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

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Immunity

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

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Immunity

Review

Table 2. Gene Mutations and Susceptibility to confers a growth or survival advantage on mutated cells.
Pathogens This is the case in ALPS (Bidere et al., 2006), caused by
somatic mutations of the Fas-encoding gene. Somatic
CD40L, CD40 Pneumocystis jiroveci,
Toxoplasma, mutations are rarely found in hematopoietic precursor
Cryptosporidium cells but are abundant in accumulating mature T lympho-
cytes with a CD4 CD8 phenotype (Holzelova et al.,
IL12p40, IL12Rb, IFNgR, Mycobacteria
2004). The latter observation stresses the possible role
STAT1
of acquired mutations breaking checkpoints of self-reac-
IRAK4 encapsulated pathogens tivity in a process of multistep generation of autoimmunity
SAP, XIAP EBV (Goodnow, 2007).
The field of PID research has been very active over
UNC93B, TLR-3 HSV encephalitis
recent years. Here, some examples are highlighted of
Complement C5-C9 Neisseria the advances made in understanding the mechanisms of
EVER 1,2, gc, JAK-3 HPV-epidermodysplasia PID and how these findings have contributed to many
verruciformis different aspects of immunology.
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- Differentiation of Neutrophils
scription 1; IRAK4, interleukin-1 receptor associated kinase The analysis of developmental blocks of T and B lympho-
4; SAP, SLAM-associated protein; XIAP, X-linked inhibitor of cyte subsets has released a flood of useful information on
apoptosis; UNC93B, polytopic endoplasmic reticulum CERI- the role of molecules such as the common gc cytokine
resident membrane protein; TLR-3, Toll-like receptor 3; receptor or the Bruton tyrosine kinase in T and NK cell
EVER 1,2, Epidermodysplasia verruciformis 1, 2 genes; gc, and B cell development, respectively (Table 1 and Fig-
common cytokine g chain; JAK-3, Janus associated kinase.
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
whereas the same recessive mutations of RAG1 can, in of neutrophils. Genetic heterogeneity has been long
a given family, be associated with either a SCID phenotype known, on the basis of inheritance patterns and pheno-
(i.e., the absence of T and B lymphocytes) or OM. This find- typic differences in granulopoiesis (Skokowa et al.,
ing suggests the involvement of one or more modifier 2006). Today, nine distinct genetic disorders leading to
genes (Cornéo et al., 2001). SNC have been identified and many others are yet to be
This is not an unusual observation for PIDs, because characterized. It seems that a key common element in
many of these conditions (and especially those with auto- many of the SCN phenotypes is the defective survival of
somal-dominant [AD] inheritance, such as common vari- neutrophil precursors (Kollner et al., 2006). Horwitz et al.
able immunodeficiency, or autoimmune lymphoprolifera- (2007) have shown that mutations in ELA2, the GFI1 tran-
tive syndrome [ALPS]) exhibit variable expressivity. scription repressor, and the AP3BI gene (encoding a
Epigenetic factors and key modifier genes can account component of the AP3 adaptor) all result in mislocalization
for this variability, suggesting that there may be a contin- of elastase, which accumulates at the plasma membrane.
uum between ‘‘simple’’ and more complex genetically It is plausible, for example, that membrane elastase
determined diseases (Antonarakis and Beckmann, cleaves receptors that are involved in cell survival (or dif-
2006). Lastly, occurrence of somatic mutations in a germ- ferentiation) and thus contributes to premature apoptosis
line-mutated gene can attenuate a disease phenotype— of neutrophil precursors (Horwitz et al., 2007). Additional
at least in the T cell subset, as described for Rag-1 evidence for a role of premature apoptosis in the genesis
deficiency (Wada et al., 2005) and many other T cell immu- of SCN was recently provided by a report of recessive
nodeficiencies. These observations have two implications. mutations in the HAX1 gene in Kostmann patients (Klein
First, somatic mutations occur more frequently than might et al., 2007). HAX-1 is a mitochondrial protein with bcl2
be expected and, second, they can be detected in T lym- homology domains (BH1 and BH2) domains involved in
phocyte PIDs—probably because T cell progenitors are the maintenance of membrane potential. Its defective ex-
deemed to have a very high cell-division capacity whereas pression results in increased apoptosis of neutrophils and
mature T cells are long-lived (Fischer et al., 2005). Sec- their precursors. It is worth noting that despite ubiquitous
ondary somatic mutations of a second gene can alter expression of HAX-1, the consequences of defects are
the course of a PID, as observed in the severe congenital limited to neutrophils—evidencing nonredundant, antia-
neutropenia (SCN) caused by elastase deficiency (Gits poptotic HAX-1 activity in the latter. Together, these re-
et al., 2006). Somatic mutations of the G-CSF receptor sults provide strong mechanistic support for the efficacy
have been reported and provide a selective growth ad- of granulocyte-colony stimulating factor (G-CSF) adminis-
vantage, favoring the occurrence of myeloid leukemia tration in restoring granulocyte survival in most SCN
(Gits et al., 2006). Finally, somatic mutations can create patients, because this prevents granulocyte precursor
a PID, provided that it occurs early in ontogenesis and cell death (Maianski et al., 2002).

