The exposome represents all exogenous and endogenous environmental exposures that begin at preconception and carry on throughout life, while the microbiome reflects the microbial component of the exposome. We recently introduced the concept of infectome and autoinfectome as a means of studying the totality of infections throughout life that participate in the induction as well as the progression of autoimmune diseases in an affected individual. The investigation of the autoinfectome could help us understand why some patients develop more than one autoimmune disease, a phenomenon also known as mosaic of autoimmunity. It could also explain the infectious and autoantibody burden of various autoimmune rheumatic diseases. The close interplay between infections and the immune system should be studied over time, long before the onset of autoaggression and autoimmunity. Tracking down each individual’s exposure to infectious agents (as defined by the autoinfectome) would be important for the establishment of a causative link between infection and autoimmunity.
SmykDRigopoulouEIBaumHBurroughsAKVerganiDBogdanosDP. Autoimmunity and environment: Am I at risk?Clin Rev Allergy Immunol2011; 42: 199–212.
2.
BurekCLTalorMV. Environmental triggers of autoimmune thyroiditis. J Autoimmun2009; 33: 183–189.
3.
ChighizolaCMeroniPL. The role of environmental estrogens and autoimmunity. Autoimmun Rev2012; 11: A493–A501.
4.
CutoloMPizzorniCSulliA. Vitamin D endocrine system involvement in autoimmune rheumatic diseases. Autoimmun Rev2011; 11: 84–87.
5.
HajasASandorJCsathyL. Vitamin D insufficiency in a large MCTD population. Autoimmun Rev2011; 10: 317–324.
6.
DoriaASarzi-PuttiniPShoenfeldY. Infections, rheumatism and autoimmunity: The conflicting relationship between humans and their environment. Autoimmun Rev2008; 8: 1–4.
7.
FujinamiRSvon HerrathMGChristenUWhittonJL. Molecular mimicry, bystander activation, or viral persistence: Infections and autoimmune disease. Clin Microbiol Rev2006; 19: 80–94.
8.
AnayaJM. Common mechanisms of autoimmune diseases (the autoimmune tautology). Autoimmun Rev2012; 11: 781–784.
9.
CostenbaderKHGaySAlarcón-RiquelmeMEIaccarinoLDoriaA. Genes, epigenetic regulation and environmental factors: Which is the most relevant in developing autoimmune diseases?Autoimmun Rev2012; 11: 604–609.
10.
TakahashiK. Influence of bacteria on epigenetic gene control. Cell Mol Life Sci2014; 71: 1045–1054.
11.
TammenSAFrisoSChoiSW. Epigenetics: The link between nature and nurture. Mol Aspects Med2012; 34: 753–764.
12.
ZhangLHouDChenX. Exogenous plant MIR168a specifically targets mammalian LDLRAP1: Evidence of cross-kingdom regulation by microRNA. Cell Res2011; 22: 107–126.
13.
SilmanAJNewmanJMacGregorAJ. Cigarette smoking increases the risk of rheumatoid arthritis. Results from a nationwide study of disease-discordant twins. Arthritis Rheum1996; 39: 732–735.
14.
StoltPBengtssonCNordmarkB. Quantification of the influence of cigarette smoking on rheumatoid arthritis: Results from a population based case-control study, using incident cases. Ann Rheum Dis2003; 62: 835–841.
15.
Hsieh LF, Wei JC, Lee HY, Chuang CC, Jiang JS, Chang KC. Aerobic capacity and its correlates in patients with ankylosing spondylitis. Int J Rheum Dis. Epub ahead of print 23 April 2014.
16.
BogdanosDPSmykDSRigopoulouEI. Twin studies in autoimmune disease: Genetics, gender and environment. J Autoimmun2012; 38: J156–J169.
17.
SmykDSRigopoulouEIMuratoriLBurroughsAKBogdanosDP. Smoking as a risk factor for autoimmune liver disease: What we can learn from primary biliary cirrhosis. Ann Hepatol2012; 11: 7–14.
18.
de PabloPChappleILBuckleyCDDietrichT. Periodontitis in systemic rheumatic diseases. Nat Rev Rheumatol2009; 5: 218–224.
19.
