Primary Immunodeficiencies and Inflammatory Disease: A Growing

TrendsAlterations in numbers and activity ofimmune cells and associated responsesresult in infectious and inflammatory dis-eases, which are two of the most com-mon disease areas in humans.

Complex genomic data sets involvinghundreds of genes are emerging fromgenome-wide association studies ofsusceptibility to common inflammatorydiseases, and from whole-exomesequencing of patients suffering fromprimary immunodeficiencies.

Combined analysis of risk loci for 22common human inflammatory dis-eases, and of all primary immunodefi-ciencies with a known genetic lesionidentifies a highly significant geneticoverlap between the two groups ofdiseases.

The cellular and molecular pathwaysanchored around these genes aretherefore required for protectionagainst infections, but their persistentor dysregulated engagement forpathological inflammation in humans.

1Department of Biochemistry,Complex Traits Group, McGillUniversity, Montreal, QC, CanadazThese authors contributed equally tothis article

*Correspondence:[email protected] (P. Gros).

TREIMM 1250 No. of Pages 15

ReviewPrimary Immunodeficienciesand Inflammatory Disease:A Growing GeneticIntersectionNassima Fodil,1,z David Langlais,1,z and Philippe Gros1,*

Recent advances in genome analysis have provided important insights into thegenetic architecture of infectious and inflammatory diseases. The combinedanalysis of loci detected by genome-wide association studies (GWAS) in 22inflammatory diseases has revealed a shared genetic core and associatedbiochemical pathways that play a central role in pathological inflammation.Parallel whole-exome sequencing studies have identified 265 genes mutatedin primary immunodeficiencies (PID). Here, we examine the overlap betweenthese two data sets, and find that it consists of genes essential for protectionagainst infections and in which persistent activation causes pathological inflam-mation. Based on this intersection, we propose that, although strong or inacti-vating mutations (rare variants) in these genes may cause severe disease (PIDs),their more subtle modulation potentially by common regulatory/coding variantsmay contribute to chronic inflammation.

Genomics Meet Human Infectious and Inflammatory DiseasesThe ‘disease state’ results from interactions between intrinsic genetic risks from the host andextrinsic environmental triggers. The genetic component may be simple, involving powerfulmutations that inactivate key physiological pathways, or may be complex and heterogeneous,involving combinations of weak genetic lesions whose accumulation phenotypically mimics theeffect of a strong mutation. On the other hand, environmental triggers of disease are oftencomplex, heterogeneous, and generally poorly understood. Genetic analysis of susceptibility toinfections has proven particularly successful to study how the interface between host andenvironment causes clinical disease [1–3]. In infectious diseases, exposure to the environmentaltrigger (e.g., microbial pathogens) is absolutely required to reveal the host genetic diversity andassociated risk. In most extreme cases, selective pressure by lethal microbes has impacted thehuman genome and has left identifiable genetic fingerprints in areas of endemic disease andfollowing epidemics. Striking examples include the protective role of hemoglobin (Hb) andACKR1 (DARC) variants against malaria [4], and of CCR5 deletion against HIV [5]. Dramaticincreases in performance and affordability of DNA sequencing now permits genome and whole-exome sequencing (WES) of unique human patients or families that display unusual susceptibilityto infections, including pure or syndromic PIDs (see Glossary) [6–8]. The analysis of suchpatients has generated a rich genetic data set on the association of rare variants with this groupof diseases.

On the other hand, burns, trauma, and environmental insults may disrupt protective tissuebarriers and lead to acute or chronic exposure to microbes present at mucosal surfaces and/or

Trends in Immunology, Month Year, Vol. xx, No. yy http://dx.doi.org/10.1016/j.it.2015.12.006 1© 2015 Elsevier Ltd. All rights reserved.

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http://dx.doi.org/10.1016/j.it.2015.12.006


GlossaryComplex disorders: diseases thatare likely associated with the effectsof multiple genes in combination withlifestyle and environmental factors.Expression quantitative trait loci(eQTL): loci that affect mRNAexpression levels of a specific geneor group of genes.Genome-wide association study(GWAS): aims to associate diseasephenotypes with specific geneticmarkers or loci (SNPs), and isgenerally conducted in largepopulations.Immunochip: custom genotypingarray containing genetic markersassociated with immune-relatedgene(s).Linkage disequilibrium (LD):situation when multiple physicallylinked genetic markers (andassociated genes) associated withdisease are inherited together as‘haplotype blocks’, due to absenceof recombination events betweenthem in the population studied. Thedisease-causing genetic lesion maymap within the boundaries of thehaplotype block or may be physicallylinked outside the limits of thehaplotype block.Mendelian disorders: geneticdiseases that follow simple Mendelianpatterns of inheritance.Meta-analysis: a combined analysisof multiple published GWAS toprovide additional statistical power toidentify disease loci.Polygenic disease: a disease with agenetic component that involvesseveral genes.Primary immunodeficiency (PID):disorders resulting from inheriteddefects of the immune systemcharacterized by an increasedsusceptibility to infections and, insome cases, increased incidence ofautoimmunity and malignancies.Quantitative trait loci (QTL): part ofthe genome (locus) that modulates aquantitative phenotype.Single nucleotide polymorphism(SNP): single-nucleotide difference inthe DNA sequence of individualmembers of a given species.SNP chips (SNP arrays): an arrayof SNPs that allows genome-wideassignment and is used forassociation studies.

