190
Views
53
CrossRef citations to date
0
Altmetric
Review

Autoimmune heart disease: role of sex hormones and autoantibodies in disease pathogenesis

, , &
Pages 269-284 | Published online: 10 Jan 2014

References

  • Roger VL, Go AS, Lloyd-Jones DM et al. Heart disease and stroke statistics – 2011 update: a report from the American Heart Association. Circulation104, 276–308 (2011).
  • Jacobson DL, Gange SJ, Rose NR, Graham NMH. Epidemiology and estimated population burden of selected autoimmune disease in the United States. Clin. Immunol. Immunopathol.84, 223–243 (1997).
  • Cooper LT Jr. Myocarditis. N. Engl. J. Med.360, 1526–1538 (2009).
  • McNamara DM, Starling RC, Cooper LT et al. Clinical and demographic predictors of outcomes in recent onset dilated cardiomyopathy: results of the IMAC (Intervention in Myocarditis and Acute Cardiomyopathy)-2 study. J. Am. Coll. Cardiol.58, 1112–1118 (2011).
  • Rubtsov A, Rubtsova K, Kappler JW, Marrack P. Genetic and hormonal factors in female-biased autoimmunity. Autoimm. Rev.9, 494–498 (2010).
  • Nussinovitch U, Shoenfeld Y. Autoimmunity and heart diseases: pathogenesis and diagnostic criteria. Arch. Immunol. Ther. Exp.57, 95–104 (2009).
  • Sherer Y, Shoenfeld Y. Mechanisms of disease: atherosclerosis in autoimmune disease. Nat. Clin. Pract. Rheum.2, 99–106 (2006).
  • Lago F, Gomez R, Conde J, Scotece M, Gomez-Reino JJ, Gualillo O. Cardiometabolic co-morbidities and rheumatic diseases: focus on the role of fat mass and adipokines. Arthritis Care Res. (Hoboken)63, 1083–1090 (2011).
  • Haque S, Gordon C, Isenberg D et al. Risk factors for clinical coronary heart disease in systemic lupus erythematosus: the lupus and atherosclerosis evaluation of risk (LASER) study. J. Rheumatol.37, 322–329 (2010).
  • Urowitz MB, Gladman D, Ibanez D et al. Atherosclerotic vascular events in a multinational inception cohort of systemic lupus erythematosus. Arthritis Care Res.62, 881–887 (2010).
  • Symmons DPM, Gabriel SE. Epidemiology of CVD in rheumatic disease, with a focus on RA and SLE. Nat. Rev. Rheumatol.7, 399–408 (2011).
  • Lu L-J, Wallace DJ, Ishimori ML, Scofield RH, Weisman MH. Male systemic lupus erythematosus: a review of sex disparities in this disease. Lupus19, 119–129 (2010).
  • Agmon-Levin N, Mosca M, Petri M, Shoenfeld Y. Systemic lupus erythematosus one disease or many? Autoimmun. Rev. doi:10.1016/j.autrev.2011.10.020 (2011) (Epub ahead of print).
  • Wallberg-Jonsson S, Ohman ML, Dahlqvist SR. Cardiovascular morbidity and mortality in patients with seropositive rheumatoid arthritis in northern Sweden. J. Rheumatol.24, 445–451 (1997).
  • Avina-Zubieta JA, Choi HK, Sadatsafavi M, Etminan M, Esdaile JM, Lacaille D. Risk of cardiovascular mortality in patients with rheumatoid arthritis: a meta-analysis of observational studies. Arthitis Rheum.59, 1690–1697 (2008).
  • Innala L, Moller B, Ljung L et al. Cardiovascular events in early RA are a result of inflammatory burden and traditional risk factors: a five year prospective study. Arthritis Res. Ther.13, R131 (2011).
  • Kallwellis-Opara A, Dorner A, Poller WC et al. Autoimmunological features in inflammatory cardiomyopathy. Clin. Res. Cardiol.96, 469–480 (2007).
  • Fairweather D, Frisancho-Kiss S, Rose NR. Sex differences in autoimmune disease from a pathologic perspective. Am. J. Pathol.173, 600–609 (2008).
  • Vitale C, Mendelsohn ME, Rosano GMC. Gender differences in the cardiovascular effect of sex hormones. Nat. Rev. Cardiol.6, 532–542 (2009).
  • Regitz-Zagrosek V, Oertelt-Prignione S, Seeland U, Hetzer R. Sex and gender differences in myocardial hypertrophy and heart failure. Circ. J.74, 1265–1273 (2010).
  • Kaushik M, Sontineni SP, Hunter C. Cardiovascular disease and androgens: a review. Int. J. Cardiol.142, 8–14 (2010).
  • Lee LV, Foody JM. Women and heart disease. Cardiol. Clin.29, 35–45 (2011).
  • Tan YY, Gast GM, van der Schouw YT. Gender differences in risk factors for coronary heart disease. Maturitas65, 149–160 (2010).
  • Blauwet LA. Sex and race/ethnicity reporting in clinical trials: a necessity, not an option. J. Women’s Health20, 313–314 (2011).
  • Mendelsohn ME, Karas RH. Molecular and cellular basis of cardiovascular gender differences. Science308, 1583–1587 (2005).
