Immunity

Review

Human Primary Immunodeficiency Diseases

Alain Fischer1,2,3,*
1Inserm, U768, Paris F-75015, France
2UniversitéRené Descartes-Paris 5, Paris F-75006, France, and Hôpital Necker-Enfants Malades, 149 rue de Sèvres,
Paris F-75015, France
3Unité d’Immunologie et Hématologie Pédiatrique, Assistance Publique, Paris F-75015, France

*Correspondence: fischer@necker.fr
DOI 10.1016/j.immuni.2007.11.012

Primary immunodeficiency diseases (PID) provide invaluable insight into immune system, notably
in vivo immune responses to microorganisms as based on the variable vulnerability to pathogens
and opportunistic agents. PID are also very informative in defining key checkpoints controlling immu-
nity to self. Despite a Mendelian inheritance of most PID, mutations of a given gene can lead to a vast
array of phenotypes as a function of the type of mutations, environmental factors, the occurrence of
additional somatic mutations, or regulatory factors, which add considerable but hitherto underesti-
mated complexity. Understanding the molecular pathophysiology of PID is not only contributing to
a better knowledge of the immune system but may also favor new therapeutic approaches.

Introduction 2007), and a unique phenotype with aberrant lymphocyte

In humans, more than 150 Mendelian conditions involving
an impaired immune response have been described.
Thanks often to fruitful international collaborations, analy-
sis of these pathologies has now led to the identification of
mutations in 130 or so genes (Geha et al., 2007). All facets
of the immune system are involved—from innate immunity
to adaptive immunity (and the interface between them)
and from cell differentiation to the impairment of regula-
tory and effector functions. Most of the described muta-
tions lead to loss of function of the respective genes,
although gains of function have been reported in a few
instances. In recent years, genetic dissection of PIDs
has resulted in (1) the discovery of genes (and hence their
products) that play key roles in the immune system (Table
1) and/or (2) elucidation of the function(s) of genes that had
been cloned previously (Table 1). However, identifying
a gene and its mutations does not always immediately im-
ply that the function of the corresponding gene product is
also known. Nevertheless, it is very clear that the study of
natural mutants has become a powerful tool for dissecting
the immune system.
From an experimental viewpoint, primary immunodefi-
ciency diseases offer an interesting spectrum of vulnera-
bilities to microorganisms and thus enable the in vivo
assessment of the respective roles of immune response
effectors during an infectious challenge. The conse-
quences of mutation can vary from a very strong predispo-
sition to infection by a broad range of microorganisms
(from strict pathogens to opportunistic agents, as ob-
served in severe combined immunodeficiencies [SCIDs])
to a remarkably narrow predisposition. Examples of the
latter include Mendelian susceptibility to mycobacterial
disease (Casanova and Abel, 2002), epidermodysplasia
verruciformis (herpes papilloma virus [HPV] disease)
(Ramoz et al., 2002), susceptibility to herpes simplex virus
1 (HSV-1) encephalitis (Casrouge et al., 2006; Zhang et al.,
responses to Epstein-Barr virus infection (Ma et al., 2007;
Rigaud et al., 2006). These observations are obviously of
major value in identifying the protective effectors in non-
mutated individuals (Table 2). Another striking and intrigu-
ing observation is that vulnerability to infectious diseases
can vary over time. Predispositions to invasive infections
by encapsulated bacteria or viruses (HSV-1 encephalitis)
caused by defects in the Toll-like receptor (TLR) pathway
interleukin-1 receptor associated kinase 4 (IRAK-4) and
polytopic endoplasmic reticulum CERI-resident mem-
brane protein (UNC93B) or TLR3 deficiencies, respec-
tively, are limited in time (Casrouge et al., 2006; Medvedev
et al., 2003; Ku et al., 2007; Zhang et al., 2007). These
observations suggest that once an adaptive immune
response has occurred, it is protective. It would be worth
testing (in relevant genetically deficient rodents, for exam-
ple) how an efficient adaptive response contains such
infections and whether or not it can be fully explained by
the presence of neutralizing antibodies. Predisposition to
autoimmunity is another major consequence of primary
immunodeficiency diseases. As discussed below, vulner-
ability can again either be extremely broad or narrower
and time-limited in nature.
The Complexity of the Mendelian Genetics of PIDs
Human Mendelian genetics is not as simple as it first
appears. The environment, the occurrence of somatic
mutations, and the role of modifier genes should at least
be considered as potentially impacting the phenotype. It
is obvious that the environment can modify the spectrum
of infectious diseases encountered in a given PID. For
instance, aggressive tuberculosis has been frequently
reported in patients with chronic granulomatous disease
(a condition in which reactive oxygen species-dependent
microorganism killing is impaired) in Hong Kong but not
elsewhere (Lau et al., 1998). More striking is the

