- Progress in Autoimmune Diseases Research, Report to Congress, National Institutes of Health, The Autoimmune Diseases Coordinating Committee, March 2005
- Jacobson DL, Gange SJ, Rose NR, Graham NMH. Epidemiology and estimated population burden of selected autoimmune disease in the United States. Clin Immunol Immunopathol. 1997;84:223–243.
- Dooley MA, Hogan SL. Environmental epidemiology and risk factors for autoimmune disease. Curr Opin Rheumatol. 2003;15:99–103.
- Gleicher N, Barad DH. Gender as risk factor for autoimmune diseases. J Autoimmun. 2007;28:1–6.
- Styrt B, Sugarman B. Estrogens and infection. Rev Infect Dis. 1991;13:1139–1150.
- Girón-González JA, Moral FJ, Elvira J, Garcia-Gil D, Guerrero F, Gavilan I, Escobar L. Consistent production of a higher Th1: Th2 cytokine ratio by stimulated T cells in men compared with women. Eur J Endocrinol. 2000;143:31–36.
- Klein SL. The effects of hormones on sex differences in infection: from genes to behavior. Neurosci Biobehav Rev. 2000;24:627–638.
- Lang TJ. Estrogen as an immunomodulator. Clin Immunol. 2004;113:224–230.
- Kher A, Wang M, Tsai BM, Pitcher JM, Greenbaum ES, Nagy RD, Patel KM, Wairiuko GM, Markel TA, Meldrum DR. Sex differences in the myocardial inflammatory response to acute injury. Shock. 2005;23:1–10.
- Straub RH. The complex role of estrogens in inflammation. Endocrine Rev. 2007;28:521–574.
- Fairweather D. Autoimmune disease: mechanisms. Chichester: John Wiley & Sons Ltd.,; Encyclopedia of Life Sciences. 2007 DOI: 10.1002/9780470015902.a0020193.
- Tiller T, Tsuiji M, Yurasov S, Velinzon K, Nussenzweig MC, Wardemann H. Autoreactivity in human IgG+ memory B cells. Immunity. 2007;26:205–213.
- Notkins AL. Pathogenic mechanisms in autoimmune disease. Autoimmun Rev. 2004;3(Suppl 1):S7–S9.
- Wilder RL. Neuroendocrine-immune system interactions and autoimmunity. Annu Rev Immunol. 1995;13:307–338.
- Fairweather D, Rose NR. Immunopathogenesis of autoimmune disease. Luebke R, House R, Kimber I, editors. Boca Raton: CRC Press,; Immunotoxicology and Immunopharmacology. (ed 3) 2007:pp 423–436.
- Fairweather D, Frisancho-Kiss S, Yusung SA, Barrett MA, Davis SE, Steele RA, Gatewood SJL, Rose NR. IL-12 protects against coxsackievirus B3-induced myocarditis by increasing IFN-γ and macrophage and neutrophil populations in the heart. J Immunol. 2005;174:261–269.
- Stockinger B, Veldhoen M, Martin B. Th17 T cells: linking innate and adaptive immunity. Semin Immunol. 2007;19:353–361.
- Matsuzaki G, Umemura M. Interleukin-17 as an effector molecule of innate and acquired immunity against infections. Microbiol Immunol. 2007;51:1139–1147.
- Pappu BP, Angkasekwinai P, Dong C. Regulatory mechanisms of helper T cell differentiation: new lessons learned from interleukin 17 family cytokines. Pharmacol Ther. 2008;117:374–384.
- Annacker O, Burlen-Defranoux O, Pimenta-Araujo R, Cumano A, Bandeira A. Regulatory CD4 T cells control the size of the peripheral activated/memory CD4 T cell compartment. J Immunol. 2000;164:3573–3580.
- Stockinger B, Veldhoen M. Differentiation and function of Th17 T cells. Curr Opin Immunol. 2007;19:281–286.
- Raimondi G, Turner MS, Thomson AW, Morel PA. Naturally occurring regulatory T cells: recent insights in health and disease. Crit Rev Immunol. 2007;27:61–95.
- Fairweather D, Yusung S, Frisancho-Kiss S, Barrett M, Gatewood S, Steele R, Rose NR. IL-12Rβ1 and TLR4 increase IL-1β and IL-18-associated myocarditis and coxsackievirus replication. J Immunol. 2003;170:4731–4737.
- Fairweather D, Frisancho-Kiss S, Rose NR. Viruses as adjuvants for autoimmunity: evidence from coxsackievirus-induced myocarditis. Rev Med Virol. 2005;15:17–27.
- Morwood SR, Nicholson LB. Modulation of the immune response by extracellular matrix proteins. Arch Immunol Ther Exp. 2006;54:367–374.