to appetizing self-antigens. This triggers an inflammatory response in the host, a normalphysiological process that involves initial recognition of tissue damage, elimination of thecausative lesion, and restoration of tissue homeostasis. Tight regulation of this response iscritical: in the presence of persistent tissue injury or sustained microbial insult, overexpression ofproinflammatory mediators or insufficient production of anti-inflammatory signals results inimmunopathology, including inflammatory or autoimmune disease or allergy. Genetic analysisof susceptibility to acute (sepsis, encephalitis) or chronic inflammatory diseases with possiblemicrobial, autoimmune, and/or autoinflammatory etiologies (inflammatory bowel disease, rheu-matoid arthritis, psoriasis to name only a few) has offered additional opportunities to identifyimportant elements of host response to microbial and autoimmune stimuli [9]. Population andfamily studies have long established a strong genetic component to susceptibility to inflamma-tory diseases. The recent availability of high-density arrays of polymorphic variants genome-wide(SNP chips) or clustered around ‘immune’ loci (immunochips) has facilitated the search forgenetic determinants (common variants) of susceptibility to inflammatory diseases in humans.Such GWAS in very large cohorts of human patients (>50 000) from different populations, andsubsequent meta-analyses of multiple published GWAS of the same disease, have mappedhundreds of genetic loci, each with small effect size, but that together define a rich geneticarchitecture for several of these complex disorders [10–18].

This flurry of technology development has produced very detailed genetic maps for susceptibilityto infections and to inflammation, and those have been reviewed elsewhere [19–21]. Althoughthese are briefly cited herein, the specific focus of this review is on the nature and extent ofshared genetic risks across both groups of diseases. Specifically, we discuss how this geneticintersection points to specific genes and pathways that are required for protection againstinfections but whose sustained engagement in the presence of persistent insult leads topathological inflammation. We also review how this intersection may provide information onthe etiology of certain inflammatory conditions and, conversely, how the two parallel data setsmay help identify and validate morbid genes at candidate loci. Finally, this intersection lendssupport to the hypothesis that strong but rare mutations at specific genes of this overlap mayindependently cause severe diseases (PIDs), while more subtle modulation by common codingor regulatory variants may contribute to chronic inflammation in the presence of a persistenttissue insult.

Primary ImmunodeficienciesIn addition to classical genetic approaches (linkage mapping, immune phenotype-driven candi-date gene sequencing, and studies from animal models), WES has dramatically increased thepace at which causative genes are being discovered for PIDs. WES has been most effective inidentifying ‘morbid’ genes in groups of PID patients [3_TD$DIFF] (Mendelian disorders) where the presence ofhomozygosity for deleterious mutations is likely to be high, including: (i) familial cases, consan-guinity, or cases from isolated populations; (ii) patients presenting with particularly severepathological form of an otherwise more benign condition (unusual pathogenesis); and (iii) rareearly-onset pediatric cases. To date, mutations in 265 genes have been shown to cause PIDs,providing a rich data set for the systematic characterization of cellular and molecular networksinvolved in the development, activity, and regulation of immune cells during response toinfectious or to inflammatory stimuli (see Table S1 in the supplemental information online)[22–24]. A clinical classification has recently been provided for PIDs where the genetic etiologyis known [25]. It includes: (i) combined immunodeficiencies (T and/or B cells); (ii) combinedimmunodeficiencies with syndromic features; (iii) humoral deficiencies; (iv) diseases of immunedysregulation; (v) defects in phagocytes numbers or function; (vi) defects in innate immunity; (vii)autoinflammatory disorders; and (viii) deficiencies of the complement system. While the majorityof mutations affect the development and function of leukocytes, others are inborn errors ofmetabolisms (in so-called ‘house-keeping’ proteins) with or without syndromic features [23]. The

2 Trends in Immunology, Month Year, Vol. xx, No. yy


vast majority of genetic lesions causing PIDs are highly penetrant and inherited in a recessivefashion. However, a fraction are inherited as autosomal dominant (heterozygotes) with variablepenetrance, and associated with either haploinsufficiency, with gain-of-function, or with negativedominance [8,26–29].

The study of genotype/phenotype correlations in PIDs has been extremely productive. It has notonly identified host cells and pathways that are essential for general protection against microbialpathogens in general, but also recognized pathways that are surprisingly nonredundant and thatare required for response to unique groups of pathogen. On the one hand, several PIDs are verysevere, and manifest themselves as broad susceptibility to viral, bacterial, and parasitic patho-gens. Examples include severe combined immunodeficiency (SCID) (partial or complete loss of Tand B cells) that is caused by mutations in >30 genes, the most frequent being IL2RG, ADA,IL7RA, JAK3, RAG1, RAG2, and CD3 [25,30]. Likewise, chronic granulomatous disease (CGD)is associated with recurrent bacterial and fungal infections in the presence or absence ofneutropenia, and linked to impaired production of oxygen radicals by myeloid cells causedby mutations in constituents of the NADPH oxidase (CYBA, CYBB, NCF1, NCF2, and NCF4)[31]. Another example is CD4 lymphopenia, whose etiology includes deficiency in MAGT1, andwhich manifests by viral and bacterial infections and histoplasma. On the other hand, some PIDsdisplay very restricted infection susceptibility phenotypes. Mutations in TLR3 cause susceptibilityto herpes simplex virus (HSV) and associated encephalitis (HSE) [32], but nothing else. Remark-ably, the same restricted HSE phenotype is found in patients harboring mutations in othermembers of the TLR3-IFN//b pathways, including TRIF, TRAF3, UNC93B1, and TBK1 [33]. Asimilar situation is seen with IL17 deficiency, CARD9 deficiency, and some patients withautosomal dominant STAT1 deficiency, who uniformly display a narrow phenotype of chronicmucocutaneous candidiasis (CMC) [34]. Also, defects in the IFNg/IL12 circuit tend to cause anarrow phenotype of susceptibility to infection with environmental mycobacteria, or dissemi-nated BCG infection postvaccination, a syndrome named Mendelian Susceptibility to Myco-bacterial Disease (MSMD) [35]. These results highlight the nonredundant nature of the hostdefense mechanisms against these infections.