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Immunity

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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.

Recombination of Antigen-Receptor Genes increased sensitivity to ionizing radiation. V(D)J recombi-


Twenty years ago, analysis of the scid mouse model nation capacity and in vitro NHEJ activity were found to
turned out to be instrumental in understanding that the be defective. The gene encoding Cernunnos (NHEJ1)
combinatorial rearrangements of the T cell receptor and was cloned via a complementation strategy as well as
B cell receptor genes used the nonhomologous double- through the ability of its product to interact with XRCC4,
strand end-joining repair pathway (NHEJ). The NHEJ ap- a component of the NHEJ ligation step (Ahnesorg et al.,
paratus fixes DNA breaks induced by the RAG-1:RAG-2 2006). Although Cernunnos shares homology with
complex at recombination signal sequences during V(D)J XRCC4 and is part of a complex with XRCC4 and DNA li-
recombination (Bassing and Alt, 2004). Scid mice were gase 4, further studies will be required to define its precise
shown to carry mutations in the catalytic subunit of DNA- molecular function. Strikingly, patients with Cernunnos
dependent protein kinase (DNA PKcs), a key component and DNA ligase 4 deficiencies exhibit developmental
of the NHEJ apparatus. Human SCID diseases have since defects and microcephaly, which is reminiscent of similar
contributed to the identification of new components of the findings observed in mice defective in DNA ligase 4 and
NHEJ pathway. A condition phenotypically similar to that XRCC4. Premature apoptosis of postmitotic neurons has
caused by DNA-PKcs deficiency in the mouse prompted been observed in these murine models, suggesting that
cloning of the gene encoding the Artemis protein (De Villar- the NHEJ pathway is involved in repairing reactive oxygen
tay et al., 2003). On phosphorylation by DNA PK, Artemis species-induced DNA lesions (Gao et al., 1998). Descrip-
cleaves hairpins bridging both strands at coding ends. tion of the DNA repair factors involved in T and B cell devel-
Whereas the role of DNA ligase 4 in the final ligation step opment is probably not yet complete, given that some
in NHEJ was confirmed by description of a T+B cell immu- patients with a fairly similar phenotype do not display
nodeficiency (albeit of variable severity) in patients with any gene defects. It is striking to note the nonredundancy
DNA ligase 4 deficiency (O’Driscoll et al., 2001), another of the mutations affecting the few genes governing the
component of the NHEJ repair pathway (Cernunnos or determination of adaptive immunity. When mutated,
XLF) has been recently discovered (Buck et al., 2006). It the key lymphoid-specific genes RAG1 and RAG2 and
was found that cells from a group of patients presenting the gene AICDA (encoding AID) led to SCID and hyper-
severe, progressive T+B cell lymphopenia exhibited greatly IgM syndrome (defective Ig class switch recombination),