Immunity 27, December 2007 ª2007 Elsevier Inc. 835

 Immunity

Review

Table 1. Genes and Primary Immunodeficiencies

Disease Natural Mutant Protein Function
Genes Discovered by Studying Primary Immunodeficiencies
scid DNA-PKcs VDJ (NHEJ)
SCID Artemis VDJ (NHEJ)
SCID Cernunnos, XLF VDJ (NHEJ)
T cell deficiency Orai-1, CRACMI Ca channel
Agammaglobulinemia Btk cell activation
XLP SAP coactivation (SLAM family), NKT
AT ATM DNA lesion sensing
NBS Nibrin (NBS1) DNA repair
DC Dyskerin telomere maintenance
T cell deficiency RFXAP, ANK, RFX5, CIITA HLA class II transcription
(HLA II expression)
WAS WASP cell cytoskeleton, migration
IPEX scurfy FOXP3 Treg function
APECED AIRE negative selection of T cells
motheaten SHP-1 phosphatase, regulation
FHLH Munc 13-4 exocytosis of lytic granules
CGD gp91phox, p22phox, NADPH oxidase
p47phox, p67phox
Previously Known Genes but Function Understood by the Study of Primary Immunodeficiency Diseases
SCID gc, JAK3 T (NK) cell development
SCN HAX-1 prevention of apoptosis (neut.)
LAD b2integrin adhesion
HIGM CD40L activation of Ig CSR
HIGM AID Ig CSR and SHM
lpr, gld fas, fasL apoptosis
Griscelli ashen Rab27a exocytosis of lytic granules
FHLH syntaxin11 cytotoxicity
XLP2 XIAP control of apoptosis (NKT)
Abbreviations: SCID (scid), severe combined immunodeficiency; DNA PKcs, DNA dependent-protein kinase, catalytic subunit;
VDJ, V(D)J recombination; NHEJ, nonhomologous end-joining; XLF, XRCC4-like factor; Btk, Bruton tyrosine kinase; XLP, X-linked
proliferative syndrome; SAP, SLAM-associated protein; AT, ataxia telangiectasia; NBS, Nijmegen Breakage syndrome; DC, dysker-
atosis congenita; WAS, Wiskott-Aldrich syndrome; WASP, Wiskott-Aldrich syndrome protein; IPEX, immunoproliferative enterop-
athy X-linked syndrome; Treg, regulatory T cells; APECED, autoimmune polyendocrinopathy candidiasis ectodermal dysplasia;
FHLH, familial hemophagocytic lymphohistiocytosis; CGD, chronic granulomatous disease; SCN, severe congenital neutropenia;
LAD, leukocyte adhesion deficiency; HIGM, hyper-IgM syndrome (Ig class switch recombination deficiency [CSR]); SHM, somatic
hypermutations; AID, activation-induced deaminase; lpr, lymphoproliferation; gld, generalized lymphadenopathy disease; XLP2,
X-linked proliferative syndrome type 2; XIAP, X-linked inhibitor of apoptosis.

observation that the occurrence of a given infectious dis-
ease can itself substantially modify the immunological
phenotype of a PID. Thus, hypomorphic mutations of the
RAG1 gene result in a limited T cell repertoire diversity
and hence severe T and B cell immunodeficiency (Villa
et al., 2001). Occurrence of cytomegalovirus (CMV) infec-
tions early in life in such patients triggers a massive expan-
sion of oligoclonal non-Vg9Vd2 gd T cells (presumably by
direct activation) (de Villartay et al., 2005; Ehl et al., 2005)
in association with autoimmune manifestations. Rag-1
deficiency best illustrates the phenotypic variability asso-
ciated with mutations of a given gene. In addition to the
consequences of CMV infection, it is also well known
that certain hypomorphic mutations cause oligoclonal
expansion of self-reactive T cells (a condition referred to
as Omenn syndrome [OM]; Villa et al., 2001, see below),

