Immunity

Review
Human Primary Immunodeficiency Diseases
Alain Fischer1,2,3,*
U768, Paris F-75015, France ´ ˆ ` Rene Descartes-Paris 5, Paris F-75006, France, and Hopital Necker-Enfants Malades, 149 rue de Sevres, Paris F-75015, France 3Unite d’Immunologie et Hematologie Pediatrique, Assistance Publique, Paris F-75015, France ´ ´ ´ *Correspondence: fischer@necker.fr DOI 10.1016/j.immuni.2007.11.012
2Universite ´ 1Inserm,

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 immunity 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 underestimated 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 In humans, more than 150 Mendelian conditions involving an impaired immune response have been described. Thanks often to fruitful international collaborations, analysis 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 regulatory and effector functions. Most of the described mutations 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 imply 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 immunodeficiency diseases offer an interesting spectrum of vulnerabilities to microorganisms and thus enable the in vivo assessment of the respective roles of immune response effectors during an infectious challenge. The consequences of mutation can vary from a very strong predisposition to infection by a broad range of microorganisms (from strict pathogens to opportunistic agents, as observed 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.,

2007), and a unique phenotype with aberrant lymphocyte 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 nonmutated individuals (Table 2). Another striking and intriguing 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 membrane protein (UNC93B) or TLR3 deficiencies, respectively, 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 example) 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, vulnerability 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
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Table 1. Genes and Primary Immunodeficiencies Disease Natural Mutant scid SCID SCID T cell deficiency Agammaglobulinemia XLP AT NBS DC T cell deficiency (HLA II expression) WAS IPEX APECED motheaten FHLH CGD scurfy Protein DNA-PKcs Artemis Cernunnos, XLF Orai-1, CRACMI Btk SAP ATM Nibrin (NBS1) Dyskerin RFXAP, ANK, RFX5, CIITA WASP FOXP3 AIRE SHP-1 Munc 13-4 gp91phox, p22phox, p47phox, p67phox Function VDJ (NHEJ) VDJ (NHEJ) VDJ (NHEJ) Ca channel cell activation coactivation (SLAM family), NKT DNA lesion sensing DNA repair telomere maintenance HLA class II transcription cell cytoskeleton, migration Treg function negative selection of T cells phosphatase, regulation exocytosis of lytic granules NADPH oxidase Genes Discovered by Studying Primary Immunodeficiencies

Previously Known Genes but Function Understood by the Study of Primary Immunodeficiency Diseases SCID SCN LAD HIGM HIGM lpr, gld Griscelli FHLH XLP2 ashen gc, JAK3 HAX-1 b2integrin CD40L AID fas, fasL Rab27a syntaxin11 XIAP T (NK) cell development prevention of apoptosis (neut.) adhesion activation of Ig CSR Ig CSR and SHM apoptosis exocytosis of lytic granules cytotoxicity 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, dyskeratosis congenita; WAS, Wiskott-Aldrich syndrome; WASP, Wiskott-Aldrich syndrome protein; IPEX, immunoproliferative enteropathy 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 disease 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) infections early in life in such patients triggers a massive expansion of oligoclonal non-Vg9Vd2 gd T cells (presumably by
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direct activation) (de Villartay et al., 2005; Ehl et al., 2005) in association with autoimmune manifestations. Rag-1 deficiency best illustrates the phenotypic variability associated 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),

Immunity

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Table 2. Gene Mutations and Susceptibility to Pathogens CD40L, CD40 Pneumocystis jiroveci, Toxoplasma, Cryptosporidium Mycobacteria encapsulated pathogens EBV HSV encephalitis Neisseria HPV-epidermodysplasia verruciformis

IL12p40, IL12Rb, IFNgR, STAT1 IRAK4 SAP, XIAP UNC93B, TLR-3 Complement C5-C9 EVER 1,2, gc, JAK-3

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 lymphocytes with a CD4À CD8À phenotype (Holzelova et al., 2004). The latter observation stresses the possible role of acquired mutations breaking checkpoints of self-reactivity 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.