ArkemaEVKarlsonEWCostenbaderKH. A prospective study of periodontal disease and risk of rheumatoid arthritis. J Rheumatol2010; 37: 1800–1804.
20.
GregersenPKSilverJWinchesterRJ. The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum1987; 30: 1205–1213.
21.
WordsworthBPLanchburyJSSakkasLIWelshKIPanayiGSBellJI. HLA-DR4 subtype frequencies in rheumatoid arthritis indicate that DRB1 is the major susceptibility locus within the HLA class II region. Proc Natl Acad Sci USA1989; 86: 10049–10053.
22.
ChoyEHPanayiGS. Cytokine pathways and joint inflammation in rheumatoid arthritis. N Engl J Med2001; 344: 907–916.
23.
McInnesIBSchettG. The pathogenesis of rheumatoid arthritis. N Engl J Med2011; 365: 2205–2219.
24.
ToussirotERoudierJ. Pathophysiological links between rheumatoid arthritis and the Epstein-Barr virus: An update. Joint Bone Spine2007; 74: 418–426.
25.
NielenMMvan SchaardenburgDReesinkHW. Specific autoantibodies precede the symptoms of rheumatoid arthritis: A study of serial measurements in blood donors. Arthritis Rheum2004; 50: 380–386.
26.
ArkemaEVGoldsteinBLRobinsonW. Anti-citrullinated peptide autoantibodies, human leukocyte antigen shared epitope and risk of future rheumatoid arthritis: A nested case-control study. Arthritis Res Ther2013; 15: R159–R159.
27.
SnirOWidheMvon SpeeC. Multiple antibody reactivities to citrullinated antigens in sera from patients with rheumatoid arthritis: Association with HLA-DRB1 alleles. Ann Rheum Dis2009; 68: 736–743.
28.
van BeersJJWillemzeAJansenJJ. ACPA fine-specificity profiles in early rheumatoid arthritis patients do not correlate with clinical features at baseline or with disease progression. Arthritis Res Ther2013; 15: R140–R140.
29.
AlexiouIGermenisAKoutroumpasAKontogianniATheodoridouKSakkasLI. Anti-cyclic citrullinated peptide-2 (CCP2) autoantibodies and extra-articular manifestations in Greek patients with rheumatoid arthritis. Clin Rheumatol2008; 27: 511–513.
30.
AlexiouIGermenisAZiogasATheodoridouKSakkasLI. Diagnostic value of anti-cyclic citrullinated peptide antibodies in Greek patients with rheumatoid arthritis. BMC Musculoskelet Disord2007; 8: 37–37.
31.
ScallySWPetersenJLawSC. A molecular basis for the association of the HLA-DRB1 locus, citrullination, and rheumatoid arthritis. J Exp Med2013; 210: 2569–2582.
32.
CantaertTBrouardSThurlingsRM. Alterations of the synovial T cell repertoire in anti-citrullinated protein antibody-positive rheumatoid arthritis. Arthritis Rheum2009; 60: 1944–1956.
33.
Linn-RaskerSPvan der Helm-van MilAHvan GaalenFA. Smoking is a risk factor for anti-CCP antibodies only in rheumatoid arthritis patients who carry HLA-DRB1 shared epitope alleles. Ann Rheum Dis2006; 65: 366–371.
34.
VassalloRLuckeyDBehrensM. Cellular and humoral immunity in arthritis are profoundly influenced by the interaction between cigarette smoke effects and host HLA-DR and DQ genes. Clin Immunol2014; 152: 25–35.
LundbergKKinlochAFisherBA. Antibodies to citrullinated alpha-enolase peptide 1 are specific for rheumatoid arthritis and cross-react with bacterial enolase. Arthritis Rheum2008; 58: 3009–3019.
37.
MahdiHFisherBAKällbergH. Specific interaction between genotype, smoking and autoimmunity to citrullinated alpha-enolase in the etiology of rheumatoid arthritis. Nat Genet2009; 41: 1319–1324.
38.
ReichertSHaffnerMKeyßerG. Detection of oral bacterial DNA in synovial fluid. J Clin Periodontol2013; 40: 591–598.
39.
