammaglobulinaemia.
tissue, accompanied by the absence of normal thymic
architecture, T-cell development is achievable after
the introduction of normal haematopoietic stem
cells12. At present, bone-marrow transplantation using
either unfractionated HLA-identical haematopoietic
stem cells or T-cell-depleted haploidentical (parental)
haematopoietic stem cells is the standard of care for
these infants, with improved survival in patients who
receive a transplant within the first 4 weeks of life13.
Successful intervention depends on early identification of infants, before the development of opportunistic
infections that contribute to the increased morbidity
and mortality that is associated with delayed transplantation. Nevertheless, there is no programme in place
for screening newborns for SCID; such a programme
would allow therapy to be provided within this vital
window of opportunity. In the United States, the
Centers for Disease Control and Prevention has identified SCID as a candidate for the development of a newborn-screening protocol, because SCID meets many of
the accepted screening criteria14. Many modalities
of testing have been explored; most recently, the
examination of TCELLRECEPTOR EXCISION CIRCLES (TRECs)
in DNA isolated from dried blood spots has shown
promise15. TRECs are more abundant in T cells from
a healthy newborn than from an adult. Their absence
has been confirmed in patients with SCID15, and largescale implementation of this screening tool might help
to identify affected infants.
Defects that involve T-cell immunity
Patients with defects that involve T cells do not have
adequate cellular immune responses and are predisposed to developing opportunistic infections. These
T-cell deficiencies are reflected in reduced absolute
cell numbers, defective activation and function, and
disrupted immunoregulation (FIG. 1; TABLE 2. DiGeorge
syndrome has classically been thought of as the model
Table 1 | Aetiologies of severe combined immunodeficiency
Type of SCID
–
+
Chromosomal location
Reference
+
T B NK
Interleukin-7 receptor α-chain deficiency
5p13
2
CD3 δ-chain deficiency
11q23
3
CD3 ε-chain deficiency
11q23
4
T –B+NK–
X-linked recessive SCID (γc deficiency)
Xq13.1
5
CD45 deficiency
1q31–1q32
6
JAK3 deficiency
19p13.1
7
Artemis gene-product deficiency
10p13
8
RAG1 and RAG2 deficiency
11p13
9
T –B –NK+
T –B –NK–
Adenosine-deaminase deficiency
20q13.11
10
γc, common cytokine-receptor γ-chain; JAK3, Janus kinase 3; NK, natural killer;
RAG, recombination-activating gene; SCID, severe combined immunodeficiency.
NATURE REVIEWS | IMMUNOLOGY
for thymic insufficiency leading to a T-cell deficiency,
although it also involves abnormal development of spatially related embryological tissues that leads to cardiac,
parathyroid and other abnormalities. DiGeorge syndrome is characterized by a decrease in the number of
CD3+ cells or an absence of CD3+ cells as a consequence
of hypoplasia or aplasia of the thymus. Depending on
the number of peripheral T cells, the immune phenotype falls within a range of immunodeficiencies, from
full immunocompetence to a SCID-like phenotype.
Unlike other forms of SCID, severe DiGeorge syndrome
can be treated effectively by thymic transplantation,
which allows for the maturation of recipient T cells.
Several candidates for the genetic defect in DiGeorge
syndrome have been identified; most recently, a member of the T-box transcription-factor family, TBX1, has
been implicated as a cause of most of the main signs of
DiGeorge syndrome16,17.
Genetic defects also affect the signal-transduction
pathways that are essential for T-cell activation.
Components of these pathways include the γ-chain
of CD3 (CD3γ), CD3ε, MHC class I molecules, MHC
class II molecules, LCK, ZAP70 (ζ-chain-associated
protein kinase of 70 kDa) and CD8α18–25. The resulting defects are highly variable and range from severe
cellular dysfunction (from a deficiency in MHC
class II molecules) to negligible dysfunction (from a
deficiency in CD8α).
In addition to genetic defects that reduce or eliminate T-cell-based immunity, there is a growing list of
immune defects that result in overactive or abnormal
T-cell function that leads to immunodeficiency. An
example of a functional mutation is seen in patients
with XLINKED LYMPHOPROLIFERATIVE SYNDROME (XLP); these
individuals have a mutation in SH2D1A, which encodes
SLAM-associated protein (SAP), a cytoplasmic adaptor protein that binds signalling lymphocytic activation
molecule (SLAM) and other SLAM-family molecules26.
SLAM is a transmembrane protein that is expressed at
low levels at the surface of resting cells and at higher
levels after cellular activation; intracytoplasmic binding
of SLAM by SAP has an inhibitory role. For reasons that
are unclear, defects in SAP result in uncontrolled proliferation of T cells in individuals who are infected with
Epstein–Barr virus, as well as ineffective viral elimination, lymphoma or hypogammaglobulinaemia. SH2D1A
mutations result in fatal infectious mononucleosis in a
high proportion of cases.
Another emerging role for T cells is that of
regulation of the immune response to prevent the
recognition of self. Recent studies have outlined
aspects of the molecular basis of T-cell defects in
three disease states that are characterized by T-cell
immunodysregulation.
IPEX. Immunodysregulation, polyendocrinopathy and enteropathy, X-linked syndrome (IPEX)
can often be fatal and is a recessive disorder of early
childhood that involves the classic clinical triad
of endocrinopathy (most commonly in the form of
early-onset type 1 diabetes), severe enteropathy with
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the molecular defect29. FOXP3 is mainly expressed
by, and is a reliable marker of, CD4 CD25 REGULATORY
30
T CELLS . The role of FOXP3 in the development and
function of CD4+CD25hi regulatory T cells, however,
is largely an enigma.
At present, immunosuppressive agents that are
directed at activated T cells, such as CYCLOSPORIN A OR
TACROLIMUS (Prograf; Astellas Pharma US, Inc.) (administered together with an optional corticosteroid), are
watery, sometimes bloody, diarrhoea, and eczematous
dermatitis27, resulting from a severe deficiency or
absence of regulatory T cells. This syndrome is associated with autoimmune conditions that affect several
organ systems and with moderate to severe recurrent infections with Enterococcus and Staphylococcus
species28. Mutation of the forkhead box P3 (FOXP3)
gene, which encodes a forkhead (also known as winged
helix) transcription factor, has been identified as
+
hi
a
DiGeorge syndrome
ADA
IL-7Rα
γc
JAK3
NK cells
Thymic medulla
Thymic cortex
Bone marrow
RAG1, RAG2
CD3δ, CD3ε
artemis
CD45
AIRE
CD3
complex
B cells
pTα
CD8+
T cell
αβ-TCR
CD8
CD4
CD8α
MHC class I
molecules
(TAP1, TAP2)
LCK
ZAP70
TCR-β
CD3ζ
Lymphoid
lineages
CD34+
Pro-T cell:
CD4–
CD8–
CD25+
CD44+
HSC
Pre-T cell:
CD4–
CD8–
CD25+
CD44–
DP T cell:
CD4+
CD8+
Positive
and
negative
selection
MHC class II
molecules
(CIITA and
RFX-family
proteins)
CD4+
T cell
Myeloid
lineages
b
IPEX
ALPS
CD4+
CD25+
TReg
cell
DISC,
caspase-8
and caspase-10
Calcineurin inhibitors that
are used to prevent transplant
rejection and that function
by inhibiting nuclear factor
of activated T cells (NFAT).