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Immunity
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Table 2. Gene Mutations and Susceptibility to
Pathogens
CD40L, CD40 Pneumocystis jiroveci,
Toxoplasma,
Cryptosporidium
IL12p40, IL12Rb, IFNgR, Mycobacteria
STAT1
IRAK4 encapsulated pathogens
SAP, XIAP EBV
UNC93B, TLR-3 HSV encephalitis
Complement C5-C9 Neisseria
EVER 1,2, gc, JAK-3 HPV-epidermodysplasia
verruciformis
Abbreviations: IL12p40, p40 subunit of interleukin 12; IL12Rb,
b chain of the IL12 receptor; IFNgR, receptor of the interferon
g receptor; STAT1, signal transducer and activator of tran-
scription 1; IRAK4, interleukin-1 receptor associated kinase
4; SAP, SLAM-associated protein; XIAP, X-linked inhibitor of
apoptosis; UNC93B, polytopic endoplasmic reticulum CERI-
resident membrane protein; TLR-3, Toll-like receptor 3;
EVER 1,2, Epidermodysplasia verruciformis 1, 2 genes; gc,
common cytokine g chain; JAK-3, Janus associated kinase.
whereas the same recessive mutations of RAG1 can, in
a given family, be associated with either a SCID phenotype
(i.e., the absence of T and B lymphocytes) or OM. This find-
ing suggests the involvement of one or more modifier
genes (Cornéo et al., 2001).
This is not an unusual observation for PIDs, because
many of these conditions (and especially those with auto-
somal-dominant [AD] inheritance, such as common vari-
able immunodeficiency, or autoimmune lymphoprolifera-
tive syndrome [ALPS]) exhibit variable expressivity.
Epigenetic factors and key modifier genes can account
for this variability, suggesting that there may be a contin-
uum between ‘‘simple’’ and more complex genetically
determined diseases (Antonarakis and Beckmann,
2006). Lastly, occurrence of somatic mutations in a germ-
line-mutated gene can attenuate a disease phenotype—
at least in the T cell subset, as described for Rag-1
deficiency (Wada et al., 2005) and many other T cell immu-
nodeficiencies. These observations have two implications.
First, somatic mutations occur more frequently than might
be expected and, second, they can be detected in T lym-
phocyte PIDs—probably because T cell progenitors are
deemed to have a very high cell-division capacity whereas
mature T cells are long-lived (Fischer et al., 2005). Sec-
ondary somatic mutations of a second gene can alter
the course of a PID, as observed in the severe congenital
neutropenia (SCN) caused by elastase deficiency (Gits
et al., 2006). Somatic mutations of the G-CSF receptor
have been reported and provide a selective growth ad-
vantage, favoring the occurrence of myeloid leukemia
(Gits et al., 2006). Finally, somatic mutations can create
a PID, provided that it occurs early in ontogenesis and
confers a growth or survival advantage on mutated cells.
This is the case in ALPS (Bidere et al., 2006), caused by
somatic mutations of the Fas-encoding gene. Somatic
mutations are rarely found in hematopoietic precursor
cells but are abundant in accumulating mature T lympho-
cytes with a CD4 CD8 phenotype (Holzelova et al.,
2004). The latter observation stresses the possible role
of acquired mutations breaking checkpoints of self-reac-
tivity in a process of multistep generation of autoimmunity
(Goodnow, 2007).
The field of PID research has been very active over
recent years. Here, some examples are highlighted of
the advances made in understanding the mechanisms of
PID and how these findings have contributed to many
different aspects of immunology.
Differentiation of Neutrophils
The analysis of developmental blocks of T and B lympho-
cyte subsets has released a flood of useful information on
the role of molecules such as the common gc cytokine
receptor or the Bruton tyrosine kinase in T and NK cell
and B cell development, respectively (Table 1 and Fig-
ure 1). This is now being extended to neutrophils. More
than 50 years ago, an arrest in neutrophil production
was recognized as causing SCN in Kostmann’s disease,
a condition characterized by an almost complete absence
of neutrophils. Genetic heterogeneity has been long
known, on the basis of inheritance patterns and pheno-
typic differences in granulopoiesis (Skokowa et al.,
2006). Today, nine distinct genetic disorders leading to
SNC have been identified and many others are yet to be
characterized. It seems that a key common element in
many of the SCN phenotypes is the defective survival of
neutrophil precursors (Kollner et al., 2006). Horwitz et al.
(2007) have shown that mutations in ELA2, the GFI1 tran-
scription repressor, and the AP3BI gene (encoding a
component of the AP3 adaptor) all result in mislocalization
of elastase, which accumulates at the plasma membrane.
It is plausible, for example, that membrane elastase
cleaves receptors that are involved in cell survival (or dif-
ferentiation) and thus contributes to premature apoptosis
of neutrophil precursors (Horwitz et al., 2007). Additional
evidence for a role of premature apoptosis in the genesis
of SCN was recently provided by a report of recessive
mutations in the HAX1 gene in Kostmann patients (Klein
et al., 2007). HAX-1 is a mitochondrial protein with bcl2
homology domains (BH1 and BH2) domains involved in
the maintenance of membrane potential. Its defective ex-
pression results in increased apoptosis of neutrophils and
their precursors. It is worth noting that despite ubiquitous
expression of HAX-1, the consequences of defects are
limited to neutrophils—evidencing nonredundant, antia-
poptotic HAX-1 activity in the latter. Together, these re-
sults provide strong mechanistic support for the efficacy
of granulocyte-colony stimulating factor (G-CSF) adminis-
tration in restoring granulocyte survival in most SCN
patients, because this prevents granulocyte precursor
cell death (Maianski et al., 2002).
Immunity 27, December 2007 ª2007 Elsevier Inc. 837