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Immunity

Review

respectively, whereas deficiencies of elements involved in tional assay (such as Ca2+ influx or anything else enabling
downstream DNA repair (i.e., NHEJ, see above) or down- the unequivocal identification of functionally heterozygous
stream of AID (e.g., uracil N-glycosylase, UNG) cause sim- carriers) is likely to be of tremendous help in uncovering
ilar diseases (De Villartay et al., 2003; Durandy et al., 2007). mutated gene(s) involved in signal transduction pathways
Another implication is that developmental defects of the (Fischer and Notarangelo, 2003).
immune system can result from the mutation of genes
with a ‘‘pleiotropic function in ontogeny’’ affecting devel- Cytokine Signaling and Immunodeficiencies
opment of multiple organs such as the brain or bones. Analysis of primary immunodeficiencies (specifically SCID
characterized by defective differentiation of T and NK lym-
Lymphocyte Activation phocytes) has been instructive in understanding the
This assumption has been nicely confirmed by the recent respective functions of the many gc-dependent cytokine
discovery of a key element governing Ca2+ influx in lym- receptors and the gc-associated Janus associated kinase
phocytes and other cells—the Orai-1 (CRACM1) molecule 3 (JAK3) kinase (Leonard, 2001). Similarly, deficiencies in
(Feske et al., 2006; Vig et al., 2006b). More than 10 years STAT1 (‘‘signal transducer and transcription activator’’),
ago, separate reports described a severe, recessive, which is activated when type I and II interferons bind to
autosomal T and B cell (‘‘combined’’) primary immunode- their receptors, shed light on their respective functions in
ficiency characterized by defective TCR- and BCR-medi- controlling viral and mycobacterial infections in humans
ated cell activation, a calcium (Ca2+) influx deficiency in (Casanova and Abel, 2002). Recent findings have broad-
lymphocytes, and defective NF-AT nuclear factor of acti- ened the scope of investigation into cytokine receptor
vated T cells (NFAT) translocation to the nucleus (Feske signaling in PID, via the description of STAT5b and Tyk-
et al., 1996, 2001; Le Deist et al., 1995). These children 2 deficiencies (Bernasconi et al., 2006; Minegishi et al.,
were also found to suffer from nonprogressive myopathy 2006). Despite considerable homology with STAT5a, the
and anhydrotic ectodermic dysplasia (Feske et al., phenotype observed in three immunodeficient patients
2006). A defect in Ca2+ release-activated Ca2+ (ICRAC) with a STAT5b deficiency clearly established that (at least
channel activity was postulated on the grounds that for some functions) these proteins are nonredundant. In
Ca2+ release from the endoplasmic reticulum was main- one case, the immunological phenotype (associated with
tained, whereas direct patch-clamp measurements of short stature because of growth hormone unresponsive-
ICRAC in patient lymphocytes and fibroblasts were flat ness) was partially characterized (Bernasconi et al.,
(Feske et al., 2001; Partiseti et al., 1994). Despite the rarity 2006). The patient had a nonsense homozygous mutation
of this condition, its description confirmed the importance and no detectable Stat5b protein, and the immunological