882 | NOVEMBER 2005
CD95L
SAP
APC
TCR
CYCLOSPORIN A AND
TACROLIMUS
SLAM
CD95
TEff
cell
A thymus-derived
subpopulation of T cells that
expresses the transcription
factor forkhead box P3
(FOXP3) and is involved in
the suppression of immune
responses, either by cell–cell
contact or cytokine release.
SAP
CD95
FOXP3
CD4+CD25hi REGULATORY
T CELLS
XLP
CD95L
Caspase-8
Caspase-10
Peptide –
MHC class I or class II
Proliferation
inhibited
Figure 1 | Protein and gene defects in T-cell development and function. a | Haematopoietic stem cell (HSC)-derived
lymphoid progenitor cells migrate from the bone marrow to the thymus and develop into progenitor (pro)-T cells, which then
rearrange their T-cell receptor (TCR) genes and differentiate into either γδ or αβ T cells in the cortex. The latter initially co-express
CD8 and CD4, which interact with MHC class I and class II molecules, respectively, at the surface of medullary thymic stromal
cells. This interaction allows T cells to be ‘educated’ regarding self-antigens and non-self-antigens (enabling the positive or
negative selection of T cells in the thymus) before their migration to the periphery, where they exclusively express CD4 or CD8.
Numerous defects in maturation have been elucidated. Defects in the genes encoding the molecules listed in the yellow boxes
(and the primary immunodeficiency diseases listed) are known to affect the developmental steps indicated. b | Functional
defects are also observed after maturation is complete. In patients with IPEX (immunodysregulation, polyendocrinopathy and
enteropathy, X-linked syndrome), self-reactive effector T (TEff) cells are not inhibited, because mutations in the forkhead box P3
gene (FOXP3) result in a loss of CD4+CD25+ regulatory T (TReg)-cell activity. In patients with autoimmune lymphoproliferative
syndrome (ALPS), defects in the CD95, CD95 ligand (CD95L), caspase-8 or caspase-10 genes abrogate formation of the deathinducing signalling complex (DISC), thereby interfering with apoptosis of TEff cells. In patients with X-linked lymphoproliferative
syndrome (XLP), uncontrolled proliferation of T cells occurs as a result of a mutation in SH2D1A, which encodes SAP (signalling
lymphocytic activation molecule (SLAM)-associated protein). ADA, adenosine deaminase; AIRE, autoimmune regulator;
APC, antigen-presenting cell; γc, common cytokine-receptor γ-chain; CIITA, MHC class II transactivator; DP, double positive;
IL-7Rα, interleukin-7 receptor α-chain; JAK3, Janus kinase 3; NK cell, natural killer cell; pre-T cell, precursor-T cell; pTα, pre-TCR
α-chain; RAG, recombination-activating gene; RFX, regulatory factor X; TAP, transporter associated with antigen processing;
ZAP70, ζ-chain-associated protein kinase of 70 kDa.
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the most effective therapy for the treatment of patients
with IPEX31. However, for the most affected patients,
no acceptable regimen can maintain long-term
remission of the disease. Bone-marrow transplantation has been carried out for several patients with
IPEX, although the results have mostly been disappointing32,33. Intriguingly, one patient had improved
glucose regulation and reduced diarrhoea during the
conditioning regimen before bone-marrow transplantation32, underscoring the role of selectively targeting
Table 2 | Defects that involve T cells
Name
Clinical phenotype
Chromosomal
location
Genetic defect
Refs
DiGeorge
syndrome
Thymic, cardiac and parathyroid defects, and decreased numbers
or absence of CD3+ cells
22q11.2
Possibly TBX1
WHN defect
Congenital alopecia, and nail dystrophy
17q11–17q12
WHN
113
CD3 deficiency
Autoimmune haemolytic anaemia and severe infections
Recurrent Haemophilus influenzae pneumonia and otitis media
11q23
11q23
CD3G
CD3E
18
19
MHC class I
deficiency
Decreased numbers of CD8+ T cells
6p21.3
TAP1
TAP2
20
21
MHC class II
deficiency
Persistent diarrhoea, bacterial pneumonia, Pneumocystis carinii
pneumonia, viral and candidal infections, and low numbers of
CD4+ T cells
1q21.1–1q21.3
13q14
19p12
16p13
RFX5
RFXAP
RFXANK
CIITA
22
22
22
22
LCK deficiency
Bacterial, viral and fungal infections, lymphopaenia and
hypogammaglobulinaemia
1p34.3–1p35
LCK
23
ZAP70
deficiency
Decreased numbers of CD8+ T cells, normal or decreased
numbers of CD4+ T cells, and severe recurrent infections
2q12
ZAP70
24
CD8 deficiency
Absence of CD8+ T cells, and recurrent respiratory infections
2p12
CD8A
25
HIGM1
Pneumocystis carinii pneumonia, pyogenic infections, normal
or increased level of IgM, and low level or absence of serum IgG,
IgA and IgE
Xq26–Xq27
CD40L
50
HIGM3
Pneumocystis carinii pneumonia and Cryptosporidium parvum
infections
20q12–20q13.2
CD40
AD-EDA-ID
Lymphocytosis, absence of memory T cells and unresponsive
naive T cells
14q13
NFKBIA
Uncontrolled T-cell proliferation in EBV infection, fatal infectious
mononucleosis in a high proportion of patients, ineffective viral
elimination, lymphoma and hypogammaglobulinaemia
Xq25
SH2D1A
26,87
IPEX
Triad of endocrinopathy, enteropathy and dermatitis, and
Enterococcus and Staphylococcus species infections
Xp11.23
FOXP3
27,29
APECED
Chronic mucocutaneous candidiasis, and parathyroid and
adrenal autoimmunity
21q22.3
AIRE
34
ALPS0
Autoimmunity, hypergammaglobulinaemia, lymphoproliferation,
and excessive numbers of CD3+CD4–CD8–αβ-TCR+ T cells
10q24.1
CD95 (homozygous)
41
ALPS1a
Autoimmunity, hypergammaglobulinaemia, lymphoproliferation,
and excessive numbers of CD3+CD4–CD8–αβ-TCR+ T cells
10q24.1
CD95 (heterozygous, germ line)
CD95 (heterozygous, somatic)
42
47
ALPS1b
Autoimmunity, hypergammaglobulinaemia, lymphoproliferation,
and excessive numbers of CD3+CD4–CD8–αβ-TCR+ T cells
1q23
CD95L
45
ALPS2
Autoimmunity, hypergammaglobulinaemia, lymphoproliferation,
and excessive numbers of CD3+CD4–CD8–αβ-TCR+ T cells
2q33–2q34
CASP8
CASP10
43
44
ALPS3
Autoimmunity, hypergammaglobulinaemia, lymphoproliferation,
and excessive numbers of CD3+CD4–CD8–αβ-TCR+ T cells
ND
ND
46
Development
16,17
Activation
53,54
59
Function
XLP
Regulation
AD-EDA-ID, autosomal dominant ectodermal dysplasia with immunodeficiency; AIRE, autoimmune regulator; ALPS, autoimmune lymphoproliferative syndrome;
APECED, autoimmune polyendocrinopathy-candidiasis-ectodermal-dystrophy syndrome; CIITA, MHC class II transactivator; CASP, caspase; CD40L, CD40 ligand;
CD95L, CD95 ligand; EBV, Epstein–Barr virus; FOXP3, forkhead box P3; HIGM, hyper-IgM syndrome; IPEX, immunodysregulation, polyendocrinopathy and
enteropathy, X-linked syndrome; ND, not determined; NFKBIA, gene encoding IκBα (inhibitor-of-nuclear-factor-κB α); RFX5, regulatory factor X, 5; RFXANK, RFXassociated ankyrin-containing protein; RFXAP, RFX-associated protein; SH2D1A, gene encoding SAP (signalling lymphocytic activation molecule (SLAM)-associated
protein); TAP, transporter associated with antigen processing; TBX1, T-box 1; TCR, T-cell receptor; WHN, winged-helix nude (also known as FOXN1); XLP, X-linked
lymphoproliferative syndrome; ZAP70, ζ-chain-associated protein kinase of 70 kDa.