  • Legato MJ, Leghe JK. Gender and the heart: sex-specific differences in the normal myocardial anatomy and physiology. In: Principles of Gender-Specific Medicine (2nd Edition). Legato MJ (Ed.). Elsevier, MA, USA, 151–161 (2010).
  • Isensee J, Ruiz, Noppinger P. Sexually dimorphic gene expression in mammalian somatic tissue. Gend. Med.4(Suppl. B), S75–S95 (2007).
  • Lahita RG. Sex hormones and immune function. In: Principles of Gender-Specific Medicine (2nd Edition). Legato MJ (Ed.). Elsevier, MA, USA, 615–626 (2010).
  • Regitz-Zagrosek V, Becher E, Mahmoodzadeh S, Schubert C. Sex steroid hormones. In: Cardiovascular Hormone Systems: From Molecular Mechanisms to Novel Therapeutics. Bader M (Ed.). Wiley-Blackwell, Weinheim, Germany, 39–64 (2008).
  • Cutolo M. Hormones and cytokines: gender-specific effects. In: Principles of Gender-Specific Medicine (2nd Edition). Legato MJ (Ed.). Elsevier, MA, USA, 592–596 (2010).
  • Straub RH. The complex role of estrogens in inflammation. Endocrine Rev.28, 521–574 (2007).
  • Cook IF. Sexual dimorphism of humoral immunity with vaccines. Vaccine26, 3551–3555 (2008).
  • Carreras E, Turner S, Frank MB et al. Estrogen receptor signaling promotes dendritic cell differentiation by increasing expression of the transcription factor IRF4. Blood115, 238–246 (2010).
  • Khan D, Dai R, Karpuzoglu E, Ahmed SA. Estrogen increases, whereas IL-27 and IFN-gamma decrease, splenocyte IL-17 production in WT mice. Eur. J. Immunol.40, 2549–2556 (2010).
  • Wang Y, Cela E, Gagnon S, Sweezey NB. Estrogen aggravates inflammation in Pseudomonas aeruginosa pneumonia in cystic fibrosis mice. Respir. Res.30, 166 (2010).
  • Xia X, Zhang S, Yu Y et al. Effects of estrogen replacement therapy on estrogen receptor expression and immunoregulatory cytokine secretion in surgically induced menopausal women. J. Reprod. Immunol.81, 89–96 (2009).
  • Pulendran B, Tang H, Manicassamy S. Programming dendritic cells to induce Th2 and tolergenic responses. Nat. Immunol.11, 647–655 (2010).
  • Dinesh RK, Hahn BH, Singh RP. PD-1, gender and autoimmunity. Autoimm. Rev.9, 583–587 (2010).
  • Sellner J, Kraus J, Awad A, Milo R, Hemmer B, Stuve O. The increasing incidence and prevalence of female multiple sclerosis – a critical analysis of potential environmental factors. Autoimm. Rev.10, 495–502 (2011).
  • Papenfuss TL, Powell ND, McClain MA et al. Estriol generates tolergenic dendritic cells in vivo that protect against autoimmunity. J. Immunol.186, 3346–3355 (2011).
  • Frisancho-Kiss S, Davis SE, Nyland JF et al. Cutting edge: cross-regulation by TLR4 and T cell Ig mucin-3 determines sex differences in inflammatory heart disease. J. Immunol.178, 6710–6714 (2007).
  • Giron-Gonzalez JA, Moral FJ, Elvira J et al. Consistent production of a higher TH1:TH2 cytokine ratio by stimulated T cells in men compared to women. Eur. J. Endocrinol.143, 31–36 (2000).
  • Frisancho-Kiss S, Coronado MJ, Frisancho JA et al. Gonadectomy of male BALB/c mice increases Tim-3+ alternatively activated M2 macrophages, Tim-3+ T cells, Th2 cells and Treg in the heart during acute coxsackievirus-induced myocarditis. Brain Behav. Immun.23, 649–657 (2009).
  • Onyimba JA, Coronado MJ, Garton AE et al. The innate immune response to coxsackievirus B3 predicts progression to cardiovascular disease and heart failure in male mice. Biol. Sex Differ.2, 2 (2011).
  • Curtiss LK, Tobias PS. Emerging role of Toll-like receptors in atherosclerosis. J. Lipid Res.50, S340–S345 (2009).
  • Teuscher C, Noubade R, Spach K et al. Evidence that the Y chromosome influences autoimmune disease in male and female mice. Proc. Natl. Acad. Sci. USA103, 8024–8029 (2006).
  • Ozcelik T. X chromosome inactivation and female predisposition to autoimmunity. Clinic Rev. Allerg. Immunol.34, 348–351 (2008).
  • Selmi C. The X in sex: how autoimmune diseases revolve around sex chromosomes. Best Pract. Res. Clin. Rheum.22, 913–922 (2008).
  • Arnold AP, Chen X. What does the “four core genotypes” mouse model tell us about sex differences in the brain and other tissues? Front. Neuroendocrinol.30, 1–9 (2009).
  • Lemos B, Branco AT, Hartl DL. Epigenetic effects of polymorphic Y chromosomes modulate chromatin components, immune response, and sexual conflict. Proc. Natl. Acad. Sci. USA107, 15826–15831 (2010).