of Ca2+ influx from the extracellular milieu into the cytosol defects consisted of mild T cell lymphopenia, profound gd
in the process of lymphocyte activation (Berridge et al., T cell and NK cell lymphopenia, and impaired in vitro T cell
2003). Feske et al. (2006) performed a remarkable tour proliferation in response to mitogens and antigens. B cells
de force by using a refined genetic linkage analysis in an were not affected. There might also have been partial T
affected family with two patients and heterozygous car- regulatory cell deficiency. Further studies will be required
riers (the latters’ lymphocytes had a mild Ca2+ flux defect). to specify which Stat5b-dependent, cytokine-triggered
This approach was combined with a genome-wide mRNA pathways are impaired in T and NK cell development
interference screen in Drosophila (with a hypothesis of and T cell activation. Minegishi et al. (2006) have recently
phylogenetic conservation), which consisted in inhibiting described a single case of Tyk-2 deficiency and its many
store-operated Ca2+ influx and NF-AT nuclear import. It consequences in a patient with autosomal-recessive
led to the identification of genes with human orthologs hyper-IgE syndrome (HIES). Tyk-2 is a kinase from the
(encoding Orai-1 to Orai-3). It turned out that the locus JAK family that is associated with a number of cytokine
encoding Orai-1 is located in the region circumscribed receptors, including IL-12, IL-23, IFN-a and -b, IL-10,
by genetic analysis of the affected family and was found and the IL-6 family (Watford and O’Shea, 2006). The ho-
to be mutated in the patients. Furthermore, introduction mozygous mutation of TYK2 found in this patient led to
of a normal copy of Orai-1 into patient-derived cells premature termination of translation and the absence of
restored Ca2+ influx (Feske et al., 2006). It is noteworthy detectable protein. As expected, the above-mentioned
that by using a similar Drosophila screen, Kinet’s group cytokine-induced signaling pathways were found to be
was also able to identify this gene (Vig et al., 2006b). impaired in vitro, resulting in functional consequences
Orai-1 is a plasma membrane protein with four transmem- that were more pronounced than in Tyk2 / mice. The
brane domains. Further work has provided several lines of recurrent viral and persistent mycobacterial infections
evidence that indicate that Orai-1 is a pore subunit of the suffered by the patient could well be the respective conse-
CRAC channel, which is activated by the STIM-1 ER Ca2+ quences of defective IFN-a- and IL-12-mediated cell acti-
sensor (Prakriya et al., 2006; Vig et al., 2006a; Yeromin vation. Of note was the recurrence of skin abscesses and
et al., 2006). Here again, the question of whether further lung infections which, set against a background of defec-
analysis of immunodeficiencies characterized by ill-de- tive Il-23 and IL-6 signaling, strongly suggests a deficiency
fined, defective T cell activation might help identify more in the effector Th17 subset. IL-23 is involved in Th17 main-
building blocks in the lymphocyte Ca2+ entry pathway is tenance, whereas IL-6 contributes to Th17 development
still open. In very rare cases, the ability to set up a func- (Steinman, 2007). Given that Th17 cells have been described