Recombination of Antigen-Receptor Genes
Twenty years ago, analysis of the scid mouse model
turned out to be instrumental in understanding that the
combinatorial rearrangements of the T cell receptor and
B cell receptor genes used the nonhomologous double-
strand end-joining repair pathway (NHEJ). The NHEJ ap-
paratus fixes DNA breaks induced by the RAG-1:RAG-2
complex at recombination signal sequences during V(D)J
recombination (Bassing and Alt, 2004). Scid mice were
shown to carry mutations in the catalytic subunit of DNA-
dependent protein kinase (DNA PKcs), a key component
of the NHEJ apparatus. Human SCID diseases have since
contributed to the identification of new components of the
NHEJ pathway. A condition phenotypically similar to that
caused by DNA-PKcs deficiency in the mouse prompted
cloning of the gene encoding the Artemis protein (De Villar-
tay et al., 2003). On phosphorylation by DNA PK, Artemis
cleaves hairpins bridging both strands at coding ends.
Whereas the role of DNA ligase 4 in the final ligation step
in NHEJ was confirmed by description of a T+B cell immu-
nodeficiency (albeit of variable severity) in patients with
DNA ligase 4 deficiency (O’Driscoll et al., 2001), another
component of the NHEJ repair pathway (Cernunnos or
XLF) has been recently discovered (Buck et al., 2006). It
was found that cells from a group of patients presenting
severe, progressive T+B cell lymphopenia exhibited greatly
838 Immunity 27, December 2007 ª2007 Elsevier Inc.
Immunity
Review
Figure 1. T Cell Development and
Primary Immunodeficiencies
Schematic representation of T cell develop-
ment with an indication of the eight known ef-
fector T cell subsets: TCRgd T cells (gd), cyto-
toxic T cells (Tc), helper T cells 1, 2, 17, and
follicular helper (Fh) T cells, regulatory T cells
(Treg), and NKT cells. The major cytokines pro-
duced by these subsets are shown. Vertical
red bars indicate a complete block in cell de-
velopment or function observed in PID. Dotted
vertical bars indicate partial block.
Abbreviations: SCID, severe combined immu-
nodeficiency; ZAP-70, zeta-associated protein
70 deficiency; TAP, TAP-1 and TAP-2 defi-
ciencies; HLA-class II, T cell immunodeficiency
with defective HLA class II gene transcription;
Orai-1, T cell immunodeficiency with defective
Ca2+ channels; HLH, hemophagocytic lym-
phohistiocytosis; Tyk2, autosomal recessive
hyper-IgE syndrome with Tyk2 deficiency;
STAT 3, dominant-negative mutations found
in the hyper-IgE syndrome; CD40L, hyper-
IgM syndrome with CD40L deficiency; XLP,
X-linked proliferative syndrome with either
SAP or XIAP deficiency; IPEX, X-linked immu-
noproliferative enteropathy (FoxP3 deficiency);
HSCs, hematopoietic stem cells; CLPs, com-
mon lymphoid progenitors.
increased sensitivity to ionizing radiation. V(D)J recombi-
nation capacity and in vitro NHEJ activity were found to
be defective. The gene encoding Cernunnos (NHEJ1)
was cloned via a complementation strategy as well as
through the ability of its product to interact with XRCC4,
a component of the NHEJ ligation step (Ahnesorg et al.,
2006). Although Cernunnos shares homology with
XRCC4 and is part of a complex with XRCC4 and DNA li-
gase 4, further studies will be required to define its precise
molecular function. Strikingly, patients with Cernunnos
and DNA ligase 4 deficiencies exhibit developmental
defects and microcephaly, which is reminiscent of similar
findings observed in mice defective in DNA ligase 4 and
XRCC4. Premature apoptosis of postmitotic neurons has
been observed in these murine models, suggesting that
the NHEJ pathway is involved in repairing reactive oxygen
species-induced DNA lesions (Gao et al., 1998). Descrip-
tion of the DNA repair factors involved in T and B cell devel-
opment is probably not yet complete, given that some
patients with a fairly similar phenotype do not display
any gene defects. It is striking to note the nonredundancy
of the mutations affecting the few genes governing the
determination of adaptive immunity. When mutated,
the key lymphoid-specific genes RAG1 and RAG2 and
the gene AICDA (encoding AID) led to SCID and hyper-
IgM syndrome (defective Ig class switch recombination),
Immunity
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respectively, whereas deficiencies of elements involved in
downstream DNA repair (i.e., NHEJ, see above) or down-
stream of AID (e.g., uracil N-glycosylase, UNG) cause sim-
ilar diseases (De Villartay et al., 2003; Durandy et al., 2007).
Another implication is that developmental defects of the
immune system can result from the mutation of genes
with a ‘‘pleiotropic function in ontogeny’’ affecting devel-
opment of multiple organs such as the brain or bones.
Lymphocyte Activation
This assumption has been nicely confirmed by the recent
discovery of a key element governing Ca2+ influx in lym-
phocytes and other cells—the Orai-1 (CRACM1) molecule
(Feske et al., 2006; Vig et al., 2006b). More than 10 years
ago, separate reports described a severe, recessive,
autosomal T and B cell (‘‘combined’’) primary immunode-
ficiency characterized by defective TCR- and BCR-medi-
ated cell activation, a calcium (Ca2+) influx deficiency in
lymphocytes, and defective NF-AT nuclear factor of acti-
vated T cells (NFAT) translocation to the nucleus (Feske
et al., 1996, 2001; Le Deist et al., 1995). These children
were also found to suffer from nonprogressive myopathy
and anhydrotic ectodermic dysplasia (Feske et al.,
2006). A defect in Ca2+ release-activated Ca2+ (ICRAC)
channel activity was postulated on the grounds that
Ca2+ release from the endoplasmic reticulum was main-
tained, whereas direct patch-clamp measurements of
ICRAC in patient lymphocytes and fibroblasts were flat
(Feske et al., 2001; Partiseti et al., 1994). Despite the rarity
of this condition, its description confirmed the importance