  • Faulk C, Dolinoy DC. Timing is everything: the when and how of environmentally induced changes in the epigenome of animals. Epigenetics6, 791–797 (2011).
  • Renaudineau Y, Youinou P. Epigenetics and autoimmunity, with special emphasis on methylation. Keio. J. Med.60, 10–16 (2011).
  • Hansson GK, Hermansson A. The immune system in atherosclerosis. Nat. Immunol.12, 204–212 (2011).
  • Libby P, Ridker PM, Hansson GK. Progress and challenges in translating the biology of atherosclerosis. Nature473, 317–325 (2011).
  • White HD, Chew DP. Acute myocardial infarction. Lancet372, 570–584 (2008).
  • Laczik R, Szodoray P, Veres K et al. Assessment of IgG antibodies to oxidized LDL in patients with acute coronary syndrome. Lupus20, 730–735 (2011).
  • Shi G-P. Immunomodulation of vascular diseases: atherosclerosis and autoimmunity. Eur. J. Vasc. Endovasc. Surg.39, 485–494 (2010).
  • Dart ML, Jankowska-Gan E, Huang G et al. Interleukin-17-dependent autoimmunity to collagen type V in atherosclerosis. Circ. Res.107, 1106–1116 (2010).
  • Bergmark C, Wu R, de Faire U, Lefvert AK, Swedenborg J. Patients with early-onset peripheral vascular disease have increased levels of autoantibodies against oxidized LDL. Arterioscler. Thromb. Vasc. Biol.15, 441–445 (1995).
  • Greco TP, Conti-Kelly AM, Anthony JR et al. Oxidized-LDL/beta(2)-glycoprotein I complexes are associated with disease severity and increased risk for adverse outcomes in patients with acute coronary syndromes. Am. J. Clin. Pathol.133, 737–743 (2010).
  • Ait-Oufella H, Salomon BL, Potteaux S et al. Natural regulatory T cells control the development of atherosclerosis in mice. Nat. Med.12, 178–180 (2006).
  • Van Leeuwen M, Damoiseaux J, Duijvestijn A, Cohen JW, Cohen Tervaert JW. The therapeutic potential of targeting B cells and anti-oxLDL antibodies in atherosclerosis. Autoimm. Rev.9, 53–57 (2009).
  • Bjorkbacka H, Kunjathoor VV, Moore KJ et al. Reduced atherosclerosis in MyD88-null mice links elevated serum cholesterol levels to activation of innate immunity signaling pathways. Nat. Med.10, 416–421 (2004).
  • Kirii H, Niwa T, Yamada Y et al. Lack of interleukin-1beta decreases the severity of atherosclerosis in ApoE-deficient mice. Arterioscler. Thromb. Vasc. Biol.23, 656–660 (2003).
  • Elhage R, Jawien J, Rudling M et al. Reduced atherosclerosis in interleukin-18 deficient apolipoprotein E-knockout mice. Cardiovasc. Res.59, 234–240 (2003).
  • Mullick AE, Tobias PS, Curtiss LK. Modulation of atherosclerosis in mice by Toll-like receptor 2. J. Clin. Invest.115, 3149–3156 (2005).
  • Michelsen KS, Wong MH, Shah PK et al. Lack of Toll-like receptor 4 or myeloid differentiation factor 88 reduces atherosclerosis and alters plaque phenotype in mice deficient in apolipoprotein E. Proc. Natl. Acad. Sci. USA101, 10679–10684 (2004).
  • Sakao S, Tanabe N, Tatsumi K. The estrogen paradox in pulmonary arterial hypertension. Am. J. Physiol. Lung Cell. Mol. Physiol.299, L435–L438 (2010).
  • Regitz-Zagrosek V. Therapeutic implications of the gender-specific aspects of cardiovascular disease. Nat. Rev. Drug Discov.5, 425–438 (2006).
  • Villablanca AC, Jayachandran M, Banka C. Atherosclerosis and sex hormones: current concepts. Clin. Sci.119, 493–513 (2010).
  • McCrohon JA, Death AK, Nakhla S et al. Androgen receptor expression is greater in macrophages from male than from female donors. A sex difference with implications for atherogenesis. Circulation101, 224–226 (2000).
  • Wilson ME, Sengoku T, Allred KF. Estrogen prevents cholesteryl ester accumulation in macrophages induced by the HIV protease inhibitor ritonavir. J. Cell Biochem.103, 1598–1606 (2008).
  • Badeau RM, Metso J, Wahala K, Tikkanen MJ, Jauhiainen M. Human macrophage cholesterol efflux potential is enhanced by HDL-associated 17beta-estradiol fatty acyl esters. J. Steroid Biochem. Mol. Biol.116, 44–49 (2009).
  • Hodgin JB, Krege JH, Reddick RL, Korach KS, Smithies O, Maeda N. Estrogen receptor alpha is a major mediator of 17beta-estradiol’s atheroprotective effects on lesion size in Apoe-/- mice. J. Clin. Invest.107, 333–340 (2001).
  • Deshpande R, Khalili H, Pergolizzi RG, Michael SD, Change MD. Estradiol down-regulates LPS-induced cytokine production and NFκB activation in murine macrophages. Am. J. Reprod. Immunol.38, 46–54 (1997).