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 transcription 1; IRAK4, interleukin-1 receptor associated kinase 4; SAP, SLAM-associated protein; XIAP, X-linked inhibitor of apoptosis; UNC93B, polytopic endoplasmic reticulum CERIresident 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 finding suggests the involvement of one or more modifier ´ genes (Corneo et al., 2001). This is not an unusual observation for PIDs, because many of these conditions (and especially those with autosomal-dominant [AD] inheritance, such as common variable immunodeficiency, or autoimmune lymphoproliferative syndrome [ALPS]) exhibit variable expressivity. Epigenetic factors and key modifier genes can account for this variability, suggesting that there may be a continuum between ‘‘simple’’ and more complex genetically determined diseases (Antonarakis and Beckmann, 2006). Lastly, occurrence of somatic mutations in a germline-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 immunodeficiencies. These observations have two implications. First, somatic mutations occur more frequently than might be expected and, second, they can be detected in T lymphocyte 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). Secondary 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 advantage, 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

Differentiation of Neutrophils The analysis of developmental blocks of T and B lymphocyte 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 Figure 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 phenotypic 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 transcription 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 differentiation) 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 expression 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, antiapoptotic HAX-1 activity in the latter. Together, these results provide strong mechanistic support for the efficacy of granulocyte-colony stimulating factor (G-CSF) administration in restoring granulocyte survival in most SCN patients, because this prevents granulocyte precursor cell death (Maianski et al., 2002).
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Figure 1. T Cell Development and Primary Immunodeficiencies
Schematic representation of T cell development with an indication of the eight known effector T cell subsets: TCRgd T cells (gd), cytotoxic 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 produced by these subsets are shown. Vertical red bars indicate a complete block in cell development or function observed in PID. Dotted vertical bars indicate partial block. Abbreviations: SCID, severe combined immunodeficiency; ZAP-70, zeta-associated protein 70 deficiency; TAP, TAP-1 and TAP-2 deficiencies; HLA-class II, T cell immunodeficiency with defective HLA class II gene transcription; Orai-1, T cell immunodeficiency with defective Ca2+ channels; HLH, hemophagocytic lymphohistiocytosis; Tyk2, autosomal recessive hyper-IgE syndrome with Tyk2 deficiency; STAT 3, dominant-negative mutations found in the hyper-IgE syndrome; CD40L, hyperIgM syndrome with CD40L deficiency; XLP, X-linked proliferative syndrome with either SAP or XIAP deficiency; IPEX, X-linked immunoproliferative enteropathy (FoxP3 deficiency); HSCs, hematopoietic stem cells; CLPs, common lymphoid progenitors.

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 doublestrand end-joining repair pathway (NHEJ). The NHEJ apparatus 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 DNAdependent 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 Villartay 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 immunodeficiency (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
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increased sensitivity to ionizing radiation. V(D)J recombination 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 ligase 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). Description of the DNA repair factors involved in T and B cell development 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 hyperIgM syndrome (defective Ig class switch recombination),

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respectively, whereas deficiencies of elements involved in downstream DNA repair (i.e., NHEJ, see above) or downstream of AID (e.g., uracil N-glycosylase, UNG) cause similar 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 development 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 lymphocytes 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 immunodeficiency characterized by defective TCR- and BCR-mediated cell activation, a calcium (Ca2+) influx deficiency in lymphocytes, and defective NF-AT nuclear factor of activated 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 maintained, 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 carriers (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 transmembrane 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-defined, 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 functional 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 lymphocytes) 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 broadened the scope of investigation into cytokine receptor signaling in PID, via the description of STAT5b and Tyk2 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 unresponsiveness) 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 homozygous 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 Tyk2À/À mice. The recurrent viral and persistent mycobacterial infections suffered by the patient could well be the respective consequences of defective IFN-a- and IL-12-mediated cell activation. Of note was the recurrence of skin abscesses and lung infections which, set against a background of defective Il-23 and IL-6 signaling, strongly suggests a deficiency in the effector Th17 subset. IL-23 is involved in Th17 maintenance, 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 transducer and transcription activator 3 (STAT3) (Holland et al., 2007; Minegishi et al., 2007). It would thus be worth testing the Th17 pathway in these patients, given the phenotypic similarity with Tyk-2 deficiency in terms of the occurrence of bacterial and fungal lung and skin infections (Grimbacher et al., 2005). The recent characterization of human Th17 cells expressing CCR4 and CCR6 chemokine 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 understood 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 patients. 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 hypomorphic mutations of the RAG1 or RAG2 genes (Notarangelo 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 consequence of defective negative T cell selection (Fischer, 2004). Indeed, OS thymi show markedly reduced expression of Aire and defective expression of ‘‘ectopic tissuespecific antigens’’ (TSA) in thymic epithelial cells (TECs) (Cavadini et al., 2005). Defective Aire expression was thought to be the consequence of defective thymic epithelial cell differentiation in the context of a paucity of T cell precursors, thus resulting in a lack of lymphocyte-epithelial 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).
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Both models correspond fairly well to human OS (despite a few differences) and can thus be considered as useful tools for delineating this unique immunopathological phenomenon. Four pieces of information have been gathered: (1) the phenotype can develop in a pathogenfree 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 transferring 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 expansion 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-reactive 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 (Aschenbrenner 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 frequent 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 patient with a WASP gene somatic mutant leading to reversion, there is a selective advantage for revertants within the Treg subset, combined with the remission of autoimmune hemolytic anemia (Humblet-Baron et al., 2007). With WasÀ/À 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 suppressive 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 colitis. 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