- Chen K, Huang J, Gong W, Iribarren P, Dunlop NM, Wang JM. Toll-like receptors in inflammation, infection and cancer. Int Immunopharmacol. 2007;7:1271–1285.
- van Duin D, Medzhitov R, Shaw AC. Triggering TLR signaling in vaccination. Trends Immunol. 2006;27:49–55.
- Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell. 2006;124:783–801.
- Frisancho-Kiss S, Nyland JF, Davis SE, Frisancho JA, Barrett MA, Rose NR, Fairweather D. Sex differences in coxsackievirus B3-induced myocarditis: IL-12Rβ1 signaling and IFN-γ increase inflammation in males independent from STAT4. Brain Res. 2006;1126:139–147.
- Fremond CM, Togbe D, Doz E, Rose S, Vasseur V, Maillet I, Jacobs M, Ryffel B, Quesniaux VF. IL-1 receptor-mediated signal is an essential component of MyD88-dependent innate response to Mycobacterium tuberculosis infection. J Immunol. 2007;179:1178–1189.
- Leber JH, Crimmins GT, Raghavan S, Meyer-Morse NP, Cox JS, Portnoy DA. Distinct TLR- and NLR-mediated transcriptional responses to an intracellular pathogen. PLoS Pathog. 2008;4:e6.
- Frisancho-Kiss S, Davis SE, Nyland JF, Frisancho JA, Cihakova D, Rose NR, Fairweather D. Cutting edge: cross-regulation by TLR4 and T cell Ig mucin-3 determines sex differences in inflammatory heart disease. J Immunol. 2007;178:6710–6714.
- Frisancho-Kiss S, Nyland JF, Davis SE, Barrett MA, Gatewood SJL, Njoku DB, Cihakova D, Silbergeld EK, Rose NR, Fairweather D. Cutting edge: T cell Ig mucin-3 reduces inflammatory heart disease by increasing CTLA-4 during innate immunity. J Immunol. 2006;176:6411–6415.
- Karin M, Lawrence T, Nizet V. Innate immunity gone awry: linking microbial infections to chronic inflammation and cancer. Cell. 2006;124:823–835.
- Meyers JH, Sabatos CA, Chakravarti S, Kuchroo VK. The TIM gene family regulates autoimmune and allergic diseases. Trends Mol Med. 2005;11:362–369.
- Sun J, Walsh M, Villarino AV, Cervi L, Hunter CA, Choi Y, Pearce EJ. TLR ligands can activate dendritic cells to provide a MyD88-dependent negative signal for Th2 cell development. J Immunol. 2005;174:742–751.
- Dillon S, Agrawal A, van Dyke T, Landreth G, McCauley L, Koh A, Maliszewski C, Akira S, Pulendran B. A Toll-like receptor 2 ligand stimulates Th2 responses in vivo via induction of extracellular signal-regulated kinase mitogen-activated protein kinase and c-Fos in dendritic cells. J Immunol. 2004;172:4733–4743.
- Re F, Strominger JL. IL-10 released by concomitant TLR2 stimulation blocks the induction of a subset of Th1 cytokines that are specifically induced by TLR4 or TLR3 in human dendritic cells. J Immunol. 2004;173:7548–7555.
- Imanishi T, Hara H, Suzuki S, Suzuki N, Akira S, Saito T. Cutting edge: TLR2 directly triggers Th1 effector functions. J Immunol. 2007;178:6715–6719.
- Jones B, Chen J. Inhibition of IFN-gamma transcription by site-specific methylation during T helper cell development. EMBO J. 2006;25:2443–2452.
- Djuretic IM, Levanon D, Negreanu V, Groner Y, Rao A, Ansel KM. Transcription factors T-bet and Runx3 cooperate to activate Ifng and silence Il4 in T helper type 1 cells. Nat Immunol. 2007;8:145–153.
- Kumar V, Abbas AK, Fausto N, editors. Philadelphia: Elsevier Saunders,; Acute and chronic inflammation. Robbins and Cotran Pathologic Basis of Disease. (ed 7) 2005:pp 47–86.
- Fairweather D, Frisancho-Kiss S, Yusung SA, Barrett MA, Gatewood SJL, Davis SE, Njoku DB, Rose NR. 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. 2004;165:1883–1894.
- Kumar V, Abbas AK, Fausto N, editors. Philadelphia: Elsevier Saunders,; Tissue renewal and repair: regeneration, healing and fibrosis. Robbins and Cotran Pathologic Basis of Disease. (ed 7) 2005:pp 87–118.
- Lane JR, Neumann DA, Lafond-Walker A, Herskovitz A, Rose NR. Interleukin 1 or tumor necrosis factor can promote coxsackievirus B3-induced myocarditis in resistant B10 A mice. J Exp Med. 1992;175:1123–1129.