Additional insight into different, cell-specific molecular functions of a PID gene product cansometimes be reflected by the heterogeneity of clinical phenotypes associated with differenttypes of mutation in the same gene. For example, heterozygosity for inactivating mutations inSTAT1 cause a decrease in protein phosphorylation and DNA binding, resulting in diminishedproduction of IFNg, which is clinically expressed as susceptibility to mycobacterial infections [36].Conversely, mutations affecting STAT1 coiled-coil and DNA-binding domains lead to an excessof p-STAT1-driven target gene transcription. These heterozygote STAT1 mutations impairnuclear dephosphorylation of p-STAT1, causing both increased transcriptional activity anddecreased IL17 production by T cells, which are clinically expressed as susceptibility toCMC, and phenotypically mimicking mutations of the IL17F, IL17RA, and ACT1 genes [37].Similarly, hemizygosity for loss-of-function mutations in WASP (Wiskott Aldrich Syndrome)cause thrombocytopenia, eczema, decreased T and B cell function, and recurrent infections,while activating WASP mutations cause neutropenia with no risk of infection [38]. Finally,penetrance and expressivity of a specific PID mutation can be dramatically influenced indifferent patients by additional, yet to be defined, genetic or environmental effects. For example,GATA2 mutations are associated with a constellation of phenotypes in different patients,including familial myelodysplasia, dendritic cells/monocytes/B and NK cell deficiency, anddecreased monocytes counts with susceptibility to mycobacteria [39–41]. Also, patientsbearing the same inactivating TYK2 deletion show different phenotypes with or without HyperIgE syndrome with associated viral, fungal, and BCG infections at clinical presentation in onepatient, while another patient with the samemutation had BCGosis and brucellosis with normalIgE levels [42,43].

Trends in Immunology, Month Year, Vol. xx, No. yy 3


In conclusion, the rapidly increasing list of PID mutations is identifying critical mechanisms ofprotection against microbial pathogens (see Table S1 in the supplemental information online). Ingenotype–genotype comparisons (see below), these mutations can also validate loci andassociated gene effects in unrelated diseases with a suspected microbial etiology and thathave been detected as GWAS loci. This is particularly important when the identity of a morbidgene at such GWAS loci remains elusive due, for example, to linkage disequilibrium (LD) nearmapped loci. Concordance between PID genes andGWAS disease loci may provide critical newinsight into host cells and pathways that play a role in pathogenesis of an unrelated disease, andmay even point to a specific pathogen or group of pathogens as participating in the etiology ofthis unrelated condition.

Inflammatory DiseasesA strong genetic component has long been established (through familial clustering, gendereffect, segregation analyses, and twin studies) for major diseases of inflammation, such asinflammatory bowel disease (IBD), multiple sclerosis (MS), rheumatoid arthritis (RA), Celiacdisease (CeD), type I diabetes (T1D), systemic lupus erythematosus (SLE), psoriasis (Pso.),and several other such disorders. Over the past 10 years, the genetic architectures of thesediseases have beenmapped by GWAS in large cohorts of patients and controls (>10 000), and indifferent populations. In addition, results from independent GWAS studies have been combined inlarge meta-analyses (>50 000 patients), resulting in the mapping and validation of hundreds ofgenetic risk loci[4_TD$DIFF] (polygenic diseases). Public GWAS databases to which the reader is referred(NHGRIGWASCatalog,GWASdb,Gen2Phen,GWASCentral, and ImmunoBase) provide regularupdates; at the last count, >600 loci (genome-wide significance threshold p <5 � 10–8[2_TD$DIFF]) affectingsusceptibility to chronic inflammatory and/or autoimmune diseases had been mapped by thisapproach [44–47]. As reviewed below, many of these loci are shared between different diseases,while others appear to be disease specific. The careful scrutiny of the shared genetic risk providesvaluable insight into the host mechanisms that underlie the process of pathological inflammation,while disease-specific pathwaysmay reflect specific gene–environment interactions unique to thatdisease and/or tissue affected. An important caveat of the GWAS data sets is that, with theexception of HLA, the effect size of individual loci is small with low odds ratios. Thismay be causedby a number of factors, including complexity of the genetic determinants, heterogeneity in thedisease phenotype, whose current definition is restricted to a clinical end-point, and complexgene–environment interactions.

The deepest genetic data sets come from IBD [13], MS [17,18], and RA [14]. IBD encompassesboth ulcerative colitis (UC) and Crohn's disease (CD), two related intestinal inflammatoryconditions with distinct clinical and pathological manifestations. The most recent meta-analysisof 75 000 cases and controls detected a total of 163 genetic risk loci, 110 of them in common inboth UC and CD, with an additional 23 UC-specific loci, and 30 CD-specific loci, with strongcandidate genes identified for 53% of the loci [13]. About one-third (n = 66) of the loci were alsofound to be shared in common with other inflammatory and autoimmune diseases. Cell-specificgene expression studies show that the major cell type ‘hosting’ these genetic effects is primarilydendritic cells followed by CD4+ T cells and NK cells, while biological network analysis pointed tocytokine production, lymphocytes numbers and activation, and response to bacterial productsas the key associated response pathways in these cells [13]. The most recent meta-analysis ofMS genetic risk combining GWAS results and independent immunochip genotyping (80 000cases and controls), identified a total of 110 non-MHC loci [18]. Of those, 97 variants fell within50 kb of genes loosely annotated as immune function (prior annotation, organ- and cell-specificexpression), with 35 linked to the GO term ‘immune system process’. Importantly, the geneticarchitecture solved in this analysis identified a clear overlap with risk loci for IBD (17%), UC (13%),CD (15%), and primary biliary cirrhosis (10%), as well as CeD (7%), RA (4.5%), and 3.6% withPso. [18]. For RA, a recently published meta-analysis of GWAS and immunochip data of