of Ca2+ influx from the extracellular milieu into the cytosol
in the process of lymphocyte activation (Berridge et al.,
2003). Feske et al. (2006) performed a remarkable tour
de force by using a refined genetic linkage analysis in an
affected family with two patients and heterozygous car-
riers (the latters’ lymphocytes had a mild Ca2+ flux defect).
This approach was combined with a genome-wide mRNA
interference screen in Drosophila (with a hypothesis of
phylogenetic conservation), which consisted in inhibiting
store-operated Ca2+ influx and NF-AT nuclear import. It
led to the identification of genes with human orthologs
(encoding Orai-1 to Orai-3). It turned out that the locus
encoding Orai-1 is located in the region circumscribed
by genetic analysis of the affected family and was found
to be mutated in the patients. Furthermore, introduction
of a normal copy of Orai-1 into patient-derived cells
restored Ca2+ influx (Feske et al., 2006). It is noteworthy
that by using a similar Drosophila screen, Kinet’s group
was also able to identify this gene (Vig et al., 2006b).
Orai-1 is a plasma membrane protein with four transmem-
brane domains. Further work has provided several lines of
evidence that indicate that Orai-1 is a pore subunit of the
CRAC channel, which is activated by the STIM-1 ER Ca2+
sensor (Prakriya et al., 2006; Vig et al., 2006a; Yeromin
et al., 2006). Here again, the question of whether further
analysis of immunodeficiencies characterized by ill-de-
fined, defective T cell activation might help identify more
building blocks in the lymphocyte Ca2+ entry pathway is
still open. In very rare cases, the ability to set up a func-
tional assay (such as Ca2+ influx or anything else enabling
the unequivocal identification of functionally heterozygous
carriers) is likely to be of tremendous help in uncovering
mutated gene(s) involved in signal transduction pathways
(Fischer and Notarangelo, 2003).
Cytokine Signaling and Immunodeficiencies
Analysis of primary immunodeficiencies (specifically SCID
characterized by defective differentiation of T and NK lym-
phocytes) has been instructive in understanding the
respective functions of the many gc-dependent cytokine
receptors and the gc-associated Janus associated kinase
3 (JAK3) kinase (Leonard, 2001). Similarly, deficiencies in
STAT1 (‘‘signal transducer and transcription activator’’),
which is activated when type I and II interferons bind to
their receptors, shed light on their respective functions in
controlling viral and mycobacterial infections in humans
(Casanova and Abel, 2002). Recent findings have broad-
ened the scope of investigation into cytokine receptor
signaling in PID, via the description of STAT5b and Tyk-
2 deficiencies (Bernasconi et al., 2006; Minegishi et al.,
2006). Despite considerable homology with STAT5a, the
phenotype observed in three immunodeficient patients
with a STAT5b deficiency clearly established that (at least
for some functions) these proteins are nonredundant. In
one case, the immunological phenotype (associated with
short stature because of growth hormone unresponsive-
ness) was partially characterized (Bernasconi et al.,
2006). The patient had a nonsense homozygous mutation
and no detectable Stat5b protein, and the immunological
defects consisted of mild T cell lymphopenia, profound gd
T cell and NK cell lymphopenia, and impaired in vitro T cell
proliferation in response to mitogens and antigens. B cells
were not affected. There might also have been partial T
regulatory cell deficiency. Further studies will be required
to specify which Stat5b-dependent, cytokine-triggered
pathways are impaired in T and NK cell development
and T cell activation. Minegishi et al. (2006) have recently
described a single case of Tyk-2 deficiency and its many
consequences in a patient with autosomal-recessive
hyper-IgE syndrome (HIES). Tyk-2 is a kinase from the
JAK family that is associated with a number of cytokine
receptors, including IL-12, IL-23, IFN-a and -b, IL-10,
and the IL-6 family (Watford and O’Shea, 2006). The ho-
mozygous mutation of TYK2 found in this patient led to
premature termination of translation and the absence of
detectable protein. As expected, the above-mentioned
cytokine-induced signaling pathways were found to be
impaired in vitro, resulting in functional consequences
that were more pronounced than in Tyk2 / mice. The
recurrent viral and persistent mycobacterial infections
suffered by the patient could well be the respective conse-
quences of defective IFN-a- and IL-12-mediated cell acti-
vation. Of note was the recurrence of skin abscesses and
lung infections which, set against a background of defec-
tive Il-23 and IL-6 signaling, strongly suggests a deficiency
in the effector Th17 subset. IL-23 is involved in Th17 main-
tenance, whereas IL-6 contributes to Th17 development
(Steinman, 2007). Given that Th17 cells have been described
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as recruiting phagocytic cells to infection sites in the skin
and lungs, the predisposition to infections observed in this
patient fits the hypothesis proposed by Watford and
O’Shea (2006). Unfortunately, data on the corresponding
cytokine profile (IL-17, etc.) were lacking. If the hypothesis
is correct, this case would represent the first observation
of a Th17 cell deficiency and, hence, indirect confirmation
of their functional existence in humans.
Autosomal-dominant HIES has recently been shown to
be related to dominant-negative mutations of signal trans-
ducer and transcription activator 3 (STAT3) (Holland et al.,
2007; Minegishi et al., 2007). It would thus be worth test-
ing the Th17 pathway in these patients, given the pheno-
typic similarity with Tyk-2 deficiency in terms of the occur-
rence of bacterial and fungal lung and skin infections
(Grimbacher et al., 2005). The recent characterization of