- Ito A, Bebo BF, Jr, Matejuk A, Zamora A, Silverman M, Fyfe-Johnson A, Offner H. Estrogen treatment down-regulates TNF-alpha production and reduces the severity of experimental autoimmune encephalomyelitis in cytokine knockout mice. J Immunol. 2001;167:542–552.
- Fairweather D, Kaya Z, Shellam GR, Lawson CM, Rose NR. From infection to autoimmunity. J Autoimmun. 2001;16:175–186.
- Fairweather D, Rose NR. Coxsackievirus-induced myocarditis in mice: a model of autoimmune disease for studying immunotoxicity. Methods. 2007;41:118–122.
- Rose NR, Mackay IR, editors. St. Louis: Elsevier Academic Press,; The Autoimmune Diseases. (ed 4) 2006
- Kumar V, Abbas AK, Fausto N, editors. Philadelphia: Elsevier Saunders,; Robbins and Cotran Pathologic Basis of Disease. (ed 7) 2005
- Verthelyi D, Klinman DM. Sex hormone levels correlate with the activity of cytokine-secreting cells in vivo. Immunology. 2000;100:384–390.
- Beeson PB. Age and sex associations of 40 autoimmune diseases. Am J Med. 1994;96:457–462.
- Lopez AD. Global and regional burden of disease and risk factors, 2001: systemic analysis of population health data. Lancet. 2006;367:1747–1757.
- Zhu C, Anderson AC, Schubart A, Xiong H, Imitola J, Khoury SJ, Zheng XX, Strom TB, Kuchroo VK. The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity. Nat Immunol. 2005;6:1245–1252.
- Whitacre CC. Sex differences in autoimmune disease. Nat Immunol. 2001;2:777–780.
- Fairweather D, Rose NR. Women and autoimmune diseases. Emerg Infect Dis. 2004;10:2005–2011.
- Zandman-Goddard G, Peeva E, Shoenfeld Y. Gender and autoimmunity. Autoimmun Rev. 2007;6:366–372.
- Kublickiene K, Luksha L. Gender and the endothelium. Pharmacol Rep. 2008;60:49–60.
- Karpuzoglu-Sahin E, Hissong BD, Ahmed SA. Interferon-γ levels are upregulated by 17-β-estradiol and diethylstilbestrol. J Reprod Immunol. 2001;52:113–127.
- Dimayuga FO, Reed JL, Carnero GA, Wang C, Dimayuga ER, Dimayuga VM, Perger A, Wilson ME, Keller JN, Bruce-Keller AJ. Estrogen and brain inflammation: effects on microglial expression of MHC, costimulatory molecules and cytokines. J Neuroimmunol. 2005;161:123–136.
- Polanczyk MJ, Carson BD, Subramanian S, Afentoulis M, Vandenbark AA, Ziegler SF, Offner H. Cutting edge: estrogen drives expansion of the CD4+CD25+ regulatory T cell compartment. J Immunol. 2004;173:2227–2230.
- Polanczyk MJ, Hopke C, Huan J, Vandenbark AA, Ziegler SF, Offner H. Enhanced FoxP3 expression and Treg cell function in pregnant and estrogen-treated mice. J Neuroimmunol. 2005;170:85–92.
- Evans MJ, Eckert A, Lai K, Adelman SJ, Harnish DC. Reciprocal antagonism between estrogen receptor and NF-κB activity in vivo. Circ Res. 2001;89:823–830.
- Demyanets S, Pfaffenberger S, Kaun C, Rega G, Speidl WS, Kastl SP, Weiss TW, Hohensinner PJ, Dietrich W, Tschugguel W, Bochkov VN, Awad EM, Maurer G, Huber K, Wojta J. The estrogen metabolite 17b-dihydroequilenin counteracts interleukin-1α induced expression of inflammatory mediators in human endothelial cells in vitro via NF-κB pathway. Thromb Haemost. 2006;95:107–116.
- Wang X, Belguise K, Kersual N, Kirsch KH, Mineva ND, Galtier F, Chalbos D, Sonenshein GE. Oestrogen signaling inhibits invasive phenotype by repressing RelB and its target BCL2. Nat Cell Biol. 2007;9:470–478.
- Feldman I, Feldman GM, Mobarak C, Dunkelberg JC, Leslie KK. Identification of proteins within the nuclear factor-kappa B transcriptional complex including estrogen receptor-alpha. Am J Obstet Gynecol. 2007;196:394.e1–394.e11.
- Paimela T, Ryhanen T, Mannermaa E, Ojala J, Kalesnykas G, Salminen A, Kaarniranta K. The effect of 17beta-estradiol on IL-6 secretion and NF-kappaB DNA-binding activity in human retinal pigment epithelial cells. Immunol Lett. 2007;110:139–144.