  • Evans MJ, Eckert A, Lai K, Adelman SJ, Harnish DC. Reciprocal antagonism between estrogen receptor and NF-kappaB activity in vivo. Circ. Res.89, 823–830 (2001).
  • Miller MA, Strazzullo P, Karanam S, Cappuccio FP. Ethnic variation in levels of circulation IgG autoantibodies to oxidized low-density lipoprotein. Atherosclerosis203, 126–136 (2009).
  • Von Dehn G, von Dehn O, Volker W et al. Atherosclerosis in apolipoprotein E-deficient mice is decreased by the suppression of endogenous sex hormones. Horm. Metab. Res.33, 110–114 (2001).
  • English KM, Mandour O, Steeds RP, Diver MJ, Jones TH, Channer KS. Men with coronary artery disease have lower levels of androgens than men with normal coronary angiograms. Eur. Heart J.21, 890–894 (2000).
  • Wexler RK, Elton T, Pleister A, Feldman D. Cardiomyopathy: an overview. Am. Fam. Physician.79, 778–784 (2009).
  • Grzybowski J, Bilinska ZT, Ruzyllo W et al. Determinants of prognosis of nonischemic dilated cardiomopathy. J. Card. Fail.2, 77–85 (1996).
  • Gupta S, Markham DW, Drazner MH, Mammen PPA. Fulminant myocarditis. Nat. Clin. Practice5, 693–706 (2008).
  • Schultheiss HP, Kuhl U, Cooper LT. The management of myocarditis. Eur. Heart J.32, 2616–2625 (2011).
  • Blauwet LA, Cooper LT. Myocarditis. Prog. Cardiovasc. Dis.52, 274–288 (2010).
  • Schultheiss HP, Kuhl U. Why is diagnosis of infectious myocarditis such a challenge? Expert Rev. Anti Infect. Ther.9(12), 1093–1095 (2011).
  • Andreoletti L, Venteo L, Douche-Aourik F et al. Active coxsackieviral B infection is associated with disruption of dystrophin in endomyocardial tissue of patients who died suddenly of acute myocardial infarction. J. Am. Coll. Cardiol.50, 2207–2214 (2007).
  • Huber SA. Autoimmunity in coxsackievirus B3 induced myocarditis. Autoimmunity39, 55–61 (2006).
  • Fairweather D, Rose NR. Coxsackievirus-induced myocarditis in mice: a model of autoimmune disease for studying immunotoxicity. Methods41, 118–122 (2007).
  • Ellis NM, Kurahara DK, Vohra H et al. Priming the immune system for heart disease: a perspective on group A streptococci. J. Infect. Dis.202, 1059–1067 (2010).
  • Huber SA, Job LP. Cellular immune mechanisms in coxsackievirus group B, type 3 induced myocarditis in BALB/c mice. Adv. Exp. Med. Biol.161, 491–508 (1983).
  • Cihakova D, Barin JG, Afanasyeva M et al. Interleukin-13 protects against experimental autoimmune myocarditis by regulating macrophage differentiation. Am. J. Pathol.172, 1195–1208 (2008).
  • Fairweather D, Kaya Z, Shellam GR, Lawson CM, Rose NR. From infection to autoimmunity. J. Autoimm.16, 175–186 (2001).
  • Huber SA, Sartini D, Exley M. Vgamma4(+) T cells promote autoimmune CD8(+) cytolytic T-lymphocyte activation in coxsackievirus B3-induced myocarditis in mice: role for CD4(+) Th1 cells. J. Virol.76, 10785–10790 (2002).
  • Huber SA. T lymphocytes kill T regulatory cells through CD1d. Immunology131, 202–209 (2010).
  • Frisancho-Kiss S, Nyland JF, Davis SE et al. Cutting Edge: T cell Ig mucin-3 reduces inflammatory heart disease by increasing CTLA-4 during innate immunity. J. Immunol.176, 6411–6415 (2006).
  • Fairweather D, Cihakova D. Alternatively activated macrophages in infection and autoimmunity. J. Autoimm.33, 222–230 (2009).
  • Huber SA. Cd1d expression on hemopoietic cells promotes CD4+ Th1 response in coxsackievirus B3 induced myocarditis. Virology352, 226–236 (2006).
  • Noutsias M, Rohde M, Goldner K et al. Expression of functional T-cell markers and T-cell receptor Vbeta repertoire in endomyocardial biopsies from patients presenting with acute myocarditis and dilated cardiomyopathy. Eur. J. Heart Fail.13, 611–618 (2011).
  • Yuan J, Cao AL, Yu M et al. Th17 cells facilitate the humoral immune response in patients with acute viral myocarditis. J. Clin. Immunol.30, 226–234 (2010).
  • Baldeviano GC, Barin JG, Talor MV et al. Interleukin-17A is dispensable for myocarditis but essential for the progression to dilated cardiomyopathy. Circ. Res.106, 1646–1655 (2010).
  • Abston ED, Coronado MJ, Bucek A et al. Th2 regulation of viral myocarditis in mice: different roles for TLR3 vs. TRIF in progression to chronic disease. Clin. Dev. Immunol.2012, 129486 (2012).
  • Mann DL. The emerging role of innate immunity in the heart and vascular system: for whom the cell tolls. Circ. Res.108, 1133–1145 (2011).