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cells do not form this type of filament very well either (Maillard 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 deficiency, 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 interaction 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 characterizing the invariant NKT cell subset that recognizes endogenous and exogenous glycolipids presented by the CD1d molecule (Bendelac et al., 2007). On the basis of experimental 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 humans. 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 mutation 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 hemophagocytic 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 interaction 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-deficient 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 negative selection of thymocytes development and function of regulatory T cells

APECED IPEX

AIRE FOXP3, CD25

Three major syndromes—ALPS (autoimmune lymphoproliferative 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-reactive 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 family 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 considerably strengthened by the recent description of XLP2, a condition characterized by a very similar clinical phenotype in terms of the almost complete absence of circulating NKT cells but in which 2B4-mediated cell cytotoxicity is undisturbed (Rigaud et al., 2006). XLP2 is the consequence of a deficiency in XIAP, a molecule that presumably acts in vivo as a major inhibitor of cell apoptosis. It is not yet known how XIAP deficiency leads to an apparently 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 additional report of a molecularly uncharacterized NKT cell deficiency 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 countermeasure 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 associated with viral infections. NK Cells Selective NK cell deficiency has been recognized as a separate 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 lymphocytes in conjunction with recurrent (mostly viral)
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infections (Bernard et al., 2004; Biron et al., 1989; Eidenschenk et al., 2006a, 2006b; Etzioni et al., 2005; Notarangelo 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-dependent cytolytic activity (as discussed in Orange, 2006). Similarly, a NK cell activity deficiency was found in a murine strain (Jinx) into which a Munc13-4 (Unc13d) gene mutation 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 impairment in NK cytolysis favors an immunopathological reaction likely to be associated with a persistent, infectious trigger. These observations fit very well with the many reports 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 genetically 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 humans, there is one setting that corresponds to what appears to be a selective NK cell deficiency; it consists of NKÀ SCID (gc and JAK 3 deficiencies) after nonmyeloablative 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 robust 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)assessment of NK cell-associated immune functions in man. Further observations of human NK cell deficiency should lead to a thorough investigation of the other effectors of immu842 Immunity 27, December 2007 ª2007 Elsevier Inc.

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 elucidating important pathways in the immune system, it also has medical impact by prompting the design of new diagnostic tools and opening up new fields of therapeutic research. In some instances, gene product supplementation might be envisaged, as is the case with adenosine deaminase deficiency that results in a SCID phenotype. Understanding 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 patients 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 glycosylation sites can cause protein unfolding and degradation. Chemicals able to modify glycosylation may be able to complement these defects by preventing protein degradation, 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. Nonsense mutations (which account for a relatively high fraction of mutations) lead to premature translation termination, 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 premature 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 consequences 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 immunological 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 technologies 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