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activated T cells. Nevertheless, the usefulness of either
immunosuppression or bone-marrow transplantation
would mainly depend on its early implementation,
before the onset of permanent organ damage. Further
understanding of the mechanisms that are involved in
FOXP3 expression and its influence in patients with
IPEX will undoubtedly provide therapeutic targets for
patients with IPEX and potentially for individuals with
other autoimmune diseases.
CLASSSWITCH
RECOMBINATION
(CSR). A switch in the DNA
that encodes the constant
region of the immunoglobulin
heavy chain, from Cµ (which
encodes the constant region
of IgM) to DNA that is further
downstream and encodes the
constant region of another
immunoglobulin class: that is,
to Cγ, Cα or Cε, which encode
the constant region of IgG,
IgA and IgE, respectively.
This is accomplished through
an intrachromosomal deletional
rearrangement.
SOMATIC HYPERMUTATION
(SHM). The introduction
of point mutations at a high
frequency in the variable
regions of immunoglobulin
genes.
884 | NOVEMBER 2005
APECED. Autoimmune polyendocrinopathycandidiasis-ectodermal-dystrophy syndrome (APECED;
also known as APS1) results from a defect in the
autoimmune regulator (AIRE) gene34. Patients with
APECED usually have chronic mucocutaneous candidiasis, as well as autoimmune manifestations that most
commonly affect the parathyroid or adrenal glands and,
to a lesser extent, the thyroid gland, liver and skin35.
AIRE is expressed at high levels by purified human
thymic stromal cells, especially medullary thymic
epithelial cells, and it is thought to regulate the ectopic
cell-surface expression of tissue-specific proteins, such
as insulin and thyroglobulin36. Expression of these
self-proteins allows the negative selection of autoreactive T cells during their development. The absence of
this key regulatory step results in the organ-specific
autoimmune destruction that is seen in patients with
APECED.
Thymic stromal lymphopoietin, an interleukin-7
(IL-7)-like cytokine, has been shown to induce human
peripheral-blood CD11c+ dendritic cells (DCs) to
upregulate AIRE mRNA expression strongly, in conjunction with cell-surface MHC class II molecules and
the co-stimulatory molecules CD80 and CD86 REF. 37.
These activated DCs were able to induce a 1,000-fold
clonal expansion in an autologous, naive CD4+ T-cell
population in culture. This further emphasizes the role
of AIRE in the presentation of self-peptides, because
the CD4+ T-cell proliferation occurred in the absence
of exogenous antigen and was therefore attributed to
the presentation of self-peptide–MHC complexes by
DCs. In vitro studies have elucidated that one role of the
AIRE protein is to function as an E3 ubiquitin ligase,
indicating its involvement in a ubiquitin–proteasome
pathway38. Furthermore, two known disease-causing
mutations in the AIRE gene abolished this ligase activity38. The precise ubiquitin–proteasome pathway and
ubiquitylation substrates of the AIRE protein have yet
to be identified, and the overall significance of this
pathway in the establishment and maintenance of
T-cell self-tolerance is not well understood at present.
ALPS. There are four known genetic defects that
have been identified in patients with autoimmune
lymphoproliferative syndrome (ALPS), an inherited
condition that is associated with dysregulation of
apoptosis mediated by CD95 (also known as FAS).
CD95 is a cell-surface receptor that is a member of the
tumour-necrosis factor (TNF)-receptor superfamily,
and after binding CD95 ligand (CD95L; also known as
FAS ligand), it initiates a complex signalling pathway
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that results in the induction of apoptosis. This pathway
involves formation of the death-inducing signalling
complex in association with caspase-8 and caspase-10.
All patients have at least three of the four main features
of ALPS: autoimmunity, hypergammaglobulinaemia
(of both IgG and IgA), lymphoproliferation and excessive numbers of CD3+CD4–CD8–αβ-TCR+ (double
negative) T cells39.
In vitro study of lymphocyte sensitivity to CD95induced apoptosis allows for a classification scheme
that is based on the underlying genetic defect 40 .
Defective CD95-induced apoptosis is observed in
homozygous CD95 deficiency 41 (classified as ALPS0),
heterozygous dominant CD95 mutations42 (classified as
ALPS1a), and signalling pathway defects that involve
caspase-8 REF. 43 or caspase-10 REF. 44 (classified
as ALPS2). CD95-induced apoptosis is intact in two
additional subtypes of patients: those with a CD95L
mutation45 (classified as ALPS1b), and those with a
clinical ALPS phenotype but in whom a molecular
defect has yet to be identified46 (classified as ALPS3).
A subset of patients who were previously categorized as
having ALPS3 has now been identified to have somatic
heterozygous CD95 mutations in unstimulated doublenegative T cells47. Interestingly, all patients in this subset
had identical CD95 mutations or mutations that led to
identical structural changes in CD95 to those observed
in patients with ALPS1a. However, mutant CD95 products could not be detected in T-cell blasts following
in vitro activation. It is unclear why the mutations in
these newly identified patients do not lead to defective
CD95 expression in activated T cells and, subsequently,
to defective CD95-induced apoptosis.