  • Lane JR, Neumann DA, Lafond-Walker A, Herskowitz A, Rose NR. LPS promotes CB3-induced myocarditis in resistant B10.A mice. Cell. Immunol.136, 219–233 (1991).
  • Fairweather D, Yusung S, Frisancho S et al. IL-12Rβ1 and TLR4 increase IL-1β and IL-18-associated myocarditis and coxsackievirus replication. J. Immunol.170, 4731–4737 (2003).
  • Cain BS, Meldrum DR, Dinarello CA et al. Tumor necrosis factor-alpha and interleukin-1beta synergistically depress human myocardial function. Crit. Care Med.27, 1309–1318 (1999).
  • Blyszczuk P, Kania G, Dieterle T et al. Myeloid differentiation factor88/ interleukin-1 signaling controls cardiac fibrosis and heart failure progression in inflammatory dilated cardiomyopathy. Circ. Res.105, 912–920 (2009).
  • Vallejo JG. Role of Toll-like receptors in cardiovascular diseases. Clin. Sci.121, 1–10 (2011).
  • Zhang P, Cox CJ, Alvarez KM, Cunningham MW. Cutting edge: cardiac myosin activates innate immune responses through TLRs. J. Immunol.183, 27–31 (2009).
  • Satoh M, Nakamura M, Akatsu T et al. Expression of Toll-like receptor 4 is associated with enteroviral replication in human myocarditis. Clin. Sci. (London)104, 577–584 (2003).
  • Fairweather D, Frisancho-Kiss S, Yusung SA et al. IFN-γ protects against chronic viral myocarditis by reducing mast cell degranulation, fibrosis, and the profibrotic cytokines TGF-β1, IL-1β, and IL-4 in the heart. Am. J. Pathol.165, 1883–1894 (2004).
  • Fairweather D, Frisancho-Kiss S, Njoku DB et al. Complement receptor 1 and 2 deficiency increases coxsackievirus B3-induced myocarditis and heart failure by increasing macrophages, IL-1β and immune complex deposition in the heart. J. Immunol.176, 3516–3524 (2006).
  • Nishikubo K, Imanaka-Yoshida K, Tamaki S et al. Th1-type immune responses by Toll-like receptor 4 signaling are required for the development of myocarditis in mice with BCG-induced myocarditis. J. Autoimm.29, 146–153 (2007).
  • Gorbea C, Makar KA, Pauschinger M et al. A role for Toll-like receptor 3 variants in host susceptibility to enteroviral myocarditis and dilated cardiomyopathy. J. Biol. Chem.285, 23208–23223 (2010).
  • Riad A, Westermann D, Escher F et al. Myeloid differentiation factor-88 contributues to TLR9-mediated modulation of acute coxsackievirus B3-induced myocarditis in vivo. Am. J. Physiol. Heart Circ. Physiol.298, H2024–H2031 (2010).
  • Pagni PP, Truab S, Demaria O, Chasson L, Alexopoulou L. Contribution of TLR7 and TLR9 signaling to the susceptibility of MyD88-deficient mice to myocarditis. Autoimmunity43, 275–287 (2010).
  • Riad A, Westermann D, Zietsch C et al. TRIF is a critical survival factor in viral cardiomyopathy. J. Immunol.186, 2561–2570 (2011).
  • Huber SA, Job LP, Woodruff JF. Sex-related differences in the pattern of coxsackievirus B3-induced immune spleen cell cytotoxicity against virus-infected myofibers. Infect. Immun.32, 68–73 (1981).
  • Robinson DP, Huber SA, Moussawi M et al. Sex chromosome complement contributes to sex differences in coxsackievirus B3 but not influenza A virus pathogenesis. Biol. Sex Differ.2, 8 (2011).
  • Huber SA. Increased susceptibility of male BALB/c mice to coxsackievirus B3-induced myocarditis: role for CD1d. Med. Microbiol. Immunol.194, 121–127 (2005).
  • Huber SA. Coxsackievirus B3-induced mycoarditis: infection of females during the estrus phase of the ovarian cycle leads to activation of T regulatory cells. Virology378, 292–298 (2008).
  • Li K, Xu W, Guo Q et al. Differential macrophage polarization in male and female BALB/c mice infected with coxsackievirus B3 defines susceptibility to viral myocarditis. Circ. Res.105, 353–364 (2009).
  • Frisancho-Kiss S, Nyland JF, Davis SE et al. Sex differences in coxsackievirus B3-induced myocarditis: IL-12Rbeta1 signaling and IFN-gamma increase inflammation in males independent from STAT4. Brain Res.1126, 139–147 (2006).
  • Kindermann I, Kindermann N, Kandolf R et al. Predictors of outcome in patients with suspected myocarditis. Circulation118, e493 (2008).
  • Cocker MS, Abdel-Aty H, Strohm O, Friedrich MG. Age and gender effects on the extent of myocardial involvement in acute myocarditis: a cardiovascular magnetic resonance study. Heart95, 1925–1930 (2009).
  • Cavasin MA, Tao ZY, Yu AL, Yang XP. Testosterone enhances early cardiac remodeling after myocardial infarction, causing rupture and degrading cardiac function. Am. J. Physiol. Heart Circ. Physiol.290, H2043–H2050 (2006).