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the phenotype detection of heterozygotes and RNAibased screening in relevant models are both powerful tools. In addition, complementation technology has become more feasible and a number of efficient transfer systems are available. The use of high-resolution comparative 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 (frequently not associated with the type of mutation) is a common 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 researchers 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 project (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 immune 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. Bernasconi, A., Marino, R., Ribas, A., Rossi, J., Ciaccio, M., Oleastro, M., Ornani, A., Paz, R., Rivarola, M.A., Zelazko, M., and Belgorosky, A. (2006). Characterization of immunodeficiency in a patient with growth hormone insensitivity secondary to a novel STAT5b gene mutation. Pediatrics 118, e1584–e1592. Berridge, M.J., Bootman, M.D., and Roderick, H.L. (2003). Calcium signalling: dynamics, homeostasis and remodelling. Nat. Rev. Mol. Cell Biol. 4, 517–529. Bidere, N., Su, H.C., and Lenardo, M.J. (2006). Genetic disorders of programmed cell death in the immune system. Annu. Rev. Immunol. 24, 321–352. Biron, C.A., Byron, K.S., and Sullivan, J.L. (1989). Severe herpesvirus infections in an adolescent without natural killer cells. N. Engl. J. Med. 320, 1731–1735. Buck, D., Malivert, L., de Chasseval, R., Barraud, A., Fondaneche, M.C., Sanal, O., Plebani, A., Stephan, J.L., Hufnagel, M., le Deist, F., et al. (2006). Cernunnos, a novel nonhomologous end-joining factor, is mutated in human immunodeficiency with microcephaly. Cell 124, 287–299. Buckley, R.H. (2004). Molecular defects in human severe combined immunodeficiency and approaches to immune reconstitution. Annu. Rev. Immunol. 22, 625–655. Casanova, J.L., and Abel, L. (2002). Genetic dissection of immunity to 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. (2006). Herpes simplex virus encephalitis in human UNC-93B deficiency. Science 314, 308–312. Cavadini, P., Vermi, W., Facchetti, F., Fontana, S., Nagafuchi, S., Mazzolari, E., Sediva, A., Marrella, V., Villa, A., Fischer, A., et al. (2005). AIRE deficiency in thymus of 2 patients with Omenn syndrome. J. Clin. Invest. 115, 728–732. 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 immunodeficiency (SCID)-X1 disease. Science 288, 669–672. ´ ¨ Corneo, B., Moshous, D., Gungor, T., Wulffraat, N., Philippet, P., Le Deist, F., Fischer, A., and de Villartay, J.P. (2001). Identical mutations in RAG1 or RAG2 genes leading to defective V(D)J recombinase activity can cause either T-B- SCID or Omenn syndrome. Blood 97, 2772–2776. Crozat, K., Hoebe, K., Ugolini, S., Hong, N.A., Janssen, E., Rutschmann, S., Mudd, S., Sovath, S., Vivier, E., and Beutler, B. (2007). Jinx, an MCMV susceptibility phenotype caused by disruption of Unc13d: a mouse model of type 3 familial hemophagocytic lymphohistiocytosis. J. Exp. Med. 204, 853–863. Curotto de Lafaille, M.A., Muriglan, S., Sunshine, M.J., Lei, Y., Kutchukhidze, N., Furtado, G.C., Wensky, A.K., Olivares-Villagomez, D., and Lafaille, J.J. (2001). Hyper immunoglobulin E response in mice with monoclonal populations of B and T lymphocytes. J. Exp. Med. 194, 1349–1359. De Villartay, J.P., Fischer, A., and Durandy, A. (2003). The mechanisms of immune diversification and their disorders. Nat. Rev. Immunol. 3, 962–972. ´ de Villartay, J.P., Lim, A., Al-Mousa, H., Dupont, S., Dechanet-Merville, J., Caumau Gatbois, E., Gougeon, M.L., Abel, L., Casanova, J.L., Fischer, A., and Le Deist, F. (2005). A novel immunodeficiency associated with hypomorphic RAG1 mutations and CMV infection. J. Clin. Invest. 115, 3291–3299. Durandy, A., Taubenheim, N., Peron, S., and Fischer, A. (2007). Pathophysiology of B-cell intrinsic immunoglobulin class switch recombination deficiencies. Adv. Immunol. 94C, 275–306. Ehl, S., Schwarz, K., Enders, A., Duffner, U., Pannicke, U., Kuhr, J., Mascart, F., Schmitt-Graeff, A., Niemeyer, C., and Fisch, P. (2005). A variant of SCID with specific immune responses and predominance of gamma delta T cells. J. Clin. Invest. 115, 3140–3148.

REFERENCES Acosta-Rodriguez, E.V., Rivino, L., Geginat, J., Jarrossay, D., Gattorno, M., Lanzavecchia, A., Sallusto, F., and Napolitani, G. (2007). Surface phenotype and antigenic specificity of human interleukin 17-producing T helper memory cells. Nat. Immunol. 8, 639–646. Ahnesorg, P., Smith, P., and Jackson, S.P. (2006). XLF interacts with the XRCC4-DNA ligase IV complex to promote DNA nonhomologous end-joining. Cell 124, 301–313. Aiuti, A., Slavin, S., Aker, M., Ficara, F., Deola, S., Mortellaro, A., Morecki, S., Andolfi, G., Tabucchi, A., Carlucci, F., et al. (2002). Correction of ADA-SCID by stem cell gene therapy combined with nonmyeloablative conditioning. Science 296, 2410–2413. Antonarakis, S.E., and Beckmann, J.S. (2006). Mendelian disorders deserve more attention. Nat. Rev. Genet. 7, 277–282. Aschenbrenner, K., D’Cruz, L.M., Vollmann, E.H., Hinterberger, M., Emmerich, J., Swee, L.K., Rolink, A., and Klein, L. (2007). Selection of Foxp3+ regulatory T cells specific for self antigen expressed and presented by Aire+ medullary thymic epithelial cells. Nat. Immunol. 8, 351–358. Bassing, C.H., and Alt, F.W. (2004). The cellular response to general and programmed DNA double strand breaks. DNA Repair (Amst.) 3, 781–796. Bendelac, A., Savage, P.B., and Teyton, L. (2007). The biology of NKT cells. Annu. Rev. Immunol. 25, 297–336. Bernard, F., Picard, C., Cormier-Daire, V., Eidenschenk, C., Pinto, G., Bustamante, J.C., Jouanguy, E., Teillac-Hamel, D., Colomb, V., FunckBrentano, I., et al. (2004). A novel developmental and immunodeficiency syndrome associated with intrauterine growth retardation and a lack of natural killer cells. Pediatrics 113, 136–141.