Hyper-IgM syndromes
General aspects. Hyper-IgM syndromes (HIGMs)
constitute a group of molecular defects that is characterized by impaired immunoglobulin CLASSSWITCH
RECOMBINATION (CSR) and SOMATIC HYPERMUTATION (SHM)
or by impaired SHM alone. Patients with these syndromes typically have recurrent bacterial infections
and often have lymphoid hyperplasia. They have
normal numbers of peripheral B cells, albeit with a
low proportion of memory B cells (which are CD27+)
and normal or increased levels of serum IgM associated with low levels or absent serum IgG, IgA and IgE.
CSR48 and SHM49 occur only after antigen binds B cells
displaying cell-surface IgM (that is, the B-cell receptor, BCR), and these are two mechanisms by which the
primary antibody repertoire is fine-tuned to generate
a highly antigen-specific immune response. These
events are T-cell dependent and are facilitated through
the interaction of CD40L at the surface of activated
T cells with its receptor CD40, which is constitutively
expressed by B cells. B cells that produce high-affinity
specific antibody as a result of SHM have a survival
advantage. Two enzymes — activation-induced cytidine deaminase (AID) and uracil-DNA glycosylase
(UNG) — are crucial for this editing process. CSR
and SHM work together so that the secondary antibody repertoire has a high affinity. Mutations in the
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components that are involved in these processes result
in the inherent defects in patients with HIGM. So far,
seven defects that are known to be involved in HIGM
have been characterized: defects in CD40L, classified
as HIGM type 1 (HIGM1; also known as X-linked
HIGM, XHIGM); defects in AID, classified as HIGM2;
defects in CD40, classified as HIGM3; defective CSR
with preserved SHM, classified as HIGM4; defects
in UNG; defects in IKKG (IκB (inhibitor of nuclear
factor-κB, NF-κB) kinase-γ; also known as NEMO);
and defects in NFKBIA (which encodes IκBα)50–59
TABLES 2,3.
Patients with defects in CD40L, who comprise the
HIGM1 subgroup, account for approximately two-thirds
of all patients with HIGM. In these patients, an absence
of, or a defect in, binding of CD40L to CD40 is caused
by a mutation that affects the extracellular domain of
CD40L50. There is no intrinsic B-cell defect observed
in these patients: their B cells generate normal immunoglobulin class-switching responses in an appropriate
microenvironment50. Furthermore, in contrast to most
patients with hypogammaglobulinaemia, individuals
with HIGM1 are susceptible to opportunistic infections,
especially to pneumonia caused by Pneumocystis carinii,
thereby underscoring an inherent T-cell defect. HIGM3
has been described in four patients from three families
and is characterized by the absence of CD40 expression
at the cell surface of B cells, macrophages and DCs53,54.
These patients are also susceptible to developing opportunistic infections. It is important to note that there
might be defects in components of the signalling pathway that are downstream of CD40–CD40L interactions
to account for other patients in the clinical spectrum of
HIGM. In addition, other repair mechanisms that work
in conjunction with, or independent of, AID and UNG
have yet to be clarified.
Patients with defects in AID or UNG have a
similar clinical phenotype51,52. Similar to patients
with a CD40L deficiency, the level of serum IgM is
normal or increased, and this occurs together with
low levels or an absence of IgG and IgA. However,
owing to intact T-cell function, these patients do not
seem to be susceptible to opportunistic infections and
might not be recognized as having an immune defect
until the second or third decade of life60. The exact
process by which AID and UNG mediate CSR and
SHM is not known; however, switch-region doublestranded-DNA breaks are required for both to occur,
Table 3 | Defects that involve B cells
Name
Clinical phenotype
Chromosomal
location
Genetic
defect
HIGM2
Pyogenic infections, lymphoid hyperplasia,
decreased CD27+ B-cell numbers, normal or
increased serum IgM level, and low level
or no serum IgG, IgA and IgE
12p13
12q23–12q24.1
AID
UNG
51
52
HIGM4
Pyogenic infections, lymphoid hyperplasia,
decreased CD27+ B-cell numbers, normal or
increased serum IgM level, and low level
or no serum IgG, IgA and IgE
ND
ND
55
XL-EDA-ID
Bacterial and mycobacterial infections,
and low levels or no antibody specific for
carbohydrates
Xq28
IKKG
Agammaglobulinaemia
Low or no levels pre-B-cell and mature B-cell
numbers, low serum immunoglobulin levels,
and pyogenic infections
Normal pro-B-cell numbers, low pre-B-cell
and mature B-cell numbers, low serum
immunoglobulin levels, and pyogenic
infections
Low serum immunoglobulin levels, and
pyogenic infections
Developmental arrest at the pro-B-cell stage,
low serum immunoglobulin levels, and
pyogenic infections
Xq21.3–Xq22
BTK
10q23.2
BLNK
22q11.22
19q13.2
14q32.2
IGLL1
Iga
IGHM
CVID
Sinopulmonary infections, low IgG and IgA
levels, and normal B-cell numbers
16p11.2
22q13.1–22q13.31
17p11.2
2q33
CD19
BAFFR
TACI
ICOS
IgAD
Many patients are asymptomatic, although
pyogenic infections are possible
17p11
Possibly 6p21.3
TACI
IGAD1
(HLA-DQ
and HLA-DR)
t(9; 20) (q33.2; q12) LRRC8
References
56–58
72
114,115
83
76
77
78,79
Unpublished*
Unpublished‡
116,117
88,89
116,117
99,100
*M. C. van Zelm, personal communication; J. L. Franco, personal communication. ‡ V. Salzer, personal communication.
AID, activation-induced cytidine deaminase; BAFFR, B-cell-activating-factor receptor; BLNK, B-cell linker; BTK, Bruton’s tyrosine kinase;
CVID, common variable immunodeficiency; HIGM, hyper-IgM syndrome; ICOS, inducible T-cell co-stimulator; Iga, gene encoding Igα;
IgAD, selective IgA deficiency; IGAD1, IgA-deficiency susceptibility 1; IGHM, gene encoding µ immunoglobulin heavy chain; IGLL1, gene
encoding λ5; IKKG, inhibitor-of-nuclear-factor-κB kinase-γ; LRRC8, leucine-rich-repeat-containing 8; ND, not determined; pre-B cell,
precursor-B cell; pro-B cell, progenitor-B cell; TACI, transmembrane activator and calcium-modulating cyclophilin-ligand interactor;
UNG, uracil-DNA glycosylase; XL-EDA-ID, X-linked ectodermal dysplasia with immunodeficiency.