  • Wolfgram LJ, Beisel KW, Rose NR. Heart-specific autoantibodies following murine coxsackievirus B3 myocarditis. J. Exp. Med.161, 1112–1121 (1985).
  • Fairweather D, Abston ED, Coronado MJ. Biomarkers of heart failure in myocarditis and dilated cardiomyopathy. In: Myocarditis. Cihakova D (Ed.). InTech Open Access Publisher, Rijeka, Croatia, 323–348 (2011).
  • Nussinovitch U, Shoenfeld Y. The clinical significance of anti-beta-1 adrenergic receptor autoantibodies in cardiac disease. Clin. Rev. Allergy Immunol. doi:10.1007/s12016-010-8228-9 (2010) (Epub ahead of print).
  • Nussinovitch U, Shoenfeld Y. The clinical and diagnostic significance of anti-myosin autoantibodies in cardiac disease. Clin. Rev. Allergy Immunol. doi:10.1007/s12016-010-8229-8 (2011) (Epub ahead of print).
  • Nussinovitch U, Shoenfeld Y. The diagnostic and clinical significance of anti-muscarinic receptor autoantibodies. Clin. Rev. Allergy Immunol. doi:10.1007/s12016-010-8235 (2011) (Epub ahead of print).
  • Limas CJ, Goldenberg IF, Limas C. Autoantibodies against beta-adrenoreceptors in human idiopathic dilated cardiomyopathy. Circ. Res.64, 97–103 (1989).
  • Mascaro-Blanco A, Alvarez K, Yu X et al. Consequences of unlocking the cardiac myosin molecule in human myocarditis and cardiomyopathies. Autoimmunity41, 442–453 (2008).
  • Jahns R, Boivin V, Hein L et al. Direct evidence for a beta 1-adrenergic receptor-directed autoimmune attack as a cause of idiopathic dilated cardiomyopathy. J. Clin. Invest.113, 1419–1429 (2004).
  • Robinson T, Smith A, Channer KS. Reversible heart failure: the role of inflammatory activation. Postgrad. Med. J.87, 110–115 (2011).
  • Wang Y-X, da Cunha V, Vincelette J et al. Antiviral and myocyte protective effects of murine interferon-β and -α2 in coxsackievirus B3-induced myocarditis and epicarditis in BALB/c mice. Am. J. Physiol. Heart Circ. Physiol.293, H69–H76 (2007).
  • Regitz-Zagrosek V, Seeland U. Sex and gender differences in myocardial hypertrophy and heart failure. Wien Med. Wochenschr.161, 109–116 (2011).
  • Murphy E, Steenbergen C. Cardioprotection in females: a role for nitric oxide and altered gene expression. Heart Fail. Rev.12, 293–300 (2007).
  • The Autoimmune Diseases Coordinating Committee. Progress in Autoimmune Disease Research, Report to Congress. National Institutes of Health, DC, USA (2005).
  • Zandman-Goddard G, Peeva E, Shoenfeld Y. Gender and autoimmunity. Autoimm. Rev.6, 366–372 (2007).
  • McCombe PA, Greer JM, Mackay IR. Sexual dimorphism in autoimmune disease. Curr. Mol. Med.9, 1058–1079 (2009).
  • Brooks WH, Le Dantec C, Pers JO, Youinou P, Renaudineau Y. Epigenetics and autoimmunity. J. Autoimmun.34, J207–J219 (2010).
  • Toms TE, Panoulas VF, Kitas GD. Dyslipidaemia in rheumatological autoimmune diseases. Open Cardiov. Med. J.5, 64–75 (2011).
  • Kung M, Stork S, Angermann CE. Cardiovascular comorbidity in rheumatic disease. Does sex play a role? Herz30, 512–521 (2005).
  • Petri M. Sex hormones and systemic lupus erythematosus. Lupus17, 412–415 (2008).
  • Weckerle CE, Niewold TB. The unexplained female predominance of systemic lupus erythematosus: clues from genetic and cytokine studies. Clinic. Rev. Allerg. Immunol.40, 42–49 (2011).
  • Petri M. Systemic lupus erythematosus: 2006 update. J. Clin. Rheumatol.12, 37–40 (2006).
  • Gualtierotti R, Biggioggero M, Penatti AE, Meroni PL. Updating on the pathogenesis of systemic lupus erythematosus. Autoimm. Rev.10, 3–7 (2010).
  • Abdou NI, Rider V. Gender differences in autoimmune diseases: immune mechanisms and clinical applications. In: Principles of Gender-Specific Medicine (2nd Edition). Legato MJ (Ed.). Elsevier, MA, USA, 858–591 (2010).
  • Wang J, Nuite M, McAlindon TE. Association of estrogen and aromatase gene polymorphisms with systemic lupus erythematosus. Lupus19, 734–740 (2010).
  • Lu L-J, Wallace DJ, Ishimori ML, Scofield RH, Weisman MH. Male systemic lupus erythematosus: a review of sex disparities in this disease. Lupus19, 119–129 (2010).
  • Niewold TB, Adler JE, Glenn SB, Lehman TJ, Harley JB, Crow MK. Age- and sex-related patterns of serum interferon-alpha activity in lupus families. Arthritis Rheum.58, 2113–2119 (2008).