Immunity 27, December 2007 ª2007 Elsevier Inc. 843

Immunity

Review
Eidenschenk, C., Dunne, J., Jouanguy, E., Fourlinnie, C., Gineau, L., Bacq, D., McMahon, C., Smith, O., Casanova, J.L., Abel, L., and Feighery, C. (2006a). A novel primary immunodeficiency with specific natural-killer cell deficiency maps to the centromeric region of chromosome 8. Am. J. Hum. Genet. 78, 721–727. Eidenschenk, C., Jouanguy, E., Alcais, A., Mention, J.J., Pasquier, B., Fleckenstein, I.M., Puel, A., Gineau, L., Carel, J.C., Vivier, E., et al. (2006b). Familial NK cell deficiency associated with impaired IL-2and IL-15-dependent survival of lymphocytes. J. Immunol. 177, 8835–8843. Etzioni, A., Eidenschenk, C., Katz, R., Beck, R., Casanova, J.L., and Pollack, S. (2005). Fatal varicella associated with selective natural killer cell deficiency. J. Pediatr. 146, 423–425. Feske, S., Muller, J.M., Graf, D., Kroczek, R.A., Drager, R., Niemeyer, C., Baeuerle, P.A., Peter, H.H., and Schlesier, M. (1996). Severe combined immunodeficiency due to defective binding of the nuclear factor of activated T cells in T lymphocytes of two male siblings. Eur. J. Immunol. 26, 2119–2126. Feske, S., Giltnane, J., Dolmetsch, R., Staudt, L.M., and Rao, A. (2001). Gene regulation mediated by calcium signals in T lymphocytes. Nat. Immunol. 2, 316–324. Feske, S., Gwack, Y., Prakriya, M., Srikanth, S., Puppel, S.H., Tanasa, B., Hogan, P.G., Lewis, R.S., Daly, M., and Rao, A. (2006). A mutation in Orai1 causes immune deficiency by abrogating CRAC channel function. Nature 441, 179–185. Fischer, A. (2004). Human primary immunodeficiency diseases: a perspective. Nat. Immunol. 5, 23–30. Fischer, A., and Notarangelo, L.D. (2003). Combined immunodeficiencies. In Immunologic Disorders in Infants and Children, Fifth Edition., E.R. Stiehm, H.D. Ochs, and J.A. Winkelstein, eds. (Philadelphia, PA: Elsevier Saunder), pp. 447–479. Fischer, A., Le Deist, F., Hacein-Bey-Abina, S., Andre-Schmutz, I., de Saint Basile, G., de Villartay, J.P., and Cavazzana-Calvo, M. (2005). Severe combined immunodeficiency. A model disease for molecular immunology and therapy. Immunol. Rev. 203, 98–109. Fischer, A., Latour, S., and de Saint Basile, G. (2007). Genetic defects affecting lymphocyte cytotoxicity. Curr. Opin. Immunol. 19, 348–353. Gao, Y., Sun, Y., Frank, K.M., Dikkes, P., Fujiwara, Y., Seidl, K.J., Sekiguchi, J.M., Rathbun, G.A., Swat, W., Wang, J., et al. (1998). A critical role for DNA end-joining proteins in both lymphogenesis and neurogenesis. Cell 95, 891–902. Geha, R.S., Notarangelo, L.D., Casanova, J.L., Chapel, H., Conley, M.E., Fischer, A., Hammarstrom, L., Nonoyama, S., Ochs, H.D., Puck, J.M., et al. (2007). Primary immunodeficiency diseases: an update from the International Union of Immunological Societies Primary Immunodeficiency Diseases Classification Committee. J. Allergy Clin. Immunol. 120, 776–794. Gits, J., van Leeuwen, D., Carroll, H.P., Touw, I.P., and Ward, A.C. (2006). Multiple pathways contribute to the hyperproliferative responses from truncated granulocyte colony-stimulating factor receptors. Leukemia 20, 2111–2118. Goodnow, C.C. (2007). Multistep pathogenesis of autoimmune disease. Cell 130, 25–35. Grimbacher, B., Holland, S.M., and Puck, J.M. (2005). Hyper-IgE syndromes. Immunol. Rev. 203, 244–250. Herve, M., Isnardi, I., Ng, Y.S., Bussel, J.B., Ochs, H.D., CunninghamRundles, C., and Meffre, E. (2007). CD40 ligand and MHC class II expression are essential for human peripheral B cell tolerance. J. Exp. Med. 204, 1583–1593. Holland, S.M., DeLeo, F.R., Elloumi, H.Z., Hsu, A.P., Uzel, G., Brodsky, N., Freeman, A.F., Demidowich, A., Davis, J., Turner, M.L., et al. (2007). STAT3 mutations in the hyper-IgE syndrome. N. Engl. J. Med. 357, 1608–1619. Holzelova, E., Vonarbourg, C., Stolzenberg, M.C., Arkwright, P.D., Selz, F., Prieur, A.M., Blanche, S., Bartunkova, J., Vilmer, E., Fischer, A., et al. (2004). Autoimmune lymphoproliferative syndrome with somatic Fas mutations. N. Engl. J. Med. 351, 1409–1418. Horwitz, M.S., Duan, Z., Korkmaz, B., Lee, H.H., Mealiffe, M.E., and Salipante, S.J. (2007). Neutrophil elastase in cyclic and severe congenital neutropenia. Blood 109, 1817–1824. Humblet-Baron, S., Sather, B., Anover, S., Becker-Herman, S., Kasprowicz, D.J., Khim, S., Nguyen, T., Hudkins-Loya, K., Alpers, C.E., Ziegler, S.F., et al. (2007). Wiskott-Aldrich syndrome protein is required for regulatory T cell homeostasis. J. Clin. Invest. 