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as recruiting phagocytic cells to infection sites in the skin Both models correspond fairly well to human OS (de-
and lungs, the predisposition to infections observed in this spite a few differences) and can thus be considered as
patient fits the hypothesis proposed by Watford and useful tools for delineating this unique immunopathologi-
O’Shea (2006). Unfortunately, data on the corresponding cal phenomenon. Four pieces of information have been
cytokine profile (IL-17, etc.) were lacking. If the hypothesis gathered: (1) the phenotype can develop in a pathogen-
is correct, this case would represent the first observation free setting; (2) reduced Aire expression was found in
of a Th17 cell deficiency and, hence, indirect confirmation the thymus (Marrella et al., 2007); (3) there is a smaller
of their functional existence in humans. than usual pool of Fox P3+ regulatory T cells (Treg)
Autosomal-dominant HIES has recently been shown to (Marrella et al., 2007); and (4) in the second murine model,
be related to dominant-negative mutations of signal trans- homeostatic expansion of T cells was evidenced by trans-
ducer and transcription activator 3 (STAT3) (Holland et al., ferring wild-type T cells into mutant mice, leading to T cell
2007; Minegishi et al., 2007). It would thus be worth test- activation and a Th2 phenotype (Khiong et al., 2007).
ing the Th17 pathway in these patients, given the pheno- These data bear some resemblance with the monoclonal
typic similarity with Tyk-2 deficiency in terms of the occur- Th2 cell expansion seen after transfer into lymphopenic
rence of bacterial and fungal lung and skin infections mice (Curotto de Lafaille et al., 2001) and oligoclonal
(Grimbacher et al., 2005). The recent characterization of expansion of T cells with a Th2 phenotype after transfer
human Th17 cells expressing CCR4 and CCR6 chemo- of a limited number of T cells again into lymphopenic
kine receptors (together with ROR gT, the transcription mice (Milner et al., 2007). In the latter model, cell expan-
factor inducing Th17 differentiation; Acosta-Rodriguez sion and disease were prevented when a higher number
et al., 2007) could help test this hypothesis. Chronic of T cells or regulatory T cells (Treg cells) were transferred.
mucocutaneous candidiasis (CMCC)—another poorly un- Taken together, these data converge with the concept of
derstood condition characterized by recurrent skin and homeostatic expansion of self-reactive T cells in OS that
mucosal infection by Candida species (Lilic, 2002)—might can be facilitated both by defective elimination of self-re-
be related to a deficiency in Th17 effector cell induction by active T cells in the thymus (because of Aire expression
Candida-associated glycan via the dectin-1 receptor and deficiency) and by a relative deficiency in regulatory T cells
its signaling pathway, which includes the tyrosine kinase (to be confirmed in OS patients). The possible interplay
syk and the adaptator CARD9 (Leibundgut-Landmann between nonredundant regulatory pathways (Aschen-
et al., 2007). brenner et al., 2007) further emphasizes the possible
occurrence of T cell-mediated autoimmunity in settings
Self-Reactivity and PID characterized by persistent or even transient reductions
Omenn syndrome has attracted much interest because of in thymopoiesis.
its unique phenotype. It is characterized by an oligoclonal Major advances have also occurred in the study of the
expansion of T cells with a Th2 phenotype. These T cells predisposition to autoimmunity observed in Wiskott-Aldrich
are found mostly in the skin and the gut of affected pa- syndrome (WAS). WAS is the consequence of a deficiency
tients. Although OS can be observed in patients carrying in the WAS protein (WASP) involved in actin polymerization
hypomorphic mutations of genes that lead to impaired in hematopoietic cells. Autoimmunity and colitis are fre-
T and B cell differentiation, it is mainly associated with hy- quent in severe cases of WAS (Ochs and Thrasher, 2006).
pomorphic mutations of the RAG1 or RAG2 genes (Nota- Three recent reports have pinpointed a defect in the
rangelo et al., 2006). Omenn syndrome is characterized by FoxP3+ Treg subset as the likely mechanism underlying
early-onset skin and gut infiltration by oligoclonal T cells autoimmunity. Indeed, it has been shown that in a WAS pa-
with a TH2 phenotype. It has been suggested that these tient with a WASP gene somatic mutant leading to rever-
symptoms result from the uncontrolled expansion of sion, there is a selective advantage for revertants within
self-reactive, oligoclonal T cells—possibly as a conse- the Treg subset, combined with the remission of autoim-
quence of defective negative T cell selection (Fischer, mune hemolytic anemia (Humblet-Baron et al., 2007).
2004). Indeed, OS thymi show markedly reduced expres- With Was / mice, impaired expansion and homing of
sion of Aire and defective expression of ‘‘ectopic tissue- FoxP3 Treg have been demonstrated after cell transfer
specific antigens’’ (TSA) in thymic epithelial cells (TECs) (Humblet-Baron et al., 2007; Marangoni et al., 2007),
(Cavadini et al., 2005). Defective Aire expression was together with an inability to control colitis (Maillard et al.,
thought to be the consequence of defective thymic epithe- 2007). In two reports (Maillard et al., 2007; Marangoni
lial cell differentiation in the context of a paucity of T cell et al., 2007), an in vitro functional deficiency in the suppres-
precursors, thus resulting in a lack of lymphocyte-epithe- sive activity of Treg cells has been described, although this
lial cell crosstalk. Further insight into the pathophysiology was not confirmed by a third report (Humblet-Baron et al.,
of OS was recently provided by the description of two 2007). Despite these discrepancies, these reports provide
murine models of OS; one was deliberately derived by strong evidence for the deregulation of Treg biology in
the creation of a gene-targeted mouse strain expressing WAS as the mechanism underlying autoimmunity and coli-
the R229Q Rag1 mutation found in patients with OS tis. It remains for us to understand how the defect in the
(Marrella et al., 2007), whereas the second results from WASP relates to the in vivo (and possibly in vitro) functional
a natural hypomorphic mutation in Rag2 (R972Q) (Khiong Treg deficiency, given that it is not a direct consequence of
et al., 2007). defective actin filament formation because wild-type Treg