  • Ronnblom L, Alm GV, Eloranta ML. Type I interferon and lupus. Curr. Opin. Rheumatol.21, 471–477 (2009).
  • Siracusa MC, Overstreet MG, Housseau F, Scott AL, Klein SL. 17beta-estradiol alters the activity of conventional and IFN-producing killer dendritic cells. J. Immunol.180, 1423–1431 (2008).
  • Szalay G, Sauter M, Haberland M et al. Osteopontin: a fibrosis-related marker molecule in cardiac remodeling of enterovirus myocarditis in the susceptible host. Circ. Res.104, 851–859 (2009).
  • Kariuki SN, Moore JG, Kirou KA, Crow MK, Utset TO, Niewold TB. Age- and gender-specific modulation of serum osteopontin and interferon-alpha by osteopontin genotype in systemic lupus erythematosus. Genes Immun.10, 487–494 (2009).
  • Doria A, Iaccarino L, Sarzi-Puttini P, Atzeni F, Turriel M, Petri M. Cardiac involvement in systemic lupus erythematosus. Lupus14, 683–686 (2005).
  • Crosslin KL, Wiginton KL. Sex differences in disease severity among patients with systemic lupus erythematosus. Gend. Med.8, 365–371 (2011).
  • Kiani AN, Magder L, Petri M. Coronary calcium in systemic lupus erythamatosus is associated with traditional cardiovascular risk factors, but not with disease activity. J. Rheumatol.35, 1300–1306 (2008).
  • Karp I, Abrahamowicz M, Fortin PR et al. Recent corticosteroid use and recent disease activity: independent determinants of coronary heart disease risk factors in systemic lupus erythematosus? Arthritis Rheum.59, 169–175 (2008).
  • Petri MA, Kiani AN, Christopher-Stine L, Magder LS. Lupus atherosclerosis prevention study (LAPS). Ann. Rheum. Dis.70(5), 760–765 (2011).
  • Ashrafi R, Garg P, McKay E, Gosney J, Chuah S, Davis G. Aggressive cardiac involvement in systemic lupus erythematosus: a case report and a comprehensive literature review. Cardiol. Res. Pract.2011, 578390 (2011).
  • Ippolito A, Petri M. An update on mortality in systemic lupus erythematosus. Clin. Exp. Rheumatol.26(5 Suppl. 51), S72–S79 (2008).
  • Petri M. The lupus anticoagulant is a risk factor for myocardial infarction (but not atherosclerosis): Hopkins Lupus Cohort. Thromb. Res.114, 593–595 (2004).
  • Van Venrooij WJ, van Beers JJBC, Pruijn GJM. Anti-CCP antibodies: the past, the present and the future. Nat. Rev. Rheumatol.7, 391–398 (2011).
  • Steiner G, Urowitz M. Lipid profiles in patients with rheumatoid arthritis: mechanisms and the impact of treatment. Semin. Arthritis Rheum.38, 372–381 (2009).
  • Bartoloni E, Alunno A, Luccioli F et al. Atherosclerotic vascular damage and rheumatoid arthritis: a complex but intriguing link. Expert Rev. Cardiovasc. Ther.8, 1309–1316 (2010).
  • Nielsen RH, Christiansen C, Stolina M, Karsdal MA. Oestrogen exhibits type II collagen protective effects and attenuates collagen-induced arthritis in rats. Clin. Exp. Immunol.152, 21–27 (2008).
  • van Vollenhoven RF, Houbiers JG, Buttgereit F et al. The selective estrogen receptor alpha agonist Org 37663 induces estrogenic effects but lacks antirheumatic activity: a Phase IIa trial investigating efficacy and safety of Org 37663 in postmenopausal female rheumatoid arthritis patients receiving stable background methotrexate or sulfasalazine. Arthitis Rheum.62, 351–358 (2010).
  • Cutolo M. Selective estrogen receptor agonism lacks clinical benefit in rheumatoid arthritis: comment on the article by van Vollenhoven et al. Arthitis Rheum.62, 3832–3833 (2010).
  • Castagnetta LA, Carruba G, Franata OM et al. Increased estrogen formation and estrogen to androgen ratio in the synovial fluid of patients with rheumatoid arthritis. J. Rheumatol.30, 2597–2605 (2003).
  • Olsen NJ, Kovacs WJ. Hormones, pregnancy and rheumatoid arthritis. J. Gend. Specif. Med.5, 28–37 (2002).
  • Kramer HR, Giles JT. Cardiovascular disease risk in rheumatoid arthritis: progress, debate, and opportunity. Arthritis Care Res.63, 484–499 (2011).
  • Dixon WG, Watson KD, Lunt M et al. Reduction in the incidence of myocardial infarction in patients with rheumatoid arthritis who respond to anti-tumor necrosis factor alpha therapy: results from the British Society for Rheumatology Biologics Register. Arthitis Rheum.56, 2905–2912 (2007).
  • Cihakova D, Talor MV, Barin JG et al. Sex differences in a murine model of Sjorgren syndrome. Ann. N.Y. Acad. Sci.1173, 378–383 (2009).
  • Baldini C, Tlarico R, Tzioufas AG, Bombardieri S. Classification criteria for Sjögren’s syndrome: a critical review. J. Autoimm. doi:10.1016/j.jaut.2011.12.006 (2011) (Epub ahead of print).