117, 407–418. Khiong, K., Murakami, M., Kitabayashi, C., Ueda, N., Sawa, S., Sakamoto, A., Kotzin, B.L., Rozzo, S.J., Ishihara, K., Verella-Garcia, M., et al. (2007). Homeostatically proliferating CD4 T cells are involved in the pathogenesis of an Omenn syndrome murine model. J. Clin. Invest. 117, 1270–1281. Klein, C., Grudzien, M., Appaswamy, G., Germeshausen, M., Sandrock, I., Schaffer, A.A., Rathinam, C., Boztug, K., Schwinzer, B., Rezaei, N., et al. (2007). HAX1 deficiency causes autosomal recessive severe congenital neutropenia (Kostmann disease). Nat. Genet. 39, 86–92. Kollner, I., Sodeik, B., Schreek, S., Heyn, H., von Neuhoff, N., Germeshausen, M., Zeidler, C., Kruger, M., Schlegelberger, B., Welte, K., and Beger, C. (2006). Mutations in neutrophil elastase causing congenital neutropenia lead to cytoplasmic protein accumulation and induction of the unfolded protein response. Blood 108, 493–500. Ku, C.L., von Bernuth, H., Picard, C., Zhang, S.Y., Chang, H.H., Yang, K., Chrabieh, M., Issekutz, A.C., Cunningham, C.K., Gallin, J., et al. (2007). Selective predisposition to bacterial infections in IRAK-4-deficient children: IRAK-4-dependent TLRs are otherwise redundant in protective immunity. J. Exp. Med. 204, 2407–2422. Lai, C.H., Chun, H.H., Nahas, S.A., Mitui, M., Gamo, K.M., Du, L., and Gatti, R.A. (2004). Correction of ATM gene function by aminoglycoside-induced read-through of premature termination codons. Proc. Natl. Acad. Sci. USA 101, 15676–15681. Lau, Y.L., Chan, G.C., Ha, S.Y., Hui, Y.F., and Yuen, K.Y. (1998). The role of phagocytic respiratory burst in host defense against Mycobacterium tuberculosis. Clin. Infect. Dis. 26, 226–227. Le Deist, F., Hivroz, C., Partiseti, M., Thomas, C., Buc, H.A., Oleastro, M., Belohradsky, B., Choquet, D., and Fischer, A. (1995). A primary Tcell immunodeficiency associated with defective transmembrane calcium influx. Blood 85, 1053–1062. Leibundgut-Landmann, S., Gross, O., Robinson, M.J., Osorio, F., Slack, E.C., Tsoni, S.V., Schweighoffer, E., Tybulewicz, V., Brown, G.D., Ruland, J., and Reis, E.S.C. (2007). Syk- and CARD9-dependent coupling of innate immunity to the induction of T helper cells that produce interleukin 17. Nat. Immunol. 8, 630–638. Leonard, W.J. (2001). Cytokines and immunodeficiency diseases. Nat. Rev. Immunol. 1, 200–208. Levy, O., Orange, J.S., Hibberd, P., Steinberg, S., LaRussa, P., Weinberg, A., Wilson, S.B., Shaulov, A., Fleisher, G., Geha, R.S., et al. (2003). Disseminated varicella infection due to the vaccine strain of varicella-zoster virus, in a patient with a novel deficiency in natural killer T cells. J. Infect. Dis. 188, 948–953. Lilic, D. (2002). New perspectives on the immunology of chronic mucocutaneous candidiasis. Curr. Opin. Infect. Dis. 15, 143–147. Lodoen, M.B., and Lanier, L.L. (2006). Natural killer cells as an initial defense against pathogens. Curr. Opin. Immunol. 18, 391–398. Ma, C.S., Nichols, K.E., and Tangye, S.G. (2007). Regulation of cellular and humoral immune responses by the SLAM and SAP families of molecules. Annu. Rev. Immunol. 25, 337–379. Maianski, N.A., Mul, F.P., van Buul, J.D., Roos, D., and Kuijpers, T.W. (2002). Granulocyte colony-stimulating factor inhibits the mitochondria-dependent activation of caspase-3 in neutrophils. Blood 99, 672–679. Maillard, M.H., Cotta-de-Almeida, V., Takeshima, F., Nguyen, D.D., Michetti, P., Nagler, C., Bhan, A.K., and Snapper, S.B. (2007). The