human Th17 cells expressing CCR4 and CCR6 chemo-
kine receptors (together with ROR gT, the transcription
factor inducing Th17 differentiation; Acosta-Rodriguez
et al., 2007) could help test this hypothesis. Chronic
mucocutaneous candidiasis (CMCC)—another poorly un-
derstood condition characterized by recurrent skin and
mucosal infection by Candida species (Lilic, 2002)—might
be related to a deficiency in Th17 effector cell induction by
Candida-associated glycan via the dectin-1 receptor and
its signaling pathway, which includes the tyrosine kinase
syk and the adaptator CARD9 (Leibundgut-Landmann
et al., 2007).
Self-Reactivity and PID
Omenn syndrome has attracted much interest because of
its unique phenotype. It is characterized by an oligoclonal
expansion of T cells with a Th2 phenotype. These T cells
are found mostly in the skin and the gut of affected pa-
tients. Although OS can be observed in patients carrying
hypomorphic mutations of genes that lead to impaired
T and B cell differentiation, it is mainly associated with hy-
pomorphic mutations of the RAG1 or RAG2 genes (Nota-
rangelo et al., 2006). Omenn syndrome is characterized by
early-onset skin and gut infiltration by oligoclonal T cells
with a TH2 phenotype. It has been suggested that these
symptoms result from the uncontrolled expansion of
self-reactive, oligoclonal T cells—possibly as a conse-
quence of defective negative T cell selection (Fischer,
2004). Indeed, OS thymi show markedly reduced expres-
sion of Aire and defective expression of ‘‘ectopic tissue-
specific antigens’’ (TSA) in thymic epithelial cells (TECs)
(Cavadini et al., 2005). Defective Aire expression was
thought to be the consequence of defective thymic epithe-
lial cell differentiation in the context of a paucity of T cell
precursors, thus resulting in a lack of lymphocyte-epithe-
lial cell crosstalk. Further insight into the pathophysiology
of OS was recently provided by the description of two
murine models of OS; one was deliberately derived by
the creation of a gene-targeted mouse strain expressing
the R229Q Rag1 mutation found in patients with OS
(Marrella et al., 2007), whereas the second results from
a natural hypomorphic mutation in Rag2 (R972Q) (Khiong
et al., 2007).
840 Immunity 27, December 2007 ª2007 Elsevier Inc.
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Both models correspond fairly well to human OS (de-
spite a few differences) and can thus be considered as
useful tools for delineating this unique immunopathologi-
cal phenomenon. Four pieces of information have been
gathered: (1) the phenotype can develop in a pathogen-
free setting; (2) reduced Aire expression was found in
the thymus (Marrella et al., 2007); (3) there is a smaller
than usual pool of Fox P3+ regulatory T cells (Treg)
(Marrella et al., 2007); and (4) in the second murine model,
homeostatic expansion of T cells was evidenced by trans-
ferring wild-type T cells into mutant mice, leading to T cell
activation and a Th2 phenotype (Khiong et al., 2007).
These data bear some resemblance with the monoclonal
Th2 cell expansion seen after transfer into lymphopenic
mice (Curotto de Lafaille et al., 2001) and oligoclonal
expansion of T cells with a Th2 phenotype after transfer
of a limited number of T cells again into lymphopenic
mice (Milner et al., 2007). In the latter model, cell expan-
sion and disease were prevented when a higher number
of T cells or regulatory T cells (Treg cells) were transferred.
Taken together, these data converge with the concept of
homeostatic expansion of self-reactive T cells in OS that
can be facilitated both by defective elimination of self-re-
active T cells in the thymus (because of Aire expression
deficiency) and by a relative deficiency in regulatory T cells
(to be confirmed in OS patients). The possible interplay
between nonredundant regulatory pathways (Aschen-
brenner et al., 2007) further emphasizes the possible
occurrence of T cell-mediated autoimmunity in settings
characterized by persistent or even transient reductions
in thymopoiesis.
Major advances have also occurred in the study of the
predisposition to autoimmunity observed in Wiskott-Aldrich
syndrome (WAS). WAS is the consequence of a deficiency
in the WAS protein (WASP) involved in actin polymerization
in hematopoietic cells. Autoimmunity and colitis are fre-
quent in severe cases of WAS (Ochs and Thrasher, 2006).
Three recent reports have pinpointed a defect in the
FoxP3+ Treg subset as the likely mechanism underlying
autoimmunity. Indeed, it has been shown that in a WAS pa-
tient with a WASP gene somatic mutant leading to rever-
sion, there is a selective advantage for revertants within
the Treg subset, combined with the remission of autoim-
mune hemolytic anemia (Humblet-Baron et al., 2007).
With Was / mice, impaired expansion and homing of
FoxP3 Treg have been demonstrated after cell transfer
(Humblet-Baron et al., 2007; Marangoni et al., 2007),
together with an inability to control colitis (Maillard et al.,
2007). In two reports (Maillard et al., 2007; Marangoni
et al., 2007), an in vitro functional deficiency in the suppres-
sive activity of Treg cells has been described, although this
was not confirmed by a third report (Humblet-Baron et al.,
2007). Despite these discrepancies, these reports provide
strong evidence for the deregulation of Treg biology in
WAS as the mechanism underlying autoimmunity and coli-
tis. It remains for us to understand how the defect in the
WASP relates to the in vivo (and possibly in vitro) functional
Treg deficiency, given that it is not a direct consequence of
defective actin filament formation because wild-type Treg
Immunity
Review
cells do not form this type of filament very well either (Mail-
lard et al., 2007; Marangoni et al., 2007).
Multiple checkpoints controlling self-reactivity of T and
