Sex is a biological variable that affects immune responses to bacterial and other types of infectious agents. Males and females are known to have differential oral bacterial disease burden in periodontal and endodontic disease. Understanding that there is a contribution from both sex and gender to these oral diseases, we discuss in this review recent sex-based findings that provide a pathobiological basis for differences observed between males and females. Sexual dimorphism of immune responses with respect to neutrophil trafficking and osteoclast differentiation and formation is presented as a plausible mechanism to explain the sexual differences. We also emphasize that sex, as a biological variable, should be considered in these types of oral immunologic studies.
AomatsuMKatoTKasaharaEKitagawaS. 2013. Gender difference in tumor necrosis factor-alpha production in human neutrophils stimulated by lipopolysaccharide and interferon-gamma. Biochem Biophys Res Commun. 441(1):220–225.
2.
AsaiKHikiNMimuraYOgawaTUnouKKaminishiM. 2001. Gender differences in cytokine secretion by human peripheral blood mononuclear cells: role of estrogen in modulating LPS-induced cytokine secretion in an ex vivo septic model. Shock. 16(5):340–343.
3.
BajramiBZhuHKwakHJMondalSHouQGengGKaratepeKZhangYCNombela-ArrietaCParkSYet al. 2016. G-CSF maintains controlled neutrophil mobilization during acute inflammation by negatively regulating CXCR2 signaling. J Exp Med. 213(10):1999–2018.
4.
BoyleWJSimonetWSLaceyDL. 2003. Osteoclast differentiation and activation. Nature. 423(6937):337–342.
5.
CallewaertFSinnesaelMGielenEBoonenSVanderschuerenD. 2010. Skeletal sexual dimorphism: relative contribution of sex steroids, GH-IGF1, and mechanical loading. J Endocrinol. 207(2):127–134.
6.
ClaytonJA. 2016. Studying both sexes: a guiding principle for biomedicine. FASEB J. 30(2):519–524.
7.
CollinsFSTabakLA. 2014. NIH plans to enhance reproducibility. Nature. 505(7485):612–613.
8.
FanHDongGZhaoGLiuFYaoGZhuYHouY. 2014. Gender differences of B cell signature in healthy subjects underlie disparities in incidence and course of sle related to estrogen. J Immunol Res. 2014:814598.
9.
FischerJJungNRobinsonNLehmannC. 2015. Sex differences in immune responses to infectious diseases. Infection. 43(4):399–403.
10.
GarletGPAvila-CamposMJMilaneziCMFerreiraBRSilvaJS. 2005. Actinobacillus actinomycetemcomitans–induced periodontal disease in mice: patterns of cytokine, chemokine, and chemokine receptor expression and leukocyte migration. Microbes Infect. 7(4):738–747.
11.
GarletGPCardosoCRSilvaTAFerreiraBRAvila-CamposMJCunhaFQSilvaJS. 2006. Cytokine pattern determines the progression of experimental periodontal disease induced by Actinobacillus actinomycetemcomitans through the modulation of MMPs, RANKL, and their physiological inhibitors. Oral Microbiol Immunol. 21(1):12–20.
12.
GarletGPMartinsWJrFonsecaBAFerreiraBRSilvaJS. 2004. Matrix metalloproteinases, their physiological inhibitors and osteoclast factors are differentially regulated by the cytokine profile in human periodontal disease. J Clin Periodontol. 31(8):671–679.
13.
GarletGPMartinsWJrFerreiraBRMilaneziCMSilvaJS. 2003. Patterns of chemokines and chemokine receptors expression in different forms of human periodontal disease. J Periodontal Res. 38(2):210–217.
14.
GravesDTOatesTGarletGP. 2011. Review of osteoimmunology and the host response in endodontic and periodontal lesions. J Oral Microbiol. 3. doi:10.3402/jom.v3i0.5304
HannahMFBajicVBKleinSL. 2008. Sex differences in the recognition of and innate antiviral responses to Seoul virus in Norway rats. Brain Behav Immun. 22(4):503-516.
JacquinCGranDELeeSKLorenzoJAAguilaHL. 2006. Identification of multiple osteoclast precursor populations in murine bone marrow. J Bone Miner Res. 21(1):67–77.
19.
JevonMSabokbarAFujikawaYHirayamaTNealeSDWassJAthanasouNA. 2002. Gender- and age-related differences in osteoclast formation from circulating precursors. J Endocrinol. 172(3):673–681.