840 Immunity 27, December 2007 ª2007 Elsevier Inc.


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cells do not form this type of filament very well either (Mail- Table 3. Susceptibility to Autoimmunity
lard et al., 2007; Marangoni et al., 2007).
Disease or
Multiple checkpoints controlling self-reactivity of T and
Syndrome Gene Product(s) Mechanism
B cells as well have been described by Goodnow (2007)
ALPS FAS, FAS L apoptosis of
(Table 3). Analysis of PID can also help deciphering their
self-reactive lymphocytes
existence and importance. A recent study by Herve
in the periphery
et al. (2007) has shown that, in patients with CD40L defi-
ciency, there is overexpression of autoreactive antibodies APECED AIRE negative selection
of thymocytes
in naive but not newly emigrant B cells. This result
stresses the existence of a peripheral B cell tolerance IPEX FOXP3, CD25 development and function
step that is dependent on CD40L-CD40 interaction. A of regulatory T cells
similar observation has been made by analyzing B cells Three major syndromes—ALPS (autoimmune lymphoprolifer-
from a patient with major histocompatibility complex ative syndrome), APECED, and IPEX with a mendelian genetic
class II molecule deficiency. Therefore, T-B cell interac- inheritance—result in a predisposition to autoimmunity.
tion is likely to be involved in the control of self-reactive Mechanisms are indicated. Omenn syndrome, a condition
naive B cells, by a mechanism that remains to be better caused by hypomorphic mutation of genes controlling T+B
determined. 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
NKT Lymphocytes
syndrome is an X-linked PID that is frequently associated with
Major advances have recently been made in characteriz- severe autoimmunity. Defective development and survival
ing the invariant NKT cell subset that recognizes endoge- functions of FoxP3+ regulatory T cells.
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 et al., 2005), suggesting a role for one or more SLAM fam-
that the subset plays a role in the control of autoimmunity ily receptor(s) in transduction of the positive signals
and in rapid responses to bacterial and (possibly) viral required for NKT cell differentiation. As such, this finding
infections. It is noteworthy that there is a striking paucity alone remained anecdotal with respect to a hypothetical
of NKT cells in humans, compared with rodents (Bendelac link between NKT cell deficiency and defective control of
et al., 2007). It is thus questionable whether NKT cells have EBV infection. However, the hypothesis has been consid-
been selected as important effectors of immunity in hu- erably strengthened by the recent description of XLP2,
mans. Genetic defects leading to NKT cell deficiencies a condition characterized by a very similar clinical pheno-
might thus provide clues concerning the importance of type in terms of the almost complete absence of circulat-
these cells and the circumstances in which they intervene. ing NKT cells but in which 2B4-mediated cell cytotoxicity
Strikingly, two inherited conditions associated with severe is undisturbed (Rigaud et al., 2006). XLP2 is the conse-
EBV infection are characterized by a NKT cell deficiency: quence of a deficiency in XIAP, a molecule that presum-
(1) X-linked proliferative syndrome (XLP) caused by muta- ably acts in vivo as a major inhibitor of cell apoptosis. It
tion of the SH2D1A gene and (2) XLP2 syndrome caused is not yet known how XIAP deficiency leads to an appar-
by mutations of the XIAP-encoding gene (Ma et al., ently isolated NKT cell immune deficiency. How NKT cells
2007; Rigaud et al., 2006). In both conditions, patients might be involved in immunity to EBV and which lipid(s) is
newly infected by EBV develop either an inappropriate (are) recognized are stimulating, open questions. An addi-
CD8+ T cell and macrophage response (called hemopha- tional report of a molecularly uncharacterized NKT cell de-
gocytic lymphohistiocytic syndrome, HLH), lymphomas, ficiency in a patient with post-vaccination-disseminated
and/or hypogammaglobulinemia (Ma et al., 2007). In varicella infection further strengthens the hypothesis of
XLP, the defective gene product (SAP) is an adaptor a role for NKT cells in the control of herpes viruses (Levy
from the SLAM family of receptors, which includes (among et al., 2003). In addition, the fact that HSV and Kaposi
others) SLAM, 2B4, and NTBA (Ma et al., 2007). Multiple sarcoma herpes virus induce downregulation of CD1d
signaling pathways are triggered through receptor-ligand expression might represent a viral protective countermea-
interaction in immune system effector cells, leading to sure against a NKT cell response (Sanchez et al., 2005). It
(among other effector functions) increased T cell and NK is thus worth paying more attention to NKT cells in the
cell cytotoxicity. It has been found that NK cell-mediated analysis of currently ill-defined immune deficiencies asso-
cytotoxicity is defective (and even inhibited) after interac- ciated with viral infections.
tion between 2B4 and its ligand (CD48) in the absence of
SAP (Ma et al., 2007). However, XLP patients also display NK Cells
a complete lack of circulating NKT cells (Nichols et al., Selective NK cell deficiency has been recognized as a sep-
2005; Pasquier et al., 2005), mirroring findings in SAP-de- arate entity in primary immunodeficiency and has an entry
ficient mice in which NKT cells are absent in all organs in the Online Mendelian Inheritance in Man database
(Nichols et al., 2005; Pasquier et al., 2005). In these (609981) (Orange, 2006). This is based on several reports
mice, NKT cell deficiency is caused by an intrathymic describing a profound deficiency in circulating NK lym-
developmental block (Pasquier et al., 2005; Nichols phocytes in conjunction with recurrent (mostly viral)