>30 000 cases and 73 000 controls identified a total of 101 non-MHC genetic risk loci containinga minimum aggregate number of 377 genes (defined by LD) [14]. Interestingly, almost two-thirdsof the mapped genetic risk loci are shared with other immune-related diseases. Forty-four locishow cis-regulatory variants [expression QTLs (eQTLs)] that are active in CD4+ T cells, inCD14+ cells, or in PBMCs. Pathway and gene expression analysis also shows significantenrichment of T cell- and B cell- dependent pathways and of cytokine signaling pathways[14]. Finally, a recent study defined cis-regulatory regions in a variety a hematopoietic cells [48]. Itfound that �60% of GWAS loci for inflammatory diseases are associated with cis-regulatoryregions that display disease-associated and cell type-specific effects (for example, CD and UChits have strong association with T cell enhancers, whereas RA, MS, and SLE are also linked to Bcells).

The careful delineation of the shared genetic risk in inflammatory and other immune relateddiseases is of particularly interest to understand the basic mechanisms of pathological inflam-mation, and to identify possible novel drug targets of broad therapeutic value. A combinedanalysis of these GWAS data sets for 22 of the most common inflammatory diseases identified atotal of 439 unique genetic risk loci; of these, 203 (46%) are shared with at least one otherinflammatory disease, 88 loci are shared by 2 diseases, 39 by 3 diseases, 34 by 4 diseases,while a surprising 42 loci (9.6% of the loci tested) were shared in common by 5 or more diseases(Figure 1, Key Figure) (see Table S2 in the supplemental information online). The Circos plotshown in Figure 1 illustrates the genetic loci shared by 4 or more inflammatory diseases. Incomparing the extent of overlap in genetic risk loci across the different diseases, it is important toremember that this overlap will be affected by the number of loci mapped in each disease, whichis in part determined by the number of patients analyzed in each study (statistical power), and thestrength of the genetic component in each disease. (To maximize the capture of shared geneticloci across different inflammatory diseases, we used a reduced statistical threshold and p value<1 � 10–5). Hence, the overlaps identified in Figure 1 (see Table S2 in the supplementalinformation online) are likely to be underestimates, negatively influenced by the relative smallersize of certain GWAS studies. Conversely, the bias for informative SNPs at ‘immune genes’ in theimmunochip [49] used in a few of the GWAS may positively affect the size of the genetic overlapbetween mapped loci in different diseases. Among these 76 ubiquitous genetic loci (detected in4 or more diseases) (Figure 1), the HLA-DQ/HLA-DR region of the MHC (or specific portions of it)was most prominent, being positive for association in all of the 22 diseases tested. Other sharedloci in this group related to cell types, responses, and pathways already known for relevance topathogenesis, including: (i) pattern recognition receptors of the innate immune system andassociated signaling cascades; (ii) antigen processing and presentation, production of cytocidalspecies, and secretion of proinflammatory mediators by myeloid cells; (iii) T and B lymphocytematuration, including control of autoreactive T and B cells; (iv) antigen receptors of T and B cellsfor recognition in the context of Class I or Class II MHC; and (v) production of proinflammatorycytokines, and associated regulation of Th1, Th17, and Treg polarization of the immuneresponse. Interestingly, about a quarter of these 76 most commonly shared loci do not showa clear biological candidate.

Genetic Intersections between Primary Immunodeficiencies andInflammatory DiseasesThe selective pressure imposed by pathogens during human evolution has shaped the hostdefense gene repertoire, but this has been suggested to have a fitness cost predisposing toinflammatory diseases (reviewed in [50]). Interestingly, we note a significant overlap betweenGWAS loci for inflammatory diseases (LD regions from theGWASCatalog) and genesmutated inPIDs, with 80 of the 265 identified PID genes (30%) falling within boundaries of GWAS loci(Table 1). This overlap is statistically highly significant, when using 10 independent training sets of250 genes as controls (p value compared with random expectations = 3.5 � 10–12; Fisher's



Key Figure

Genome-Wide Association Studies of Inflammatory Diseases: MajorShared Genetic Loci

Figure 1. Graphical representation of the genetic architecture of susceptibility to major inflammatory diseases (Circos plot).The outside rim identifies the 22 human chromosomes in individual colors. The inflammatory diseases surveyed areidentified and depicted by concentric circles onto which the mapped loci shared by 2 or more diseases are positioned (bluedots). Two genetic risk loci are considered overlapping when the most significant SNP at a given locus maps <50 kb fromanother locus (see Table S2 in the supplemental information online). Red intersecting lines identify loci that are shared incommon by 4 or more of the diseases surveyed. An abbreviated list of genes in linkage disequilibrium (LD; the number ofgenes in LD are in brackets) at each locus radiates to the outer part of the plot. Abbreviations: AA, alopecia areata; AD,atopic dermatitis; AS, ankylosing spondylitis; Asth., asthma; Behc., Behçet's disease; CD, Crohn's disease; CeD, celiacdisease; Grav., Graves’ disease; Hypoth., hypothyroidism; Kawa., Kawasaki disease; MS, multiple sclerosis; Narc.,narcolepsy; Neph., nephropathy; PBC, primary biliary cirrhosis; Pso., psoriasis; RA, rheumatoid arthritis; SLE, systemiclupus erythematosus; SS, systemic sclerosis; T1D, type 1 diabetes; T2D, type 2 diabetes.; UC, ulcerative colitis; Vit., vitiligo.

exact test). In addition, over half of these PID genes (44/80) are associated with susceptibility tomore than one inflammatory disease. The greatest overlap is with CD (34), UC (30), RA (24), andMS (23) possibly due to the greater number of loci mapped in these diseases. Interestingly, of the24 PID genes associated with RA loci, 8 are specific for RA. Globally, most of the genes in these



Table 1. Genes Mutated in Primary Immunodeficiencies and Detected as Risk Loci in Genome-Wide Association Studies of Major InflammatoryDiseasesa

PID Gene

Major Inflammatory Disease b

CD

UC

CeD

MS

RA

Pso

.