20.
KabashimaHYonedaMNagataKHirofujiTMaedaK. 2002. The presence of chemokine (MCP-1, MIP-1alpha, MIP-1beta, IP-10, RANTES)–positive cells and chemokine receptor (CCR5, CXCR3)–positive cells in inflamed human gingival tissues. Cytokine. 20(2):70–77.
21.
KawaiTEisen-LevRSekiMEastcottJWWilsonMETaubmanMA. 2000. Requirement of B7 costimulation for Th1-mediated inflammatory bone resorption in experimental periodontal disease. J Immunol. 164(4):2102–2109.
22.
KayEGomez-GarciaLWoodfinAScotlandRSWhitefordJR. 2015. Sexual dimorphisms in leukocyte trafficking in a mouse peritonitis model. J Leukoc Biol. 98(5):805–817.
23.
KherAWangMTsaiBMPitcherJMGreenbaumESNagyRDPatelKMWairiukoGMMarkelTAMeldrumDR. 2005. Sex differences in the myocardial inflammatory response to acute injury. Shock. 23(1):1–10.
KleinSLFlanaganKL. 2016. Sex differences in immune responses. Nat Rev Immunol. 16(10):626–638.
26.
KleinSLJedlickaAPekoszA. 2010. The Xs and Y of immune responses to viral vaccines. Lancet Infect Dis. 10(5):338–349.
27.
LeeEYSeoMJuhnnYSKimJYHongYJLeeYJLeeEBSongYW. 2011. Potential role and mechanism of IFN-gamma inducible protein-10 on receptor activator of nuclear factor kappa-B ligand (RANKL) expression in rheumatoid arthritis. Arthritis Res Ther. 13(3):R104.
MadalliSBeyrauMWhitefordJDucheneJSingh NandhraIPatelNSMotwaniMPGilroyDWThiemermannCNoursharghSet al. 2015. Sex-specific regulation of chemokine CXCL5/6 controls neutrophil recruitment and tissue injury in acute inflammatory states. Biol Sex Differ. 6:27.
30.
MantovaniACassatellaMACostantiniCJaillonS. 2011. Neutrophils in the activation and regulation of innate and adaptive immunity. Nat Rev Immunol. 11(8):519–531.
31.
MarquisVLDaoTFarzanehMAbitbolSFriedmanS. 2006. Treatment outcome in endodontics: the Toronto study. Phase III: initial treatment. J Endod. 32(4):299–306.
32.
McAbeeJLiQYuHKirkwoodKL. 2012. Sexual dimorphism in periapical inflammation and bone loss from mitogen-activated protein kinase phosphatase-1 deficient mice. J Endod. 38(8):1097–1100.
33.
MerrildDMPirapaharanDCAndreasenCMKjærsgaard-AndersenPMøllerAMDingMDelaisséJMSøeK. 2015. Pit- and trench-forming osteoclasts: a distinction that matters. Bone Res. 3:15032.
34.
MoxleyGPosthumaDCarlsonPEstradaEHanJBensonLLNealeMC. 2002. Sexual dimorphism in innate immunity. Arthritis Rheum. 46(1):250–258.
35.
NeedlemanIGarciaRGkraniasNKirkwoodKLKocherTIorioADMorenoFPetrieA. 2018. Mean annual attachment, bone level, and tooth loss: a systematic review. J Periodontol. 89Suppl 1:S120–S139.
36.
NovinceCMWhittowCRAartunJDHathawayJDPoulidesNChavezMBSteinkampHMKirkwoodKAHuangEWestwaterCet al. 2017. Commensal gut microbiota immunomodulatory actions in bone marrow and liver have catabolic effects on skeletal homeostasis in health. Sci Rep. 7(1):5747.
37.
OnoeYMiyauraCKaminakayashikiTNagaiYNoguchiKChenQRSeoHOhtaHNozawaSKudoIet al. 1996. IL-13 and IL-4 inhibit bone resorption by suppressing cyclooxygenase-2-dependent prostaglandin synthesis in osteoblasts. J Immunol. 156(2):758–764.
38.
PestkaSKrauseCDSarkarDWalterMRShiYFisherPB. 2004. Interleukin-10 and related cytokines and receptors. Annu Rev Immunol. 22:929–979.
39.