NATURE REVIEWS | IMMUNOLOGY
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REVIEWS
and CSR-induced breaks have been shown to occur
much less frequently in AID-deficient B cells than in
AID-sufficient B cells61.
Three patients have been described to have a deficiency in UNG52. All three had normal expression of
CD40, CD40L and AID, although (similar to AIDdeficient B cells) their B cells failed to generate switchregion double-stranded-DNA breaks after activation
through CD40. In addition, a skewed SHM pattern
was observed that showed mutations biased towards
transitions in dG and dC nucleotides, whereas dA and
dT nucleotides showed transitions and transversions
in similar ratios to control values from normal memory B cells. The current hypothesis to explain these
editing processes involves AID-mediated deamination of C residues into U residues, followed by UNGmediated removal of U residues. This would create an
abasic site that could be targeted by an endonuclease
to create the required DNA breaks that are crucial for
CSR and SHM. Lack of either enzyme would therefore
destabilize the development of a secondary antibody
repertoire. Replication protein A, a ubiquitous singlestranded-DNA-binding protein, has been described as
the factor that targets AID to SHM motifs to promote
their deamination62.
Approximately one-quarter of patients with the
HIGM phenotype have normal expression and function of CD40L, CD40, AID and UNG63. A subset of
these patients has been described to have defective
CSR with preserved SHM, and these individuals have
been categorized into the HIGM4 subtype55. B cells
from these patients express AID and show appropriate AID-dependent CSR-induced DNA breaks in
the switch region of Cµ (which encodes the constant
region of IgM), indicating that the molecular defect is
downstream of these events: that is, there is a deficiency
in the repair process that occurs after the induction
of double-stranded-DNA breaks. The precise defect
in individuals with HIGM4 remains undefined, and
its elucidation should further illuminate the complex
process of CSR and DNA repair.
HYPOMORPHIC MUTATION
A type of mutation that results
in either diminished quantity
of a normal gene product or
diminished function of a gene
product.
HYPODONTIA
The partial congenital absence
of one or more teeth.
TOLLLIKE RECEPTORS
(TLRs). A family of
evolutionarily conserved
pattern-recognition receptors.
These molecules are located
intracellularly and at the cell
surface of macrophages,
dendritic cells, B cells and
intestinal epithelial cells. Their
natural ligands are conserved
molecular patterns, known as
pathogen-associated molecular
patterns, that are found in
bacteria, viruses and fungi.
886 | NOVEMBER 2005
Defects in NF-κB signalling. An increasing number of
genetic mutations are being identified that have inappropriate activation of NF-κB as a common defect64.
Of these, HYPOMORPHIC MUTATIONS in IKKG are linked to
a clinical phenotype of immunodeficiency, ectodermal
dysplasia, as well as to susceptibility to pyogenic bacterial infections in early infancy or childhood and to
mycobacterial infections in early or late childhood58.
However, the clinical phenotype is remarkably heterogeneous: in some patients it involves only conical
incisors and HYPODONTIA, whereas in others, it involves
osteopetrosis with lymphoedema. The range of infections and defects in antibody production are similarly
diverse, although a severely reduced level, or an absence
of, antibody specific for carbohydrate antigens seems
to be a unifying theme. In addition, whereas NF-κB
was first noted in B cells, active NF-κB can be released
in the cytoplasm of many cells, indicating that this
defect might affect other tissues. Two important target
| VOLUME 5
genes of NF-κB-mediated transcription are AID and
UNG, so in some patients with IKK-γ deficiency, the
processes of CSR and SHM are hindered, leading to
the increased IgM levels that have been observed65. An
HIGM phenotype similar to IKKG deficiency has been
described for patients with a mutation in NFKBIA,
which encodes IκBα, an inhibitor of NF-κB. This
hypermorphic gain-of-function mutation prevents
the phosphorylation of IκBα and, in turn, the activation of NF-κB. Unlike IKKG deficiency, however, this
phenotype is associated with a T-cell deficiency that is
characterized by naive T cells that are unresponsive to
stimulation through CD3 in vitro and by the absence
of memory T cells.
Interestingly, an abnormal response to TOLLLIKE
RECEPTOR (TLR) signalling has also been noted in
patients with the IKKG mutation56. On binding and
activation of the various TLRs by their ligands, a complex signalling cascade is set in motion, the result of
which is the activation of NF-κB and the transcription
of genes encoding several pro-inflammatory cytokines
and chemokines66. Mutations in IKKG result in a substantially diminished response to lipopolysaccharide,
an activator of TLR4. This emphasizes the emerging
significance of components of the innate immune
system in the aetiology of primary immunodeficiency.
Other examples of defects of this type include mutations in the IL-1-receptor-associated kinase 4 (IRAK4)
gene and the caspase-12 gene67–69. It is crucial to note
that the innate and adaptive immune systems, which
were historically thought of as segregated, do not function as distinct entities; instead, they are interdependent
and function together to coordinate the host immune
response.
Defects that involve B-cell immunity
Deficiencies in antibody production and function are
the hallmark of the primary immunodeficiency diseases that involve B cells. Patients with these conditions
are especially vulnerable to recurrent infections with
encapsulated pathogens, such as Streptococcus pneumoniae, Haemophilus influenzae and Staphylococcus
aureus, and with Gram-negative bacteria, such as
Pseudomonas species70. A B-cell defect is defined as a
markedly decreased serum level of at least one of the
three main immunoglobulin classes: IgG, IgA and
IgM; the most marked defects lead to either reduced
levels or an absence of antibody production. Antibody
deficiencies are the largest group within the primary
immunodeficiencies, and multiple molecular defects
have been identified throughout the pathways that are
involved in B-cell development (FIG. 2; TABLE 3.
Forms of agammaglobulinaemia. Several genetic
defects have been identified that account for the
phenotype of agammaglobulinaemia, which is characterized by a B-cell defect and intact T-cell function. Of all of the forms of agammaglobulinaemia,
X-linked agammaglobulinaemia (XLA) provides the
prototypical clinical description. XLA was the first
antibody-deficiency syndrome that was recognized71,
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Bone marrow
Periphery
RAG1, RAG2
Igα
Igµ
λ5
BLNK
IL-7Rα
γc
JAK3
BTK
Igβ Pre-BCR
Pro-B cell
Immature
B cell
IgM
Igα
CVID
ICOS
CD19
HIGM4
IgAD AID
CD40 UNG IKK-γ
IgM
BAFFR
TACI
IgG,
IgA
or IgE
Mature
B cell
Plasma cell
Lymphoid
lineages
CD34+
B220low
CD10+
CD19+
CD34+
HSC
CD34+
Pre-B cell
• Negative
selection
• Receptor
editing
IgD
• Class-switch
recombination
• Somatic
hypermutation
Memory B cell
T cells
Myeloid
lineages
NK cells
Figure 2 | Protein and gene defects in B-cell development and function. Haematopoietic stem cells (HSCs) give rise to
progenitor (pro)-B cells, which then rearrange their immunoglobulin heavy-chain gene segments to generate precursor (pre)B cells. Pre-B cells subsequently rearrange their immunoglobulin light-chain gene segments to produce a functional cell-surface
receptor (IgM). This protein is composed of heavy and light chains that are derived from these gene rearrangements, and it
functions as a receptor for responding to stimulation with antigen, resulting in the induction of proliferation and differentiation of
the B cell. In the periphery, after stimulation with antigen, mature B cells further develop following class-switch recombination
and somatic hypermutation and, ultimately, differentiate into memory B cells or plasma cells. Developmental blocks throughout
B-cell maturation and differentiation occur as a result of defects in genes encoding the molecules listed in the yellow boxes.