SLE

Vit.

T1D

AS

JIA

Ast

h.

AD

PBC

AA

Beh

c.

ATD

Kaw

a.

Nar

c.

Nep

h.

SS

T2D

VEO

-IB

D

Combined Immunodeficiencies ADA BCL10 CARD11 CD247 CD27 CD40 CIITA IL21 IL7R MALT1 MAP3K14 PTPRC RAG1 RAG2 RHOH TAP1 TAP2 TNFRSF4

Well-Defined Syndromes with Immunodeficiencies ATM BLM DCLRE1B DNMT3B IKZF1 NBN NFKBIA RTEL1 SP110 STAT3 STAT5B

Predominantly An�body Deficiencies CD19 CR2 ICOS NFKB2 PRKCD UNG

Diseases of Immune Dysregula�on AIRE CASP10 CASP8 CTLA4 FAS FASLG IFIH1 IL10 IL10RB IL2RA LYST RNASEH2C

Congenital Defects of Phagocyte Number, Func�on, or Both NCF2 NCF4 RAC2



Table 1. (continued)

IRF7 IRF8 RORCSTAT1STAT2TICAM1TRAF3TRAF3IP2TYK2

Autoinflammatory DisordersCARD14LPIN2MVKNOD2PSMB8SLC29A3TNFRSF1A

Complement DeficienciesC2C3C5CFBCFHITGAM

Newly Iden fied Genes (PMID)STAT4 (25492914)

2124415525631563178101423280343

Defects in Intrinsic and Innate Immunity CARD9 CXCR4 FCGR3A IFNGR1 IFNGR2 IL12B IL12RB1

a Light-gray boxes represent GWAS p value <10–5; dark-gray boxes are for p values <10–8b Abbreviations: AA, alopecia areata; AD, atopic dermatitis; AS, ankylosing spondylitis; ATD, autoimmune thyroid disease (including Graves’ disease and hypothyroidism);Behc., Behçet's disease; CD, Crohn's disease; CeD, celiac disease; JIA, juvenile idiopathic arthritis; Kawa., Kawasaki disease; MS, multiple colitis; Narc., narcolepsy;Neph., nephropathy; PBC, primary biliary cirrhosis; PMID, PubMed ID number.; Pso., psoriasis; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; SS,systemic sclerosis; T1D, type 1 diabetes; T2D, Type 2 diabetes; UC, ulcerative colitis; VEO-IBD, very early onset inflammatory bowel disease; Vit., vitiligo

overlaps represent a ‘who's who’ of immune genes (Figure 2). This list contains mastertranscription factors (STAT1, STAT2, STAT3, STAT4, STAT5B, AIRE, IRF7, IRF8, NFkB, IKZF1,and CIITA) and regulatory proteins (ATM, CASP8, and CASP10) involved in ontogeny, andmaturation of myeloid cells and lymphoid cells; proteins participating in antigen recognition,processing, and presentation (Class I MHC, Class II MHC, NOD2, TAP1, TAP2, and CD40),inflammasome activation platforms (CARD9, CARD11, and TYK2), and antimicrobial function(NCF2 and NCF4) of myeloid cells. The list also includes a number of pro- and anti-inflammatorycytokines (IL10, IL12, and IL21) as well as cytokine receptors expressed by lymphoid andmyeloid cells (IL2R, IL7R, IL10R, IL12R, IFNGR1, INFGR2, and CXCR4), and protective serummolecules from the complement system (C2, C3, C5, CFB, CFH, and ITGAM). Therefore, it isobvious that the same cellular and molecular mechanisms that are required for protectionagainst infections may also be involved, through sustained engagement, in onset or progressionof inflammatory diseases. Figure 3 illustrates some of these proteins and associated pathways inthe immune pathogenesis of IBD, MS, and RA.



IL-2Rα

JAK3JAK1

IL-2

IL-2RγIL-2Rβ

JAK3JAK1

IL-7

IL-7Rβ IL-2Rγc

JAK2 JAK1

IFNGRα/β

Type II IFN

IFNGRα/β

IRF1,CXCL9...

ISG

F3

TYK2 JAK1

IFNAR1 IFNAR2

Type I IFN

IRF9

IRF9

OASMX1...

An�viral responses

Plasmamembrane

Cytoplasm

Nucleus

An�microbial responses

JAK1JAK1

IL-10

IL-10RβIL-10Rα

An�-inflammatory responses

Lymphopoiesis

JAK2TYK2

IL-12

IL-12Rβ1 IL-12Rβ2

Th1 differen�a�on-Prolifera�on-Ig light chain gene reagrrangment

RAG1RAG2

JAK3JAK1

IL-21

γcIL-21R

GzmaIl10...

T, B and NK prolifera�on, and

differen�a�on

Figure 2. Signaling Pathways Altered in Primary Immunodeficiencies (PIDs) and Detected as Genetic Risks ofMajor Inflammatory Diseases. Components of cytokine signaling pathways and associated transcriptional responsesaffected in PIDs and detected as genetic risk loci for common inflammatory diseases (red lettering). Upon binding of type IIFNs to their receptor (IFNAR), the canonical signal transducer (JAK1/TYK2), and activator of transcription 1 (STAT1)–STAT2–IFN-regulatory factor 9 (IRF9) signaling complex binds to IFN-stimulated response elements, leading to induction ofa large number of IFN-stimulated antiviral genes, such as OAS and MX1. Binding of Type II IFNs can also signal throughSTAT1 homodimers, inducing antimicrobial responses. The engagement of different interleukin receptors (IL-2R, IL-7R, IL-10R, IL-12R, and IL-21R) induces the transcription of target genes through several signaling pathways, including the Januskinase (JAK)–signal transducer and activator of transcription (STAT) pathway, all of which induce several immune generesponses.