844 Immunity 27, December 2007 ª2007 Elsevier Inc.

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Wiskott-Aldrich syndrome protein is required for the function of CD4(+)CD25(+)Foxp3(+) regulatory T cells. J. Exp. Med. 204, 381–391. Marangoni, F., Trifari, S., Scaramuzza, S., Panaroni, C., Martino, S., Notarangelo, L.D., Baz, Z., Metin, A., Cattaneo, F., Villa, A., et al. (2007). WASP regulates suppressor activity of human and murine CD4(+)CD25(+)FOXP3(+) natural regulatory T cells. J. Exp. Med. 204, 369–380. Marrella, V., Poliani, P.L., Casati, A., Rucci, F., Frascoli, L., Gougeon, M.L., Lemercier, B., Bosticardo, M., Ravanini, M., Battaglia, M., et al. (2007). A hypomorphic R229Q Rag2 mouse mutant recapitulates human Omenn syndrome. J. Clin. Invest. 117, 1260–1269. Medvedev, A.E., Lentschat, A., Kuhns, D.B., Blanco, J.C., Salkowski, C., Zhang, S., Arditi, M., Gallin, J.I., and Vogel, S.N. (2003). Distinct mutations in IRAK-4 confer hyporesponsiveness to lipopolysaccharide and interleukin-1 in a patient with recurrent bacterial infections. J. Exp. Med. 198, 521–531. Milner, J.D., Ward, J.M., Keane-Myers, A., and Paul, W.E. (2007). Lymphopenic mice reconstituted with limited repertoire T cells develop severe, multiorgan, Th2-associated inflammatory disease. Proc. Natl. Acad. Sci. USA 104, 576–581. Minegishi, Y., Saito, M., Morio, T., Watanabe, K., Agematsu, K., Tsuchiya, S., Takada, H., Hara, T., Kawamura, N., Ariga, T., et al. (2006). Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity. Immunity 25, 745–755. Minegishi, Y., Saito, M., Tsuchiya, S., Tsuge, I., Takada, H., Hara, T., Kawamura, N., Ariga, T., Pasic, S., Stojkovic, O., et al. (2007). Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome. Nature 448, 1058–1062. Nichols, K.E., Hom, J., Gong, S.Y., Ganguly, A., Ma, C.S., Cannons, J.L., Tangye, S.G., Schwartzberg, P.L., Koretzky, G.A., and Stein, P.L. (2005). Regulation of NKT cell development by SAP, the protein defective in XLP. Nat. Med. 11, 340–345. Notarangelo, L.D., and Mazzolari, E. (2006). Natural killer cell deficiencies and severe varicella infection. J. Pediatr. 148, 563–564. Notarangelo, L.D., Gambineri, E., and Badolato, R. (2006). Immunodeficiencies with autoimmune consequences. Adv. Immunol. 89, 321–370. O’Driscoll, M., Cerosaletti, K.M., Girard, P.M., Dai, Y., Stumm, M., Kysela, B., Hirsch, B., Gennery, A., Palmer, S.E., Seidel, J., et al. (2001). DNA ligase IV mutations identified in patients exhibiting developmental delay and immunodeficiency. Mol. Cell 8, 1175–1185. Ochs, H.D., and Thrasher, A.J. (2006). The Wiskott-Aldrich syndrome. J. Allergy Clin. Immunol. 117, 725–738. Orange, J.S. (2006). Human natural killer cell deficiencies. Curr. Opin. Allergy Clin. Immunol. 6, 399–409. Partiseti, M., Le Deist, F., Hivroz, C., Fischer, A., Korn, H., and Choquet, D. (1994). The calcium current activated by T cell receptor and store depletion in human lymphocytes is absent in a primary immunodeficiency. J. Biol. Chem. 269, 32327–32335. Pasquier, B., Yin, L., Fondaneche, M.C., Relouzat, F., Bloch-Queyrat, C., Lambert, N., Fischer, A., de Saint-Basile, G., and Latour, S. (2005). Defective NKT cell development in mice and humans lacking the adapter SAP, the X-linked lymphoproliferative syndrome gene product. J. Exp. Med. 201, 695–701. Prakriya, M., Feske, S., Gwack, Y., Srikanth, S., Rao, A., and Hogan, P.G. (2006). Orai1 is an essential pore subunit of the CRAC channel. Nature 443, 230–233. Ramoz, N., Rueda, L.A., Bouadjar, B., Montoya, L.S., Orth, G., and Favre, M. (2002). Mutations in two adjacent novel genes are associated with epidermodysplasia verruciformis. Nat. Genet. 