SahingurSEXiaXJAlamgirSHonmaKSharmaASchenkeinHA. DNA from Porphyromonas gingivalis and Tannerella forsythia induce cytokine production in human monocytic cell lines. Mol Oral Microbiol2010; 25: 123–135.
40.
KarlsonEWChangSCCuiJ. Gene-environment interaction between HLA-DRB1 shared epitope and heavy cigarette smoking in predicting incident rheumatoid arthritis. Ann Rheum Dis2009; 69: 54–60.
41.
van der WoudeDAlemayehuWGVerduijnW. Gene-environment interaction influences the reactivity of autoantibodies to citrullinated antigens in rheumatoid arthritis. Nat Genet2010; 42: 814–816;. author reply 816.
42.
WillemzeAvan der WoudeDGhideyW. The interaction between HLA shared epitope alleles and smoking and its contribution to autoimmunity against several citrullinated antigens. Arthritis Rheum2011; 63: 1823–1832.
43.
HillJABellDABrintnellW. Arthritis induced by posttranslationally modified (citrullinated) fibrinogen in DR4-IE transgenic mice. J Exp Med2008; 205: 967–979.
44.
SokoloveJZhaoXChandraPERobinsonWH. Immune complexes containing citrullinated fibrinogen costimulate macrophages via Toll-like receptor 4 and Fcgamma receptor. Arthritis Rheum2010; 63: 53–62.
45.
WillisVCGizinskiAMBandaNK. N-alpha-benzoyl-N5-(2-chloro-1-iminoethyl)-L-ornithine amide, a protein arginine deiminase inhibitor, reduces the severity of murine collagen-induced arthritis. J Immunol2011; 186: 4396–4404.
46.
MareszKJHellvardASrokaA. Porphyromonas gingivalis facilitates the development and progression of destructive arthritis through its unique bacterial peptidylarginine deiminase (PAD). PLoS Pathog2013; 9: e1003627–e1003627.
47.
MakrygiannakisDHermanssonMUlfgrenAK. Smoking increases peptidylarginine deiminase 2 enzyme expression in human lungs and increases citrullination in BAL cells. Ann Rheum Dis2008; 67: 1488–1492.
48.
SnirOWidheMHermanssonM. Antibodies to several citrullinated antigens are enriched in the joints of rheumatoid arthritis patients. Arthritis Rheum2010; 62: 44–52.
49.
AmaraKSteenJMurrayF. Monoclonal IgG antibodies generated from joint-derived B cells of RA patients have a strong bias toward citrullinated autoantigen recognition. J Exp Med2013; 210: 445–455.
50.
GomezALuckeyDYeomanCJ. Loss of sex and age driven differences in the gut microbiome characterize arthritis-susceptible 0401 mice but not arthritis-resistant 0402 mice. PLoS One2012; 7: e36095–e36095.
51.
SakkasLIXuBArtlettCMLuSJimenezSAPlatsoucasCD. Oligoclonal T cell expansion in the skin of patients with systemic sclerosis. J Immunol2002; 168: 3649–3659.
52.
KoenigMJoyalFFritzlerMJ. Autoantibodies and microvascular damage are independent predictive factors for the progression of Raynaud’s phenomenon to systemic sclerosis: A twenty-year prospective study of 586 patients, with validation of proposed criteria for early systemic sclerosis. Arthritis Rheum2008; 58: 3902–3912.
53.
SakkasLIChikanzaICPlatsoucasCD. Mechanisms of disease: The role of immune cells in the pathogenesis of systemic sclerosis. Nat Clin Pract Rheumatol2006; 2: 679–685.
54.
SgoncRGruschwitzMSDietrichHRecheisHGershwinMEWickG. Endothelial cell apoptosis is a primary pathogenetic event underlying skin lesions in avian and human scleroderma. J Clin Invest1996; 98: 785–792.
55.
Feghali-BostwickCMedsgerTAJrWrightTM. Analysis of systemic sclerosis in twins reveals low concordance for disease and high concordance for the presence of antinuclear antibodies. Arthritis Rheum2003; 48: 1956–1963.
56.
GrossmanCDovrishZShoenfeldYAmitalH. Do infections facilitate the emergence of systemic sclerosis?Autoimmun Rev2011; 10: 244–247.
57.