B cells as well have been described by Goodnow (2007)
(Table 3). Analysis of PID can also help deciphering their
existence and importance. A recent study by Herve
et al. (2007) has shown that, in patients with CD40L defi-
ciency, there is overexpression of autoreactive antibodies
in naive but not newly emigrant B cells. This result
stresses the existence of a peripheral B cell tolerance
step that is dependent on CD40L-CD40 interaction. A
similar observation has been made by analyzing B cells
from a patient with major histocompatibility complex
class II molecule deficiency. Therefore, T-B cell interac-
tion is likely to be involved in the control of self-reactive
naive B cells, by a mechanism that remains to be better
determined.
NKT Lymphocytes
Major advances have recently been made in characteriz-
ing the invariant NKT cell subset that recognizes endoge-
nous and exogenous glycolipids presented by the CD1d
molecule (Bendelac et al., 2007). On the basis of experi-
mental findings in murine models, it has been suggested
that the subset plays a role in the control of autoimmunity
and in rapid responses to bacterial and (possibly) viral
infections. It is noteworthy that there is a striking paucity
of NKT cells in humans, compared with rodents (Bendelac
et al., 2007). It is thus questionable whether NKT cells have
been selected as important effectors of immunity in hu-
mans. Genetic defects leading to NKT cell deficiencies
might thus provide clues concerning the importance of
these cells and the circumstances in which they intervene.
Strikingly, two inherited conditions associated with severe
EBV infection are characterized by a NKT cell deficiency:
(1) X-linked proliferative syndrome (XLP) caused by muta-
tion of the SH2D1A gene and (2) XLP2 syndrome caused
by mutations of the XIAP-encoding gene (Ma et al.,
2007; Rigaud et al., 2006). In both conditions, patients
newly infected by EBV develop either an inappropriate
CD8+ T cell and macrophage response (called hemopha-
gocytic lymphohistiocytic syndrome, HLH), lymphomas,
and/or hypogammaglobulinemia (Ma et al., 2007). In
XLP, the defective gene product (SAP) is an adaptor
from the SLAM family of receptors, which includes (among
others) SLAM, 2B4, and NTBA (Ma et al., 2007). Multiple
signaling pathways are triggered through receptor-ligand
interaction in immune system effector cells, leading to
(among other effector functions) increased T cell and NK
cell cytotoxicity. It has been found that NK cell-mediated
cytotoxicity is defective (and even inhibited) after interac-
tion between 2B4 and its ligand (CD48) in the absence of
SAP (Ma et al., 2007). However, XLP patients also display
a complete lack of circulating NKT cells (Nichols et al.,
2005; Pasquier et al., 2005), mirroring findings in SAP-de-
ficient mice in which NKT cells are absent in all organs
(Nichols et al., 2005; Pasquier et al., 2005). In these
mice, NKT cell deficiency is caused by an intrathymic
developmental block (Pasquier et al., 2005; Nichols
Table 3. Susceptibility to Autoimmunity
Disease or
Syndrome Gene Product(s) Mechanism
ALPS FAS, FAS L apoptosis of
self-reactive lymphocytes
in the periphery
APECED AIRE negative selection
of thymocytes
IPEX FOXP3, CD25 development and function
of regulatory T cells
Three major syndromes—ALPS (autoimmune lymphoprolifer-
ative syndrome), APECED, and IPEX with a mendelian genetic
inheritance—result in a predisposition to autoimmunity.
Mechanisms are indicated. Omenn syndrome, a condition
caused by hypomorphic mutation of genes controlling T+B
cell development, is associated with expansion of self-reac-
tive T cells (possibly related to defects in AIRE expression
and FOXP3(+) regulatory T cell development). Wiskott-Aldrich
syndrome is an X-linked PID that is frequently associated with
severe autoimmunity. Defective development and survival
functions of FoxP3+ regulatory T cells.
et al., 2005), suggesting a role for one or more SLAM fam-
ily receptor(s) in transduction of the positive signals
required for NKT cell differentiation. As such, this finding
alone remained anecdotal with respect to a hypothetical
link between NKT cell deficiency and defective control of
EBV infection. However, the hypothesis has been consid-
erably strengthened by the recent description of XLP2,
a condition characterized by a very similar clinical pheno-
type in terms of the almost complete absence of circulat-
ing NKT cells but in which 2B4-mediated cell cytotoxicity
is undisturbed (Rigaud et al., 2006). XLP2 is the conse-
quence of a deficiency in XIAP, a molecule that presum-
ably acts in vivo as a major inhibitor of cell apoptosis. It
is not yet known how XIAP deficiency leads to an appar-
ently isolated NKT cell immune deficiency. How NKT cells
might be involved in immunity to EBV and which lipid(s) is
(are) recognized are stimulating, open questions. An addi-
tional report of a molecularly uncharacterized NKT cell de-
ficiency in a patient with post-vaccination-disseminated
varicella infection further strengthens the hypothesis of
a role for NKT cells in the control of herpes viruses (Levy
et al., 2003). In addition, the fact that HSV and Kaposi
sarcoma herpes virus induce downregulation of CD1d
expression might represent a viral protective countermea-
sure against a NKT cell response (Sanchez et al., 2005). It
is thus worth paying more attention to NKT cells in the
analysis of currently ill-defined immune deficiencies asso-
ciated with viral infections.
NK Cells
Selective NK cell deficiency has been recognized as a sep-
arate entity in primary immunodeficiency and has an entry
in the Online Mendelian Inheritance in Man database
(609981) (Orange, 2006). This is based on several reports
describing a profound deficiency in circulating NK lym-
phocytes in conjunction with recurrent (mostly viral)
Immunity 27, December 2007 ª2007 Elsevier Inc. 841