Immunity 27, December 2007 ª2007 Elsevier Inc. 841


Immunity

Review

infections (Bernard et al., 2004; Biron et al., 1989; Eiden- nity to pathogens in general and, obviously, NKT and
schenk et al., 2006a, 2006b; Etzioni et al., 2005; Notaran- cytolytic T cells in particular.
gelo and Mazzolari, 2006). It is nevertheless noteworthy
that a molecular defect has not yet been reported in any New Approaches to Treating PIDs
of these cases. In addition, a NK cell cytotoxicity function Genetic analysis of PIDs is not only important for elucidat-
deficiency has been reported as a possible causative ing important pathways in the immune system, it also has
mechanism of HLH (i.e., uncontrolled CD8+ T cell and medical impact by prompting the design of new diagnos-
macrophage activation), as observed in patients with a tic tools and opening up new fields of therapeutic
deficiency in either perforin, Rab27a, Lyst, Munc13-4, or research.
Syntaxin 11—all of which are involved in perforin-depen- In some instances, gene product supplementation
dent cytolytic activity (as discussed in Orange, 2006). Sim- might be envisaged, as is the case with adenosine deam-
ilarly, a NK cell activity deficiency was found in a murine inase deficiency that results in a SCID phenotype. Under-
strain (Jinx) into which a Munc13-4 (Unc13d) gene muta- standing the pathophysiology of a PID can suggest ways
tion had been induced by mutagenesis (Crozat et al., of compensating for a missing key end product. This is
2007). The Jinx mice develop HLH when infected with best exemplified by g interferon supplementation in pa-
the lymphocytic choriomeningitis virus (Crozat et al., tients carrying IL-12 receptor mutations (Casanova and
2007). Collectively, these data suggest (1) that NK cells Abel, 2002). Direct genetic intervention by adding a normal
are involved in immunity to viruses (notably those of the copy of the mutated gene to affected cell lineages is an
herpes groups) in humans and (2) that a selective impair- obvious approach that has proved to be successful in
ment in NK cytolysis favors an immunopathological reac- SCID conditions (Aiuti et al., 2002; Cavazzana-Calvo
tion likely to be associated with a persistent, infectious et al., 2000), i.e., in settings where a selective survival or
trigger. These observations fit very well with the many re- growth advantage is conferred by transgene expression,
ports describing the role of NK cells in immune responses as is the case with the various mutations leading to
to pathogens in general and in early steps of viral infection a SCID phenotype or to the Wiskott-Aldrich syndrome.
in particular (reviewed in Lodoen and Lanier, 2006). The type of mutation in a given PID may also prompt
Nevertheless, careful assessment of the reported data new strategies. For example, mutations creating glycosyl-
on NK cell immunodeficiencies prompts one to challenge ation sites can cause protein unfolding and degradation.
these views to some extent, especially given that the NK Chemicals able to modify glycosylation may be able to
cell deficiency does not always appear to be isolated. complement these defects by preventing protein degra-
Indeed, in one case, IL-2- and IL-15-related survival of dation, as shown in vitro in several models (Vogt et al.,
T lymphocytes is also impaired (Eidenschenk et al., 2007). Clinical application of this approach might thus be
2006b), whereas in another, a NKT cell deficiency was envisaged, provided that drugs can be administered
also found (Eidenschenk et al., 2006a) Similarly, the NK with sufficient bioavailability and lack of toxicity. Non-
cell cytotoxicity deficiency found in patients with geneti- sense mutations (which account for a relatively high frac-
cally determined HLH is not isolated, as indicated by the tion of mutations) lead to premature translation termina-
fact that granule-dependent T cell cytotoxicity is also tion, mRNA decay, and thus an absence of the protein.
impaired (Fischer et al., 2007). It is noteworthy that in a Both gentamycin and PTC 124 (a recently developed,
murine model of HLH (perforin-deficient mice infected nontoxic drug) prevent termination of translation at a pre-
with LCMV), elimination of CD8+ T cells (and not NK cells) mature stop codon and offer a reasonable hope of clinical
prevented the occurrence of the disease. These data do application, as suggested by experimental data from mice
not rule out a role for NK cells but are not compatible with muscular dystrophy or cystic fibrosis (Lai et al., 2004;
with the concept of selective NK cell deficiency. In hu- Welch et al., 2007). We are likely to see more and more
mans, there is one setting that corresponds to what mutation-related strategies for the treatment of genetic
appears to be a selective NK cell deficiency; it consists diseases in general, with a benefit for PIDs. In any case,
of NK SCID (gc and JAK 3 deficiencies) after nonmyeloa- these new hopes further strengthen the need to precisely
blative allogeneic hematopoietic stem cell transplantation define genes, their mutations, and functional conse-
(HSCT) or gene therapy (for gc deficiency only). In both quences in every single form of PID.
instances, it is very frequently observed that long-term
surviving patients (for up to 30 years post-HSCT) have Conclusions
very few (if any) NK cells in their blood—in contrast to ro- PID are both potentially devastating diseases and unique
bust T cell immunity (Buckley, 2004; Fischer et al., 2005). models for identifying key molecular components of the
These patients do not suffer from serious viral infections, immune system and studying the relevance of immuno-
suggesting that there is some form of adaptation or, in logical findings in the ‘‘real’’ world of the complex natural
other words, that NK cell activity might be redundant. It environment. Despite considerable recent progress, there
is certainly premature to draw firm conclusions but these is still a lot to do! Implementation of new genetic technol-
contradictory findings should lead to a careful (re)assess- ogies is likely to be of considerable assistance in finding
ment of NK cell-associated immune functions in man. Fur- mutations associated with rare but nevertheless important
ther observations of human NK cell deficiency should lead phenotypes. Refinement of linkage analyses via single
to a thorough investigation of the other effectors of immu- nucleotide polymorphic (SNP) markers associated with