Blocks in the function of mature B cells can also occur. Primary immunodeficiency syndromes that cause these blocks are also
listed. AID, activation-induced cytidine deaminase; BAFFR, B-cell-activating-factor receptor; BCR, B-cell receptor; BLNK, B-cell
linker; BTK, Bruton’s tyrosine kinase; γc, common cytokine-receptor γ-chain; CVID, common variable immunodeficiency;
HIGM4, hyper-IgM syndrome 4; ICOS, inducible T-cell co-stimulator; IgAD, selective IgA deficiency; Igµ, µ immunoglobulin heavy
chain; IKK-γ, inhibitor-of-nuclear-factor-κB kinase-γ; IL-7Rα, interleukin-7 receptor α-chain; JAK3, Janus kinase 3; NK cell, natural
killer cell; RAG, recombination-activating gene; TACI, transmembrane activator and calcium-modulating cyclophilin-ligand
interactor; UNG, uracil-DNA glycosylase.
BRONCHIECTASIS
A permanent dilation of the
bronchi, owing to chronic
inflammation, that increases
susceptibility to recurrent
infections.
TERMINAL DEOXY
NUCLEOTIDYLTRANSFERASE
(TdT). An enzyme that inserts
nucleotides into the variable
regions of T-cell receptor and
immunoglobulin genes, thereby
creating junctional diversity.
and it results from a mutation in the gene encoding
Bruton’s tyrosine kinase (BTK), which has a crucial role
in B-cell development. This gene is a member of the
SRC family of proto-oncogenes, which encodes protein
tyrosine kinases72. These patients have precursor (pre)B cells in their bone marrow; however, the absence
of BTK prevents these cells from differentiating into
circulating, mature B cells and plasma cells65. Afflicted
patients have a low number of circulating B cells and
extremely low levels of serum immunoglobulin of all
classes. During the first few months of life, patients
with XLA are protected by circulating maternal IgG,
which crossed the placenta during gestation. Because
the concentration of this serum IgG diminishes, the
clinical presentation is one of recurrent pyogenic bacterial infections, especially sinopulmonary infections73.
BRONCHIECTASIS is the most concerning complication
of these recurrent infections and is most commonly
found in the middle or lower lobes of the lungs, with
the upper lobes being spared74. Germinal-centre formation in these patients is defective, and this leads
to the underdevelopment of lymphoid tissues, such as
the lymph nodes, Peyer’s patches, spleen, tonsils and
adenoids. The standard treatment for patients with
XLA is monthly immunoglobulin-replacement therapy
to prevent chronic lung disease and to protect against
enteroviral meningoencephalitis75.
NATURE REVIEWS | IMMUNOLOGY
Various autosomal recessive mutations and one
translocation have also been described in patients
with agammaglobulinaemia. Defects in the individual pre-BCR components λ5 (also known as
14.1, in humans) and Igα have been identified in
single patients76,77. The surrogate immunoglobulin
light chain is composed of λ5 and VpreB, and it is
normally expressed only by progenitor (pro)-B cells
and pre-B cells. It escorts the µ immunoglobulin
heavy chain (Igµ) to the cell surface and might also
assess the capacity of Igµ to bind immunoglobulin light
chains. Igα and Igβ form a complex with the surrogate
light chain and Igµ and then migrate to the cell surface,
where both Igα and Igβ function in transmembrane
signal transduction through their immunoreceptor
tyrosine-based activation motifs (ITAMs). Lack of
these crucial pre-BCR components results in the arrest
of B-cell development at the pro-B-cell stage.
Defective cell-surface expression of Igµ also results
in arrest of B-cell differentiation at the CD19+CD34+
+
TERMINAL DEOXYNUCLEOTIDYLTRANSFERASE (TdT) pro-B-cell
stage. In contrast to patients with XLA, patients with
this defect might have an earlier onset of disease that
is associated with more severe complications and no
detectable B cells78. In one study, bone-marrow-derived
pro-B cells from two patients with distinct mutations
in the gene encoding Igµ were used to investigate the
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influence of Igµ on BCR development79. Igµ expression
did not have an effect on usage of the gene segments
encoding the immunoglobulin heavy chain — the
variable-region segment (VH), the diversity segment
(D) and the joining segment (JH) — or on immunoglobulin light-chain gene recombination or expression.
However, persistent secondary VJ rearrangements of
the gene encoding Igκ were noted in Igµ-deficient
pro-B cells compared with control pro-B cells. This
is probably caused by the lack of signalling through
the BCR complex, which is required during normal
differentiation of these cells into pre-B cells. Although
the substrates for BTK have not been elucidated,
IgM at the surface of B cells is thought to be one of its
key activators80,81. Collectively, these data underscore
the important role of transmembrane IgM in B-cell
signalling and in normal B-cell development.
BTK has also been implicated in the regulation of
B-cell tolerance thresholds82. In these experiments, antibodies were cloned from isolated CD10+CD19+CD27–
IgM+ B cells (which are newly emigrated from the
bone marrow) from four patients with XLA. These
antibodies were found to have a repertoire consisting
of specific VH and D gene segments and to undergo
extensive secondary recombination on both immunoglobulin light-chain loci compared with antibodies
from normal, control B cells. In addition, B cells from
patients with XLA were found to produce a considerably higher frequency of self-reactive and polyreactive
antibodies than normal, control B cells. Taken together,
these data indicate an essential role for BTK in BCR
signalling that involves subsequent deletion of cells that
produce autoreactive antibodies.
Last, karyotypic analysis of the leukocytes of one
patient with a novel form of agammaglobulinaemia
showed a balanced chromosomal translocation
— 46,XX,t(9; 20) (q33.2; q12) — that resulted in a
truncated product being encoded by the affected
gene, leucine-rich-repeat-containing 8 (LRRC8)83. In a
mouse model, retroviral transfection of bone-marrow
cells with this mutant gene followed by bone-marrow
transplantation led to developmental arrest of B cells at
the pro-B cell stage, together with a marked deficiency
in pre-B cells. Intriguingly, the unaffected allele in this
patient could produce normal LRRC8 protein, indicating that the mutant protein has a dominant-suppressor
effect on B-cell development.