infections (Bernard et al., 2004; Biron et al., 1989; Eiden-
schenk et al., 2006a, 2006b; Etzioni et al., 2005; Notaran-
gelo and Mazzolari, 2006). It is nevertheless noteworthy
that a molecular defect has not yet been reported in any
of these cases. In addition, a NK cell cytotoxicity function
deficiency has been reported as a possible causative
mechanism of HLH (i.e., uncontrolled CD8+ T cell and
macrophage activation), as observed in patients with a
deficiency in either perforin, Rab27a, Lyst, Munc13-4, or
Syntaxin 11—all of which are involved in perforin-depen-
dent cytolytic activity (as discussed in Orange, 2006). Sim-
ilarly, a NK cell activity deficiency was found in a murine
strain (Jinx) into which a Munc13-4 (Unc13d) gene muta-
tion had been induced by mutagenesis (Crozat et al.,
2007). The Jinx mice develop HLH when infected with
the lymphocytic choriomeningitis virus (Crozat et al.,
2007). Collectively, these data suggest (1) that NK cells
are involved in immunity to viruses (notably those of the
herpes groups) in humans and (2) that a selective impair-
ment in NK cytolysis favors an immunopathological reac-
tion likely to be associated with a persistent, infectious
trigger. These observations fit very well with the many re-
ports describing the role of NK cells in immune responses
to pathogens in general and in early steps of viral infection
in particular (reviewed in Lodoen and Lanier, 2006).
Nevertheless, careful assessment of the reported data
on NK cell immunodeficiencies prompts one to challenge
these views to some extent, especially given that the NK
cell deficiency does not always appear to be isolated.
Indeed, in one case, IL-2- and IL-15-related survival of
T lymphocytes is also impaired (Eidenschenk et al.,
2006b), whereas in another, a NKT cell deficiency was
also found (Eidenschenk et al., 2006a) Similarly, the NK
cell cytotoxicity deficiency found in patients with geneti-
cally determined HLH is not isolated, as indicated by the
fact that granule-dependent T cell cytotoxicity is also
impaired (Fischer et al., 2007). It is noteworthy that in a
murine model of HLH (perforin-deficient mice infected
with LCMV), elimination of CD8+ T cells (and not NK cells)
prevented the occurrence of the disease. These data do
not rule out a role for NK cells but are not compatible
with the concept of selective NK cell deficiency. In hu-
mans, there is one setting that corresponds to what
appears to be a selective NK cell deficiency; it consists
of NK SCID (gc and JAK 3 deficiencies) after nonmyeloa-
blative allogeneic hematopoietic stem cell transplantation
(HSCT) or gene therapy (for gc deficiency only). In both
instances, it is very frequently observed that long-term
surviving patients (for up to 30 years post-HSCT) have
very few (if any) NK cells in their blood—in contrast to ro-
bust T cell immunity (Buckley, 2004; Fischer et al., 2005).
These patients do not suffer from serious viral infections,
suggesting that there is some form of adaptation or, in
other words, that NK cell activity might be redundant. It
is certainly premature to draw firm conclusions but these
contradictory findings should lead to a careful (re)assess-
ment of NK cell-associated immune functions in man. Fur-
ther observations of human NK cell deficiency should lead
to a thorough investigation of the other effectors of immu-
842 Immunity 27, December 2007 ª2007 Elsevier Inc.
Immunity
Review
nity to pathogens in general and, obviously, NKT and
cytolytic T cells in particular.
New Approaches to Treating PIDs
Genetic analysis of PIDs is not only important for elucidat-
ing important pathways in the immune system, it also has
medical impact by prompting the design of new diagnos-
tic tools and opening up new fields of therapeutic
research.
In some instances, gene product supplementation
might be envisaged, as is the case with adenosine deam-
inase deficiency that results in a SCID phenotype. Under-
standing the pathophysiology of a PID can suggest ways
of compensating for a missing key end product. This is
best exemplified by g interferon supplementation in pa-
tients carrying IL-12 receptor mutations (Casanova and
Abel, 2002). Direct genetic intervention by adding a normal
copy of the mutated gene to affected cell lineages is an
obvious approach that has proved to be successful in
SCID conditions (Aiuti et al., 2002; Cavazzana-Calvo
et al., 2000), i.e., in settings where a selective survival or
growth advantage is conferred by transgene expression,
as is the case with the various mutations leading to
a SCID phenotype or to the Wiskott-Aldrich syndrome.
The type of mutation in a given PID may also prompt
new strategies. For example, mutations creating glycosyl-
ation sites can cause protein unfolding and degradation.
Chemicals able to modify glycosylation may be able to
complement these defects by preventing protein degra-
dation, as shown in vitro in several models (Vogt et al.,
2007). Clinical application of this approach might thus be
envisaged, provided that drugs can be administered
with sufficient bioavailability and lack of toxicity. Non-
sense mutations (which account for a relatively high frac-
tion of mutations) lead to premature translation termina-
tion, mRNA decay, and thus an absence of the protein.
Both gentamycin and PTC 124 (a recently developed,
nontoxic drug) prevent termination of translation at a pre-
mature stop codon and offer a reasonable hope of clinical
application, as suggested by experimental data from mice
with muscular dystrophy or cystic fibrosis (Lai et al., 2004;
Welch et al., 2007). We are likely to see more and more
mutation-related strategies for the treatment of genetic
diseases in general, with a benefit for PIDs. In any case,
these new hopes further strengthen the need to precisely
define genes, their mutations, and functional conse-
quences in every single form of PID.
Conclusions
PID are both potentially devastating diseases and unique
models for identifying key molecular components of the
immune system and studying the relevance of immuno-
logical findings in the ‘‘real’’ world of the complex natural
environment. Despite considerable recent progress, there
is still a lot to do! Implementation of new genetic technol-
ogies is likely to be of considerable assistance in finding
mutations associated with rare but nevertheless important
phenotypes. Refinement of linkage analyses via single
nucleotide polymorphic (SNP) markers associated with
Immunity
Review
the phenotype detection of heterozygotes and RNAi-
based screening in relevant models are both powerful
tools. In addition, complementation technology has be-
come more feasible and a number of efficient transfer
systems are available. The use of high-resolution compar-
ative genomics hybridization (CGH) arrays should help us
detect microdeletions potentially associated with the
many (albeit very rare) complex syndromes that feature
an immunodeficiency. Variable disease expression (fre-
quently not associated with the type of mutation) is a com-
mon observation in the field of PID. For the most frequent
PIDs such as X-linked agammaglobulinemia (XLA), ataxia
telangiectasia, or CGD, this should certainly prompt re-
searchers to initiate the search for modifier genes, the
characterization of which will potentially be as rewarding
as has been recent gene hunting work. The HapMap pro-
ject (The International HapMap Consortium, 2006) now
provides us with a tool for performing this type of analysis.
Collectively, these efforts should provide further insight
into understanding many relevant pathways at work in im-
mune cells, possibly contributing to an integrative view of
immune responses.
ACKNOWLEDGMENTS
A.F. wishes to thanks M. Cavazzana-Calvo, G. de Saint Basile, J.P. de
Villartay, A. Durandy, S. Latour, P. Revy, F. Rieux-Laucat, and other
colleagues in the laboratory who have generated some of the data
discussed in the review and with whom continually ongoing fruitful
discussions are the basis of this review. Thanks to M. Sifouane for
her excellent secretarial assistance.
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