NeidhartMKuchenSDistlerO. Increased serum levels of antibodies against human cytomegalovirus and prevalence of autoantibodies in systemic sclerosis. Arthritis Rheum1999; 42: 389–392.
58.
LunardiCBasonCNavoneR. Systemic sclerosis immunoglobulin G autoantibodies bind the human cytomegalovirus late protein UL94 and induce apoptosis in human endothelial cells. Nat Med2000; 6: 1183–1186.
59.
LunardiCDolcinoMPeterlanaD. Antibodies against human cytomegalovirus in the pathogenesis of systemic sclerosis: A gene array approach. PLoS Med2006; 3: e2–e2.
60.
LarssonKAschanJRembergerMRingdénOWiniarskiJLjungmanP. Reduced risk for extensive chronic graft-versus-host disease in patients receiving transplants with human leukocyte antigen-identical sibling donors given polymerase chain reaction-based preemptive therapy against cytomegalovirus. Transplantation2004; 77: 526–531.
61.
HamamdzicDHarleyRAHazen-MartinDLeRoyEC. MCMV induces neointima in IFN-gammaR−/– mice: Intimal cell apoptosis and persistent proliferation of myofibroblasts. BMC Musculoskelet Disord2001; 2: 3–3.
62.
FarinaACironeMYorkM. Epstein-Barr virus infection induces aberrant TLR activation pathway and fibroblast-myofibroblast conversion in scleroderma. J Invest Dermatol2013; 134: 954–964.
63.
FerriCZakrzewskaKLongombardoG. Parvovirus B19 infection of bone marrow in systemic sclerosis patients. Clin Exp Rheumatol1999; 17: 718–720.
64.
ArtlettCMSassi-GahaSRiegerJLBoesteanuACFeghali-BostwickCAKatskikisPD. The inflammasome activating caspase 1 mediates fibrosis and myofibroblast differentiation in systemic sclerosis. Arthritis Rheum2011; 63: 3563–3574.
65.
RathinamVAJiangZWaggonerSN. The AIM2 inflammasome is essential for host defense against cytosolic bacteria and DNA viruses. Nat Immunol2010; 11: 395–402.
66.
DeapenDEscalanteAWeinribL. A revised estimate of twin concordance in systemic lupus erythematosus. Arthritis Rheum1992; 35: 311–318.
67.
ParksCGCooperGSHudsonLL. Association of Epstein-Barr virus with systemic lupus erythematosus: Effect modification by race, age, and cytotoxic T lymphocyte-associated antigen 4 genotype. Arthritis Rheum2005; 52: 1148–1159.
68.
HanlonPAvenellAAucottLVickersMA. Systematic review and meta-analysis of the sero-epidemiological association between Epstein-Barr virus and systemic lupus erythematosus. Arthritis Res Ther2014; 16: R3–R3.
69.
PooleBDScofieldRHHarleyJBJamesJA. Epstein-Barr virus and molecular mimicry in systemic lupus erythematosus. Autoimmunity2006; 39: 63–70.
70.
PooleBDGrossTMaierSHarleyJBJamesJA. Lupus-like autoantibody development in rabbits and mice after immunization with EBNA-1 fragments. J Autoimmun2008; 31: 362–371.
71.
BlankMShoenfeldYPerlA. Cross-talk of the environment with the host genome and the immune system through endogenous retroviruses in systemic lupus erythematosus. Lupus2009; 18: 1136–1143.
72.
LiJMFanWSHorsfallAC. The expression of human endogenous retrovirus-3 in fetal cardiac tissue and antibodies in congenital heart block. Clin Exp Immunol1996; 104: 388–393.
73.
SomersECRichardsonBC. Environmental exposures, epigenetic changes and the risk of lupus. Lupus2014; 23: 568–576.
74.
ZhaoSWangYLiangY. MicroRNA-126 regulates DNA methylation in CD4+ T cells and contributes to systemic lupus erythematosus by targeting DNA methyltransferase 1. Arthritis Rheum2011; 63: 1376–1386.
75.
MavropoulosAOrfanidouTLiaskosC. p38 mitogen-activated protein kinase (p38 MAPK)-mediated autoimmunity: Lessons to learn from ANCA vasculitis and pemphigus vulgaris. Autoimmun Rev2013; 12: 580–590.