RathodKSKapilVVelmuruganSKhambataRSSiddiqueUKhanSVan EijlSGeeLCBansalJPitrolaKet al. 2017. Accelerated resolution of inflammation underlies sex differences in inflammatory responses in humans. J Clin Invest. 127(1):169–182.
40.
RettewJAHuet-HudsonYMMarriottI. 2008. Testosterone reduces macrophage expression in the mouse of toll-like receptor 4, a trigger for inflammation and innate immunity. Biol Reprod. 78(3):432–437.
41.
RettewJAMarriotIHuetYM. 2010. Sex differences in innate immune responses to bacterial pathogens. In: RobertsCKleinSL editors. Sex hormones and immunity to infection.New York (NY): Springer. p. 123–146.
42.
SadikCDKimNDLusterAD. 2011. Neutrophils cascading their way to inflammation. Trends Immunol. 32(10):452–460.
43.
SasakiHHouLBelaniAWangCYUchiyamaTMullerRStashenkoP. 2000. Il-10, but not IL-4, suppresses infection-stimulated bone resorption in vivo. J Immunol. 165(7):3626–3630.
44.
SasmonoRTEhrnspergerACronauSLRavasiTKandaneRHickeyMJCookADHimesSRHamiltonJAHumeDA. 2007. Mouse neutrophilic granulocytes express mrna encoding the macrophage colony-stimulating factor receptor (CSF-1R) as well as many other macrophage-specific transcripts and can transdifferentiate into macrophages in vitro in response to CSF-1. J Leukoc Biol. 82(1):111–123.
45.
ScotlandRSStablesMJMadalliSWatsonPGilroyDW. 2011. Sex differences in resident immune cell phenotype underlie more efficient acute inflammatory responses in female mice. Blood. 118(22):5918–5927.
46.
ShiauHJReynoldsMA. 2010a. Sex differences in destructive periodontal disease: a systematic review. J Periodontol. 81(10):1379–1389.
47.
ShiauHJReynoldsMA. 2010b. Sex differences in destructive periodontal disease: exploring the biologic basis. J Periodontol. 81(11):1505–1517.
48.
SilvaTAGarletGPFukadaSYSilvaJSCunhaFQ. 2007. Chemokines in oral inflammatory diseases: apical periodontitis and periodontal disease. J Dent Res. 86(4):306–319.
49.
SpitzerJA. 1999. Gender differences in some host defense mechanisms. Lupus. 8(5):380–383.
50.
Tekamp-OlsonPGallegosCBauerDMcClainJSherryBFabreMvan DeventerSCeramiA. 1990. Cloning and characterization of cdnas for murine macrophage inflammatory protein 2 and its human homologues. J Exp Med. 172(3):911–919.
51.
TesterAMCoxJHConnorARStarrAEDeanRAPuenteXSLopez-OtinCOverallCM. 2007. LPS responsiveness and neutrophil chemotaxis in vivo require PMN MMP-8 activity. PloS One. 2(3):e312.
52.
ValerioMSBasilakosDSKirkpatrickJEChavezMHathaway-SchraderJHerbertBAKirkwoodKL. 2017. Sex-based differential regulation of bacterial-induced bone resorption. J Periodontal Res. 52(3):377–387.
53.
ValerioMSHerbertBABasilakosDSBrowneCYuHKirkwoodKL. 2015. Critical role of MKP-1 in lipopolysaccharide-induced osteoclast formation through CXCL1 and CXCL2. Cytokine. 71(1):71-80.
54.
WangXBEllisJJPennisiDJSongXBatraJHollisKBradburyLALiZKennaTJBrownMA. 2017. Transcriptome analysis of ankylosing spondylitis patients before and after TNF-alpha inhibitor therapy reveals the pathways affected. Genes Immun. 18(3):184–190.
55.
XiongQJiaoYHastyKACanaleSTStuartJMBeamerWGDengHWBaylinkDGuW. 2009. Quantitative trait loci, genes, and polymorphisms that regulate bone mineral density in mouse. Genomics. 93(5):401–414.
56.
ZenobiaCLuoXLHashimAAbeTJinLChangYJinZCSunJXHajishengallisGCurtisMAet al. 2013. Commensal bacteria-dependent select expression of CXCL2 contributes to periodontal tissue homeostasis. Cell Microbiol. 15(8):1419–1426.
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