Although many of the genes at the PID/GWAS interface are associated with general and severeimmunodeficiencies, others are associated with narrower immunodeficiency phenotypes, per-haps pointing at specific host responses and unique host–microbe interactions that may berelevant to the inflammatory diseases where they behave as genetic risks. For example,mutations in STAT1 (IBD, SLE, RA, PBC, and SS), IFNGR1 (MS), IFNGR2 (CD and RA),IL12B (IBD, MS, Pso., and AS), IL12R (MS), IRF8 (IBD, MS, RA, SLE, PBC, and SS) andTYK2 (many diseases, including MS) are associated with MSMD, a fairly narrow form ofimmunodeficiency revealed after BCG vaccination and associated with impaired Th1 response(IFNg/IL12 circuit). Interestingly, the detected overlap between MSMD genes and MS loci, withunique association of IFNGR1 and IL12R, is supporting a role of IFNg/IL12 loop in the etiology ofthis debilitating autoimmune disorder. Likewise, mutations in TRAF3IP2 (UC/CD, and Pso.), andCARD9 (UC/CD, and AS) cause a narrow invasive fungal infection phenotype in humans. Finally,TICAM1 mutations lead to herpes simplex encephalitis caused by natural HSV infection, whilethis gene is associated with vitiligo in GWAS studies. It is tempting to speculate that coincidencebetween (i) gene mutations causing narrow immunodeficiencies restricted to one group ofpathogens and (ii) GWAS loci for one or several inflammatory diseases, may point to gene–environment interactions possibly with the same group of microbes involved in the etiology ofinflammatory diseases.

Another informative data set to consider are genes mutated in unique cases of very early-onsetpediatric IBD (VEO-IBD), the list of which shows significant intersection with genes mutated inPIDs (Table 1). This group includes diverse proteins that play a critical role not only in sensing ofmicrobial products at the mucosal barrier, but also in microbicidal activity, as well as in activationand amplification of proinflammatory responses (illustration in Figure 2). Selected examplesinclude: (i) ADAM17 (metalloprotease that cleaves TNF/, L-selectin, and EGFR ligands), a genemutated in patients with neonatal onset of IBD [51]; (ii) IKBKG encoding nuclear KB essentialmodulator protein (NEMO) associated with enterocolitis with villous atrophy and epithelial cellshedding [52,53]; (iii) hemizygote mutation for X-linked inhibitor of apoptosis protein gene (XIAP)in pediatric IBD [54–57]; (iv) a homozygote mutations in the PIK3R1 gene in a patient with colitis



An�gen-presen�ng cell

T cell

C5aR1C3aR

C5b

C3bC3a

C5a

FAS

CD40

CD40L

OX40ICOS

ICOSL OX40L

TNFR1

Casp8

δεγTCR

MHC-I

ζζ

Pep�de

FASLC5

C3

CD8

Cytoplasm

Nucleus

Cytoplasm

Nucleus

CIITAIRF8

TNF

ATMRAG1RAG2

SP110DNMT3β

ERK1 orERK2

PI3K

Cell ac�va�on Cell matura�on

Phagocytosis

Apoptosis

NF-ΚB

IΚB

TRAF

CD45

LCKZAP70 LAT

PKCMAPKPLCγ

AP1NFAT

NF-ΚB

PI3K

AIRE

BLM

Casp10

CXCR4

PI3K

IKAROS

MALT1

CARD9

NOD2

MAPKs

TAP1TAP2

ER

++

Proteasome(PSB8)

Bacteria

NF-ΚB

Figure 3. Illustration of Selected Proteins and Associated Pathways mutated in Primary Immunodeficiencies(PIDs) and detected as Risk Factors in Inflammatory Diseases. Proteins (from Table 1; red lettering) involved in thefunctional crosstalk between myeloid and lymphoid cells, including antigen recognition, capture, processing, and pre-sentation to T cells, and associated responses are represented. Impaired regulation in monogenic disorders can affectadaptive immune responses (such as CD45, OX40, ICOS, and CD40 deficiencies) by effector cells, peptide presentation byantigen-presenting cells (such as PSMB8 and TAP1/2 deficiencies) or bacterial sensing (NOD2 and CARD9) exemplify theinteraction network between PID and inflammatory diseases (for further details, refer to the main text).

and B cell deficiency [58,59]; (v) TTC7Amutations in patients with intestinal atresia, enterocolitis,and combined immunodeficiency [60,61]; (vi) FOXP3 variants in individuals of European ancestrypresenting with an early-onset and atypical form of IBD [62]; (vii) multiple variants in subunits ofthe NADPH oxidase complex [63]; (viii) hypermorphic PLCG2 allele in a familial form of dominantinflammatory disease, including enterocolitis [64]; (ix) CTLA4 missense mutations (CTLA-4Y60C) have been associated with severe, early-onset CD with increased T cell activationand an increased ratio of memory to naive T cells [65]; and finally, (x) rare variants in IL10and its receptors IL10RA and IL10RB, and IL21 genes associated with chronic intestinalinflammation in early childhood [59,66–69].