76.
MavropoulosABogdanosDPLiaskosC. Flow cytometric detection of p38 MAPK phosphorylation and intracellular cytokine expression in peripheral blood subpopulations from patients with autoimmune rheumatic diseases. J Immunol Res2014; 2014: 671431–671431.
77.
MavropoulosARigopoulouEILiaskosCBogdanosDPSakkasLI. The role of p38 MAPK in the aetiopathogenesis of psoriasis and psoriatic arthritis. Clin Dev Immunol2013; 2013: 569751–569751.
78.
StegemanCATervaertJWSluiterWJMansonWLde JongPEKallenbergCG. Association of chronic nasal carriage of Staphylococcus aureus and higher relapse rates in Wegener granulomatosis. Ann Intern Med1994; 120: 12–17.
79.
PendergraftWF3rdPrestonGAShahRR. Autoimmunity is triggered by cPR-3(105-201), a protein complementary to human autoantigen proteinase-3. Nat Med2004; 10: 72–79.
SangalettiSTripodoCChiodoniC. Neutrophil extracellular traps mediate transfer of cytoplasmic neutrophil antigens to myeloid dendritic cells toward ANCA induction and associated autoimmunity. Blood2012; 120: 3007–3018.
ShapiraYAgmon-LevinNShoenfeldY. Defining and analyzing geoepidemiology and human autoimmunity. J Autoimmun2010; 34: J168–J177.
85.
ShapiraYAgmon-LevinNRenaudineauY. Serum markers of infections in patients with primary biliary cirrhosis: Evidence of infection burden. Exp Mol Pathol2012; 93: 386–390.
86.
KivitySAgmon-LevinNBlankMShoenfeldY. Infections and autoimmunity—friends or foes?Trends Immunol2009; 30: 409–414.
87.
BerlinTZandman-GoddardGBlankM. Autoantibodies in nonautoimmune individuals during infections. Ann N Y Acad Sci2007; 1108: 584–593.
88.
Agmon-LevinNShapiraYSelmiC. A comprehensive evaluation of serum autoantibodies in primary biliary cirrhosis. J Autoimmun2010; 34: 55–58.
89.
BrickmanCMShoenfeldY. The mosaic of autoimmunity. Scand J Clin Lab Invest Suppl2001; 235: 3–15.
90.
AshersonRAGunterKDayaDShoenfeldY. Multiple autoimmune diseases in a young woman: Tuberculosis and splenectomy as possible triggering factors? Another example of the “mosaic” of autoimmunity. J Rheumatol2008; 35: 1224–1226.
91.
BlankMGershwinME. Autoimmunity: From the mosaic to the kaleidoscope. J Autoimmun2008; 30: 1–4.
92.
ShoenfeldYBlankMAbu-ShakraM. The mosaic of autoimmunity: Prediction, autoantibodies, and therapy in autoimmune diseases—2008. Isr Med Assoc J2008; 10: 13–19.
93.
BogdanosDPSmykDSInvernizziP. Infectome: A platform to trace infectious triggers of autoimmunity. Autoimmun Rev2013; 12: 726–740.
94.
BogdanosDPSmykDSInvernizziP. Tracing environmental markers of autoimmunity: Introducing the infectome. Immunol Res2013; 56: 220–240.
95.
KosticADXavierRJGeversD. The microbiome in inflammatory bowel disease: Current status and the future ahead. Gastroenterology2014; 146: 1489–1499.
96.
RamMAnayaJMBarzilaiO. The putative protective role of hepatitis B virus (HBV) infection from autoimmune disorders. Autoimmun Rev2008; 7: 621–625.
97.
GordonJMichelG. Discerning trends in multiplex immunoassay technology with potential for resource-limited settings. Clin Chem2012; 58: 690–698.
98.
BissonnetteLBergeronMG. Next revolution in the molecular theranostics of infectious diseases: Microfabricated systems for personalized medicine. Expert Rev Mol Diagn2006; 6: 433–450.
99.
BissonnetteLBergeronMG. Multiparametric technologies for the diagnosis of syndromic infections. Clinical Microbiology Newsletter2012; 34: 159–168.