32, 579–581. Rigaud, S., Fondaneche, M.C., Lambert, N., Pasquier, B., Mateo, V., Soulas, P., Galicier, L., Le Deist, F., Rieux-Laucat, F., Revy, P., et al. (2006). XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome. Nature 444, 110–114. Sanchez, D.J., Gumperz, J.E., and Ganem, D. (2005). Regulation of CD1d expression and function by a herpesvirus infection. J. Clin. Invest. 115, 1369–1378. Skokowa, J., Cario, G., Uenalan, M., Schambach, A., Germeshausen, M., Battmer, K., Zeidler, C., Lehmann, U., Eder, M., Baum, C., et al. (2006). LEF-1 is crucial for neutrophil granulocytopoiesis and its expression is severely reduced in congenital neutropenia. Nat. Med. 12, 1191–1197. Steinman, L. (2007). A brief history of T(H)17, the first major revision in the T(H)1/T(H)2 hypothesis of T cell-mediated tissue damage. Nat. Med. 13, 139–145. The International HapMap Consortium (2006). A haplotype map of the human genome. Nature 437, 1299–1320. Vig, M., Beck, A., Billingsley, J.M., Lis, A., Parvez, S., Peinelt, C., Koomoa, D.L., Soboloff, J., Gill, D.L., Fleig, A., et al. (2006a). CRACM1 multimers form the ion-selective pore of the CRAC channel. Curr. Biol. 16, 2073–2079. Vig, M., Peinelt, C., Beck, A., Koomoa, D.L., Rabah, D., Koblan-Huberson, M., Kraft, S., Turner, H., Fleig, A., Penner, R., and Kinet, J.P. (2006b). CRACM1 is a plasma membrane protein essential for storeoperated Ca2+ entry. Science 312, 1220–1223. Villa, A., Sobacchi, C., Notarangelo, L.D., Bozzi, F., Abinun, M., Abrahamsen, T.G., Arkwright, P.D., Baniyash, M., Brooks, E.G., Conley, M.E., et al. (2001). V(D)J recombination defects in lymphocytes due to RAG mutations: severe immunodeficiency with a spectrum of clinical presentations. Blood 97, 81–88. Vogt, G., Vogt, B., Chuzhanova, N., Julenius, K., Cooper, D.N., and Casanova, J.L. (2007). Gain-of-glycosylation mutations. Curr. Opin. Genet. Dev. 17, 245–251. Wada, T., Toma, T., Okamoto, H., Kasahara, Y., Koizumi, S., Agematsu, K., Kimura, H., Shimada, A., Hayashi, Y., Kato, M., and Yachie, A. (2005). Oligoclonal expansion of T lymphocytes with multiple second-site mutations leads to Omenn syndrome in a patient with RAG1-deficient severe combined immunodeficiency. Blood 106, 2099–2101. Watford, W.T., and O’Shea, J.J. (2006). Human tyk2 kinase deficiency: another primary immunodeficiency syndrome. Immunity 25, 695–697. Welch, E.M., Barton, E.R., Zhuo, J., Tomizawa, Y., Friesen, W.J., Trifillis, P., Paushkin, S., Patel, M., Trotta, C.R., Hwang, S., et al. (2007). PTC124 targets genetic disorders caused by nonsense mutations. Nature 447, 87–91. Yeromin, A.V., Zhang, S.L., Jiang, W., Yu, Y., Safrina, O., and Cahalan, M.D. (2006). Molecular identification of the CRAC channel by altered ion selectivity in a mutant of Orai. Nature 443, 226–229. Zhang, S.Y., Jouanguy, E., Ugolini, S., Smahi, A., Elain, G., Romero, P., Segal, D., Sancho-Shimizu, V., Lorenzo, L., Puel, A., et al. (2007). TLR3 deficiency in patients with herpes simplex encephalitis. Science 317, 1522–1527.

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