Furthermore, the coincidence between genemutations identified in PIDs and risk loci mapped byGWAS provides valuable information for the identification of the morbid gene in GWAS risk locishowing LD. [LD is defined by the co-segregation (and absence of recombination) of markerslinked to disease on so-called ‘haplotype blocks’; The causative genetic lesion may map withinthe boundaries or be physically linked to the LD segment (Box 1)]. For example, the Chr1 locus atposition 1.1–1.3Mb associated with CD and UC contains 17 genes in LD, with limited annotationfor several of the genes; hence, the identification of TNFRSF4 in this interval as mutated in



patients with OX40 deficiency provides a testable hypothesis that this gene is responsible for theeffect in IBD. Similar situations occur for loci on Chr2 (204 Mb, 3 genes in LD group, associationwith 7 diseases; ICOS), and Chr12 (63–66 Mb, 9 genes in LD, 4 diseases; TNFRSF1A).Interestingly, certain PID genes map to GWAS loci for which a different positional candidatehad been previously proposed based on general ontology annotation. A locus on Chr21 (45 Mb)was associated with disease risk in CD, UC, CeD, and RA; from the list of 9 genes in LD at thislocus, ICOSLG was previously identified as the best candidate based to its co-stimulatoryfunction in T cells. However, the discovery that this Chr21 locus contains the PID gene andtranscription factor AIRE (Table 1) suggests an additional candidate gene to be considered forthe effect. The same situation arises for other GWAS loci: that is, the Chr15 locus (91 Mb;identified in CD, UC, RA, and T2D), where the PID gene BLMmust be considered in addition tothe current leading candidate CRTC3, and the Chr20 locus (62 Mb; CD, UC, and MS), which

Box 1. The IFIH1 Gene and Pathway at the Intersection of Inflammatory Diseases and PrimaryImmunodeficiencies

The study of tens of thousands of patients by GWAS and using SNP arrays of increasing density and informative content,have identified a rich genetic architecture in inflammatory diseases. Of the >400 unique risk loci discussed in our review,identifying the causative gene is limited in part by the presence of LD near the mapped loci. LD occurs whenchromosomal segments containing several disease-linked contiguous markers (SNPs) are inherited together as a block(haplotype blocks), with the lack of recombination making it difficult to narrow down the exact position of the causativegenetic lesion. On the other hand, the rapid identification of rare coding mutations in PID patients by WES is providing adeep data set for genes that are essential for protection against infections. Merging the 2 data sets may help identifymorbid genes at or near GWAS loci.

In the example shown (Figure I), multiple SNPs on human 2q24.2 are associated with inflammatory or autoimmunediseases: (i) rs2111485 is associated with CD, UC [13], systemic lupus erythematosus (SLE) [70], and vitiligo [71]; (ii)rs1990760 with T1D [72], IgA antibody deficiency [73], and Grave's disease [74]; and (iii) rs17716942 with psoriasis [75].LD in this region defines an interval that contains 5 or 6 candidate genes, two of which are expressed in peripheral bloodcells and associated with immune function. Interestingly, rs2111485 behaves as a cis-acting eQTL that affects IFIH1mRNA expression [70]. In addition, application of a ‘Myeloid Inflammatory Score’ (MIS) [76] that considers DNA bindingand transcriptional activation by proinflammatory transcription factors points to Ifih1 as the top positional candidate in theLD interval (Figure IB). Interestingly, mice carrying a gain-of-function mutation in IFIH1 develop spontaneous lupus-likesymptoms [77]. Moreover, rare IFIH1 variants have been associated with risk of T1D and SLE [78–81].

IFIH1 encodes the cytosolic viral RNA receptor MDA5, a member of the RIG-I-like receptor family, that mediates theinduction of a type I interferon for antiviral immunity (reviewed in [10]). The binding of long dsRNA to MDA5 helicasedomain (Figure IC) stimulates signaling through the CARD domain-associated adaptor molecule IPS-1/MAVS, itself a risklocus for asthma [82]; MDA5-IPS-1 signaling is kept under control by the negative regulator ADAR1 [83]. The activatedsignaling cascade includes several genes implicated in inflammatory diseases by GWAS or mutated in PID (genes in blueand red; Figure ID; see Table S2 in the supplemental information online). MDA5 helicase domain sequence variants havebeen found in Aicardi-Goutières syndrome (AGS) patients (elevated type I interferon levels and signaling) [84,85]. Allidentifiedmutations are autosomal dominant and cause a stabilization of the helicase domain with dsRNA. MDA5 variantshave also been detected in SLE patients, consistent with the fact that some of these AGS patients develop lupus-likesymptoms [81].

Figure I. IFIH1: A Novel Primary Immunodeficiency (PID) Gene Associated with Multiple Immune-RelatedDiseases. (A) Genome browser representation of genes at a locus bearing SNPs (black bars) associated with severalimmune-related diseases (labeled in red over the associated SNP). The SNP rs2111485 has been shown to behave as acis-eQTL for expression of IFIH1mRNA in response to IFNg [86]. The mRNA expression of genes in the interval in PBMCis shown (RNA-seq tracks density) over individual exons [87]. (B) Illustration of the corresponding mouse locus, includingthe position of the genes, the myeloid inflammation score [76] calculated for each gene for the presence and activity ofproinflammatory transcription factors; the binding sites for these transcription factors and histone marks were identifiedby ChIP-seq, and the levels of expression of each gene in macrophages in response to IFNg. (C) Domain structure ofMDA5 (IFIH1). The variants associated with immune-related diseases by GWAS (blue) and the missense mutationsrecently identified in PID patients (red) are shown. (D) The signaling pathway activated by MDA5 and RIG-I is critical forhost defense against viral infections and alterations in this pathway are associated with various immune-related diseases(blue) and PIDs (red).