  • Defendenti C, Atzeni F, Spina MF et al. Clinical and laboratory aspects of Ro/SSA-52 autoantibodies. Autoimm. Rev.10, 150–154 (2011).
  • Manoussakis MN, Boiu S, Korkolopoulou P et al. Rates of infiltration by macrophages and dendritic cells and expression of interleukin-18 and interleukin-12 in the chronic inflammatory lesions of Sjögren’s syndrome: correlation with certain features of immune hyperactivity and factors associated with high risk of lymphoma development. Arthritis Rheum.56, 3977–3988 (2007).
  • Vaudo G, Bocci EB, Schoenfeld Y et al. Precocious intima-media thickening in patients with primary Sjögren’s syndrome. Arthritis Rheum.52, 3890–3897 (2005).
  • Shanmugam VK, Swistowski DR, Saddic N, Wang H, Stten VD. Comparison of indirect immunofluorescence and multiplex antinuclear antibody screening in systemic sclerosis. Clin. Rheumatol.30, 1363–1368 (2011).
  • Au K, Singh MK, Bodukam V et al. Atherosclerosis in systemic sclerosis: a systemic review and meta-analysis. Arthritis Rheum.63, 2078–2090 (2011).
  • Mok MY, Lau CS, Chiu SS et al. Systemic sclerosis is an independent risk factor for increased coronary artery calcium deposition. Arthritis Rheum.63, 1387–1395 (2011).
  • Nguyen C, Berezne A, Baubet T et al. Association of gender with clinical expression, quality of life, disability, and depression and anxiety in patients with systemic sclerosis. PLoS ONE6, e17551 (2011).
  • Dube SR, Fairweather D, Pearson W, Felitti VJ, Anda RF, Croft JB. Cumulative childhood stress and autoimmune diseases in adults. Psychosom. Med. J. Biobehav. Med.71, 243–250 (2009).
  • Firestein GS. Evolving concepts of rheumatoid arthritis. Nature423, 356–361 (2003).
  • Carson DA, Chen PP, Fox RI et al. Rheumatoid factor and immune networks. Ann. Rev. Immunol.5, 109–126 (1987).
  • Newkirk MM. Rheumatoid factors: host resistance or autoimmunity? Clin. Immunol.104, 1–13 (2002).
  • Dorner T, Egerer K, Feist E, Burmester GR. Rheumatoid factor revisited. Curr. Opin. Rheumatol.16, 246–253 (2004).
  • Christensen P, Schroder AK. Possible role of microbial IgG Fc-binding proteins in rheumatic arthritis. Agents Actions29, 88–94 (1990).
  • Shoenfeld Y, Rose NR (Eds). Infection and Autoimmunity. Elsevier, Amsterdam, The Netherlands (2004).
  • Santegoets KCM, van Bon L, van den Berg WB, Wenink MH, Radstake TRDJ. Toll-like receptors in rheumatic diseases: are we paying a high price for our defense against bugs? FEBS Letters585, 3660–3666 (2011).
  • Tomasson G, Aspelund T, Jonsson T, Valdimarsson H, Felson DT, Gudnason V. Effect of rheumatoid factor on mortality and coronary heart disease. Ann. Rheum. Dis.69, 1649–1654 (2010).
  • Goodson NJ, Wiles NJ, Lunt M, Barrett EM, Silman AJ, Symmons DP. Mortality in early inflammatory polyarthritis: cardiovascular mortality is increased in seropositive patients. Arthritis Rheum.46, 2010–2019 (2002).
  • Goodson NJ, Symmons DP, Scott DG, Bunn D, Lunt M, Silman AJ. Baseline levels of C-reactive protein and prediction of death from cardiovascular disease in patients with inflammatory polyarthritis: a ten-year followup study of a primary care-based inception cohort. Arthritis Rheum.52, 2293–2299 (2005).
  • Naz SM, Farraqher TM, Bunn DK, Symmons DP, Bruce IN. The influence of age at symptom onset and length of followup on mortality in patients with recent-onset inflammatory polyarthritis. Arthritis Rheum.58, 985–989 (2008).
  • Mustafa A, Nityanand S, Berglund L, Lithell H, Lefvert AK. Circulating immune complexes in 50-year-old men as a strong and independent risk factor for myocardial infarction. Circulation102, 2576–2581 (2000).
  • Edwards CJ, Syddall H, Goswami R et al. The autoantibody rheumatoid factor may be an independent risk factor for ischemic heart disease in men. Heart93, 1263–1267 (2007).
  • Wolfe F, Cathey MA, Roberts FK. The latex test revisited: rheumatoid factor testing in 8,287 rheumatic disease patients. Arthritis Rheum.34, 951–960 (1991).
  • Anaya J-M, Liu GT, D’Souza E, Ogawa N, Luan X, Talal N. Primary Sjögren’s syndrome in men. Ann. Rheum. Dis.54, 748–751 (1995).
  • Doria A, Pauletto P (Eds). The Heart in Systemic Autoimmune Diseases. Elsevier, Amsterdam, The Netherlands (2004).
  • Shoenfeld Y, Rose NR (Eds). Infection and Autoimmunity. Elsevier, Amsterdam, The Netherlands (2004).

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.