INDUCIBLE TCELL
COSTIMULATOR
(ICOS). A homodimeric
transmembrane protein that
is selectively expressed at the
surface of activated T cells.
It specifically interacts with
ICOS ligand (also known as
B7-H2), which is expressed
by many cell types, including
professional antigen-presenting
cells, fibroblasts, epithelial cells
and endothelial cells.
888 | NOVEMBER 2005
CVID. Common variable immunodeficiency (CVID)
is characterized by a defect in antibody production.
Males and females are equally affected, with an incidence between 1 in 10,000 and 1 in 50,000. It is usually
diagnosed in the second or third decade of life after
a history of recurrent pyogenic sinopulmonary infections84. Serum levels of IgG and IgA are lower than in
unaffected individuals; however, approximately onehalf of patients have a normal serum level of IgM. The
number of circulating B cells is reduced or normal, and
these cells can respond and proliferate appropriately
to stimulation with antigen; however, they fail to terminally differentiate into plasma cells, which secrete
| VOLUME 5
antibody73. One approach to classifying the B-cell phenotype in patients with CVID involves characterizing the
population of class-switched memory B cells (which
have the phenotype CD27+IgM–IgD–) in these patients.
Two groups can be identified on this basis, using a classification system that was proposed by Warnatz et al.85
Patients in group 1 have a low percentage (less than
0.4%) of class-switched memory B cells, and patients in
group 2 have a normal percentage (greater than 0.4%).
The former can be subdivided into those patients with
an increased proportion of CD19+CD21– peripheral
B cells (group 1a) and those with a normal proportion
(group 1b). Many patients with splenomegaly and
autoimmune cytopaenias were found to segregate into
group 1a.
Unlike patients with XLA, T-cell proliferation to
mitogen is impaired in 40% of patients with CVID,
and it is directly associated with the serum level of
IgG86. Patients with CVID are at an increased risk
of developing numerous associated diseases or conditions, including infections, autoimmune diseases,
hepatitis, granulomatous infiltrations, gastrointestinal
and pulmonary diseases, and malignancies73,86. The
development of structural damage to the lungs that
leads to bronchiectasis is also of concern and occurs
with a similar distribution to that of patients with
XLA, although at a later age of onset74.
The mutated genes that produce the CVID
phenotype are known only for a minority of patients,
and they are diverse in their influence on immune
function. They include INDUCIBLE TCELL COSTIMULATOR
(ICOS), SH2D1A26,87 (which is involved in XLP), and
three genes that have recently been described to be
involved: CD19, B-cell-activating factor (BAFF) receptor (BAFFR) and TACI (transmembrane activator and
calcium-modulating cyclophilin-ligand interactor).
Homozygous loss of ICOS as a result of a large
genomic deletion has been characterized in nine
patients from four families that are not known to
be related 88,89. Binding of ICOS to its ligand induces
a marked increase in T-cell proliferation and cytokine production, especially of IL-10, which has been
implicated in the differentiation of B cells into plasma
cells90. Further genetic testing of these nine individuals showed that they all had identical homozygous
haplotypes in the ICOS locus, indicating that the
mutation was most probably inherited from the same
ancestor. ICOS deficiency has also been investigated
as a potential aetiology in patients with HIGM that is
caused by an unknown genetic defect91. In this study,
33 patients from 30 families were examined; however,
none showed a defect in ICOS expression by activated T cells or a defect in the sequence of the coding
region or intron–exon boundaries of ICOS. Therefore,
although it is probably involved in B-cell activation
and class switching, ICOS could not be identified as
the genetic defect that is responsible for the clinical
presentation of this subset of patients.
Patients with a clinical presentation of CVID have
also been identified to have mutations in intermediate
components in B-cell signalling and B-cell development
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pathways. Specifically, defects in CD19 (J. L. Franco,
personal communication, and M. C. van Zelm, personal
communication), BAFFR (U. Salzer, personal communication) and TACI 116,117 have recently been identified
in patients who have a B-cell-defect phenotype. BAFF
is a ligand for BAFFR, TACI and B-cell maturation
antigen (BCMA)92,93. Another TNF-family member,
a proliferation-inducing ligand (APRIL), also binds
BCMA and, with lower affinity, TACI; however, it does
not bind BAFFR94. The expression of BAFF and APRIL
has been shown to be upregulated by human DCs and
monocytes after exposure to interferon-α, interferon-γ
or CD40L95. In the presence of IL-10 or transforming
growth factor-β, BAFF and APRIL have been shown to
induce CSR from Cµ to Cγ and/or Cα gene segments
in B cells. Therefore, patients with mutations in BAFFR
or TACI probably do not have the B-cell signalling that
is provided through interaction with BAFF and APRIL
and is required to promote maturation of B cells and
generation of a diverse antibody repertoire.
IgAD. Selective IgA deficiency (IgAD) is the most
common primary immunodeficiency, with a prevalence of between 1 in 400 and 1 in 3,000 in healthy
blood donors96 . Ethnicity-specific differences are
more disparate, ranging in prevalence from 1 in 500
(in Caucasians) to 1 in 18,000 (in Japanese)97. Although
most patients are asymptomatic, recurrent pyogenic
sinopulmonary infections are the most frequent
illnesses that are associated with IgAD. Several autoimmune diseases that involve multiple organ systems
are also associated with IgAD96. The molecular defect
that accounts for the absence of class switching to
IgA is unknown in most cases, although mutations in
TACI can lead to an absence of class switching116,117.
Familial studies have implicated the existence of an
allelic relationship between IgAD and CVID, indicating that these disorders reflect differential expression
of the same molecular aetiology98. In one study of
83 multiply-affected families with IgAD and CVID,
increased allele sharing at chromosome 6p21, which is
in the proximal region of the MHC, was observed, and
this susceptibility locus was designated IGAD1 REF. 99.
More sensitive genetic analysis was later carried out
in 101 multiple-case families (in which more than
one family member is affected) and 110 single-case
families, and this further localized the defect to the
HLA-DQ and HLA-DR loci100.
Therapeutic options
Replacement therapy, haematopoietic stem-cell
transplantation (using bone marrow, cord blood or
peripheral blood) and gene therapy are the available treatments for patients with primary immunodeficiency. Immunoglobulin-replacement therapy is
the main treatment for antibody-deficiency disorders
and is usually given every 3–4 weeks. It can be given by
either an intravenous or a subcutaneous route, and the
dose and frequency of administration can be adjusted
on the basis of the clinical response of the patient
and on the adequacy of the concentration of serum IgG
NATURE REVIEWS | IMMUNOLOGY
that is maintained in the serum. Enzyme replacement
with bovine adenosine deaminase (ADA) modified
by polyethylene glycol can be used to treat patients
with ADA-deficient SCID who are not candidates for
haematopoietic stem-cell or bone-marrow transplantation101. Both modalities of replacement therapy are
generally well tolerated and provide these patients with
a much improved quality of life.