CDUCSLE

Vi�ligo

T1DGrave’sIgA deficiency Psoriasis

PBMC geneexpression

Humangenes

rs17716942rs1990760rs2111485

163.0 163.1 163.2 163.3 2q24.2(A)

(B)

(C)

(D)

cis-eQTL rs2111485 Monocyte response to IFN

Disease-associated SNP

← GCG GCA →← FAP ← KCNH7← IFIH1

← Gcg Gca →← Fap ← Kcnh7← Ifih1

5 CPM

1086420

MIS

Mouse genes

CtlIRF8IRF1

STAT1C/EBPβ

PU.1H3K4me1H3K27AcH3K4me3

ChIP-seq

Macrophagegene expression

UT

IFNγ 3h

Helicase domainCARD CARD CTD 10251

R337G

L372

FD39

3VA45

2TR46

0H(rs

1093

0046

)G49

5R

R720E

A946T

(rs19

9076

0)

R779H

/C

dsRNA ssRNA TRIM25

DDX58(RIG-I)

MAVS(IPS-1)

IFIH1(MDA5)

ADAR(ADAR1)

TMEM173(STING)

TRAF3

TBK1

IRF7

TANK

TRADD

IRF3

IKBKE(IKKε)

P P

P PIFNB, IFNA

ER

UbUb

Ub



Outstanding QuestionsHow can we identify causative diseasegenes in complex human genomic datasets? GWAS mapping relies onmarkers that are often in LD on largegenome segments containing tens ofgenes. The top linked SNP rarely is aloss of function, often mapping to non-coding regions. Both complicate theidentification of the ‘morbid’ geneand associated genetic lesions. Thefunctional annotation of GWAS lociusing the genetics intersectionsdescribed in this review may help inthis identification. A related problemarises from WES and whole-genomesequencing of sporadic cases; theseidentify numerous ‘private’ variantswith variable allele frequencies, incom-plete penetrance, and unknown modeof inheritance, and whose contributionto disease is difficult to establish. Sys-tematic validating one gene at a time isrequired for many such loci. Efficientgenome-editing techniques (CRISPR-cas9) applied to human cell lines or tomouse models will soon provide a sys-tematic catalog of such ‘morbid’ genesin which their contribution to diseasecan be tested in a well-controlledenvironment.

What is the impact of environmentalfactors on disease? Gene–environ-ment interactions are the next problemto solve for inflammatory diseaseswhere a microbial component is estab-lished or strongly suspected. Studiesinvestigating interactions between life-style, diet, and genetic factors areunderway to address this problem.Studies in mouse models reconstitutedwith human microflora should also helpaddress this issue.

What is the impact of gene–gene inter-actions in disease? A favored concep-tual framework is that human diseasesare caused by rare or common variantsin a fixed set of genes, and such var-iants cause disease with variable pen-etrance. Genetic studies in flies,worms, fish, and mice have long estab-lished that weak mutations in indepen-

contains both the PID gene RTEL1 and the published candidate TNFRSF6B, and, finally, theChr8 locus (91 Mb; CD) where the PID gene NBN gene must be considered along with RIPK2.Finally, an interesting situation emerges from the analysis of a locus on Chr12 (109–113 Mb; 6diseases), which contains a total of 57 genes in LD, including theUNG (low level of circulating IgGand IgA) and the MVK (autoinflammatory disorder caused by mevalonate kinase deficiency)genes whose inactivation causes PIDs. Hence, the GWAS hit at this location in 6 diseases maybe due to the independent effect of each gene in specific diseases, an effect that cannot besegregated due to LD; alternatively, it is interesting to consider the possibility that alterations atboth genes (either coding variants, or regulatory modulation/eSNPs) may be required to impactinflammatory pathologies.

Concluding RemarksIn conclusion, the explosion of genome technologies has dramatically increased our under-standing of the genetic architecture of human susceptibility to infections and to inflammatoryconditions [5_TD$DIFF] (see Outstanding Questions). Combined analysis of these two data sets identifies asignificant overlap composed of genes and proteins that are required for protection againstinfections but whose engagement is associated with pathological inflammation. The genes/proteins identified at this interface may represent valuable new targets for drug discovery. Thisgenetic intersection additionally suggests that, although strong mutations and/or inactivation(rare variants) of intersecting genes may independently cause severe diseases (PIDs), their moresubtle modulation through the action of common variants in the presence of a persistent tissueinsult may contribute to chronic inflammation. Because these two data sets (WES in PIDs andGWAS of inflammatory diseases) continue to expand, it is likely that the intersection betweenthem will continue to grow, increasing its informative content. Likewise, combined analysis ofGWAS and PID data sets may help prioritize and/or validate candidate genes identified bysequencing or mapping. These analyses may also point to signal transduction pathways, proteinproducts that physically interact, genes sharing the same expression pattern, and/or regulatedby cis or trans eQTL, and whose further modulation may be associated with disease. Finally, theemergence of novel methods for high efficiency genome editing (CRISPR-Cas9) opens the doorto the creation of informative animal models where the immunological and biochemical basis ofthese genes function can be studied in well-defined environments.

AcknowledgmentsThis work was supported by research grants to P.G. from the National Institutes of Health (NIAID; AI035237), and the

Canadian Institutes for Health Research. D.L. is supported by fellowships from the FRQS, the CIHR Neuroinflammation

training program, and the McGill Integrated Cancer Research Training Program. The authors are indebted to D. Filion

(Clinical Research Institute of Montreal, Canada) for the creation of Figure 1, and M. Lathrop (McGill University), S. Sawcer

(Oxford University), and J,L. Casanova (Rockefeller University) for critical comments during the preparation of this

manuscript.

[6_TD$DIFF]Supplemental information[6_TD$DIFF]Supplemental information associated with this article can be found, in the online version, at doi:10.1016/j.it.2015.12.006.

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Documents

Primary Immunodeficiencies and Inflammatory Disease: A Growing