842 Immunity 27, December 2007 ª2007 Elsevier Inc.


Immunity

Review

the phenotype detection of heterozygotes and RNAi- Bernasconi, A., Marino, R., Ribas, A., Rossi, J., Ciaccio, M., Oleastro,
M., Ornani, A., Paz, R., Rivarola, M.A., Zelazko, M., and Belgorosky, A.
based screening in relevant models are both powerful (2006). Characterization of immunodeficiency in a patient with growth
tools. In addition, complementation technology has be- hormone insensitivity secondary to a novel STAT5b gene mutation.
come more feasible and a number of efficient transfer Pediatrics 118, e1584–e1592.
systems are available. The use of high-resolution compar- Berridge, M.J., Bootman, M.D., and Roderick, H.L. (2003). Calcium
ative genomics hybridization (CGH) arrays should help us signalling: dynamics, homeostasis and remodelling. Nat. Rev. Mol.
Cell Biol. 4, 517–529.
detect microdeletions potentially associated with the
many (albeit very rare) complex syndromes that feature Bidere, N., Su, H.C., and Lenardo, M.J. (2006). Genetic disorders of
an immunodeficiency. Variable disease expression (fre- programmed cell death in the immune system. Annu. Rev. Immunol.
24, 321–352.
quently not associated with the type of mutation) is a com-
mon observation in the field of PID. For the most frequent Biron, C.A., Byron, K.S., and Sullivan, J.L. (1989). Severe herpesvirus
infections in an adolescent without natural killer cells. N. Engl. J.
PIDs such as X-linked agammaglobulinemia (XLA), ataxia
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telangiectasia, or CGD, this should certainly prompt re-
searchers to initiate the search for modifier genes, the Buck, D., Malivert, L., de Chasseval, R., Barraud, A., Fondaneche,
M.C., Sanal, O., Plebani, A., Stephan, J.L., Hufnagel, M., le Deist, F.,
characterization of which will potentially be as rewarding et al. (2006). Cernunnos, a novel nonhomologous end-joining factor,
as has been recent gene hunting work. The HapMap pro- is mutated in human immunodeficiency with microcephaly. Cell 124,
ject (The International HapMap Consortium, 2006) now 287–299.

provides us with a tool for performing this type of analysis. Buckley, R.H. (2004). Molecular defects in human severe combined
Collectively, these efforts should provide further insight immunodeficiency and approaches to immune reconstitution. Annu.
Rev. Immunol. 22, 625–655.
into understanding many relevant pathways at work in im-
mune cells, possibly contributing to an integrative view of Casanova, J.L., and Abel, L. (2002). Genetic dissection of immunity to
immune responses. mycobacteria: the human model. Annu. Rev. Immunol. 20, 581–620.

Casrouge, A., Zhang, S.Y., Eidenschenk, C., Jouanguy, E., Puel, A.,
Yang, K., Alcais, A., Picard, C., Mahfoufi, N., Nicolas, N., et al.
ACKNOWLEDGMENTS (2006). Herpes simplex virus encephalitis in human UNC-93B defi-
ciency. Science 314, 308–312.
A.F. wishes to thanks M. Cavazzana-Calvo, G. de Saint Basile, J.P. de
Cavadini, P., Vermi, W., Facchetti, F., Fontana, S., Nagafuchi, S.,
Villartay, A. Durandy, S. Latour, P. Revy, F. Rieux-Laucat, and other
Mazzolari, E., Sediva, A., Marrella, V., Villa, A., Fischer, A., et al.
colleagues in the laboratory who have generated some of the data
(2005). AIRE deficiency in thymus of 2 patients with Omenn syndrome.
discussed in the review and with whom continually ongoing fruitful J. Clin. Invest. 115, 728–732.
discussions are the basis of this review. Thanks to M. Sifouane for
her excellent secretarial assistance. Cavazzana-Calvo, M., Hacein-Bey, S., De Saint Basile, G., Gross, F.,
Yvon, E., Nusbaum, P., Selz, F., Hue, C., Certain, S., Casanova, J.L.,
et al. (2000). Gene therapy of human severe combined immunodefi-
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