Haematopoietic stem-cell transplantation has been
attempted for patients with multiple types of primary
immunodeficiency, most successfully to treat patients
with SCID102. The largest study of patients with SCID
who had received a haematopoietic stem-cell transplant
was reported by a multinational registry, the European
Group for Blood and Marrow Transplantation and the
European Society for Immunodeficiencies103. There
were 475 patients who were studied, and each had
received a transplant in the previous three decades,
including 205 (43%) who did not receive a chemoablative preconditioning regimen. Factors that were
associated with poorer outcomes among patients
receiving non-HLA-identical transplants included a
B– SCID phenotype, absence of a protective environment and/or presence of a pulmonary infection before
transplantation. Although the use of a preconditioning
regimen was shown to promote functional engraftment in the group of patients with B– SCID, this was
not statistically significant compared with the results
achieved for other groups of patients. Among patients
receiving HLA-identical transplants, survival rates
were improved when transplantation occurred at
less than 6 months of age and when prophylaxis with
the antibiotics trimethoprim and sulphamethoxazole
was used.
One study of 132 patients with SCID who had
received a haematopoietic stem-cell transplant(s)
within the previous two decades has also been
reported11. Most of these patients received neither
pre-transplantation chemotherapeutic conditioning (to aid engraftment) nor post-transplantation
graft-versus-host-disease prophylaxis. Normal T-cell
function was seen within 2 weeks of transplantation of unfractionated HLA-identical bone marrow
but was delayed by up to 4 months in patients who
received T-cell-depleted bone marrow, owing to the
fact that mature T cells are not transferred to these
patients104. The survival rate for these 132 patients
was positively correlated with Caucasian race, female
gender and younger age at the time of transplantation. It is important to note that, although patients
in this study who had not received myeloablative
pre-transplantation chemotherapy had higher rates
of survival, long-term studies that were carried out
more than a decade after transplantation have shown
an accelerated rate of decline in the TRECs in T cells
from such patients and in the development of oligoclonal populations of T cells12,105. Similar longitudinal
studies of T-cell function and thymic output have not
been carried out in patients with SCID who received
pre-transplantation conditioning. Further long-term
follow-up studies are needed to assess the efficacy
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Box 1 | Retroviral insertional mutagenesis
The clinical trials of gene therapy for the treatment of X-linked severe combined
immunodeficiency (SCID) used a retroviral vector to transduce CD34+
haematopoietic stem cells with the gene encoding the common cytokine-receptor
γ-chain (γc). Retroviral vectors can stably integrate themselves into the DNA of
the host cell; however, the precise location of their insertion cannot be predicted.
This property, combined with the propensity of these vectors to insert themselves
into transcriptionally active genes, is the reason why the unfavourable side-effect
of insertional mutagenesis is a distinct possibility, and it could result in oncogene
activation by the inserted target gene.
Two patients in the French clinical trial have developed T-cell acute lymphoblastic
leukaemia, which is probably a consequence of retroviral insertion near the LIM
domain only 2 (LMO2) oncogene109,110. A third patient developed lymphatic cancer.
Increased expression of LMO2 is postulated to block T-cell differentiation, and
expression of γc by these cells might then facilitate signalling to induce their division,
resulting in clonal proliferation110. The exact mechanism by which the LMO2 locus
was selectively targeted for pro-virus integration in these patients is uncertain.
Before this trial, the risk of retroviral insertional mutagenesis was thought to be
mainly theoretical, because a single round of transduction would not account for
the multiple mutations that are generally required for clonal proliferation. This idea
was further supported by the absence of this phenomenon in preclinical and clinical
trials using replication-incompetent retroviral vectors112. Nevertheless, insertional
mutagenesis proved to be a serious adverse event in these patients, and further insight
is needed for the design and delivery of retroviral vectors before this life-saving
therapy can be provided in the future.
of various approaches to haematopoietic stem-cell
transplantation and to assist in the identification of
patient subgroups that are likely to benefit from one
form of therapy over another.
Clinical trials have been carried out using gene
therapy for the treatment of patients with X-linked,
recessive SCID (which is caused by a deficiency in the
common cytokine-receptor γ-chain, γc ) and for patients
with ADA deficiency106–108. For patients with X-linked,
recessive SCID, those without an HLA-identical sibling
were infused with autologous CD34+ haematopoietic
stem cells (enriched from bone marrow) that had been
incubated with cytokines and exposed to a γc-encoding
retroviral vector. Initial results were promising, with nine
1.
2.
3.
4.
5.
6.
Notarangelo, L. et al. Primary immunodeficiency
diseases: an update. J. Allergy Clin. Immunol. 114,
677–687 (2004).
This is an updated summary and classification
scheme of primary immunodeficiency diseases
that is based on the most recent consensus of
the Primary Immunodeficiency Disease
Classification Committee of the International
Union of Immunological Societies.
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of ten treated patients developing normal T-cell function
and not requiring gammaglobulin-replacement therapy.
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patients developed clonal proliferation of mature T-cell
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clonal phenotype. In the first two cases, leukaemia-like
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for the use of gene therapy to treat patients with SCID
or other selective immune defects, and advances in the
selection of additional vectors and the elucidation of
the mechanisms of gene transduction might allow its
re-implementation for the treatment of these patients.
Looking forward
As we look to the future of the field that encompasses
primary immunodeficiency diseases, emphasis needs
to be placed on the early detection of life-threatening
SCID, the elucidation of the unknown molecular
defects that underlie immune dysfunction and the
implementation of new modalities of therapy that aim
to correct these genetic defects. Adoption of SCID
into newborn-screening programmes will aid in the
diagnosis, treatment and long-term management of
these patients. Advances in haematopoietic stem-cell
isolation protocols allow transplantation of far greater
numbers of highly purified haematopoietic stem
cells, and in conjunction with more efficient negative
selection of T cells, this will undoubtedly improve
the outcomes of haematopoietic stem-cell transplantation111. Gene therapy, although in its infancy, has
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Competing interests statement
The authors declare no competing financial interests.
Online links
DATABASES
The following terms in this article are linked online to:
OMIM:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM
ALPS1a | ALPS1b | APECED | CVID | DiGeorge syndrome |
HIGM1 | HIGM2 | HIGM3 | HIGM4 | IPEX | XLA | XLP
FURTHER INFORMATION
Charlotte Cunningham-Rundles homepage: http://directory.
mssm.edu/faculty/facultyInfo.php?id=18843&deptid=6
Access to this interactive links box is free online.
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