- Liu H-B, Loo KK, Palaszynski K, Ashouri J, Lubahn DB, Voskuhl RR. Estrogen receptor α mediates estrogen’s immune protection in autoimmune disease. J Immunol. 2003;171:6936–6940.
- Palaszynski K, Liu H-B, Loo KK, Voskuhl RR. Estriol treatment ameliorates disease in males with experimental autoimmune encephalomyelitis: implications for multiple sclerosis. J Neuroimmunol. 2004;149:84–89.
- Gharaee-Kermani M, Hatano K, Nozaki Y, Phan SH. Gender-based differences in bleomycin-induced pulmonary fibrosis. Am J Pathol. 2005;166:1593–1606.
- Giltay EJ, Fonk JC, von Blomberg BM, Drexhage HA, Schalkwijk C, Gooren LJ. In vivo effects of sex steroids on lymphocyte responsiveness and immunoglobulin levels in humans. J Clin Endocrinol Metab. 2000;85:1648–1657.
- Klein SL, Bird BH, Glass GE. Sex differences in immune responses and viral shedding following Seoul virus infection in Norway rats. Am J Trop Med Hyg. 2001;65:57–63.
- Loria RM. Immune up-regulation and tumor apoptosis by androstene steroids. Steroids. 2002;67:953–966.
- Desai KV, Michalowska AM, Kondaiah P, Ward JM, Shih JH, Green JE. Gene expression profiling identifies a unique androgen-mediated inflammatory/immune signature and a PTEN (phosphatase and tensin homolog deleted on chromosome 10)-mediated apoptotic response specific to the rat ventral prostate. Mol Endocrinol. 2004;18:2895–2907.
- Wang M, Tsai BM, Kher A, Baker LB, Wairiuko GM, Meldrum DR. Role of endogenous testosterone in myocardial proinflammatory and proaptotic signaling after acute ischemia-reperfusion. Am J Physiol. 2005;288:H221–H226.
- Palaszynski K, Loo KK, Ahouri JF, Liu H-B, Voskuhl RR. Androgens are protective in experimental autoimmune encephalomyelitis: implications for multiple sclerosis. J Neuroimmunol. 2004;146:144–152.
- Mendelsohn ME, Karas RH. Molecular and cellular basis of cardiovascular gender differences. Science. 2005;308:1583–1587.
- Ogawa S, Chester AE, Hewitt SC, Walker VR, Gustafsson J-A, Smithies O, Korach KS, Pfaff DW. Abolition of male sexual behaviors in mice lacking estrogen receptors α and β (αβERKO). Proc Natl Acad Sci USA. 2000;97:14737–14741.
- Kabelitz D, Wesch D, Oberg HH. Regulation of regulatory T cells: role of dendritic cells and toll-like receptors. Crit Rev Immunol. 2006;26:291–306.
- LaRosa DF, Gelman AE, Rahman AH, Zhang J, Turka LA, Walsh PT. CpG DNA inhibits CD4+CD25+ Treg suppression through direct MyD88-dependent costimulation of effector CD4+ T cells. Immunol Lett. 2007;108:183–188.
- Martin JT. Sexual dimorphism in immune function: the role of prenatal exposure to androgens and estrogens. Eur J Pharmacol. 2000;405:251–261.
- Roep BO. Are insights gained from NOD mice sufficient to guide clinical translation? Another inconvenient truth. Ann NY Acad Sci. 2007;1103:1–10.
- D’Cruz DP, Khamashta MA, Hughes GRV. Systemic lupus erythematosus. Lancet. 2007;369:587–596.
- Grimaldi CM, Cleary J, Dagtas AS, Moussai D, Diamond B. Estrogen alters thresholds for B cell apoptosis and activation. J Clin Invest. 2002;109:1625–1633.
- Grimaldi CM. Sex and systemic lupus erythematosus: the role of the sex hormones estrogen and prolactin on the regulation of autoreactive B cells. Curr Opin Rheumatol. 2006;18:456–461.
- Blank M, Mendlovic S, Fricke H, Mozes E, Talal N, Shoenfeld Y. Sex hormone involvement in the induction of experimental systemic lupus erythematosus by a pathogenic anti-DNA idiotype in naïve mice. J Rheumatol. 1990;17:311–317.
- Bhalla AK. Hormones and the immune response. Ann Rheum Dis. 1989;48:1–6.
- Ahmed SA, Verthelyi D. Antibodies to cardiolipin in normal C57BL/6J mice: induction by estrogen but not dihydrotestosterone. J Autoimmun. 1993;6:265–279.
- Akahoshi M, Nakashima H, Tanaka Y, Kohsaka T, Nagano S, Ohgami E, Arinobu Y, Yamaoka K, Niiro H, Shinozaki M, Hirakata H, Horiuchi T, Otsuka T, Niho Y. Th1/Th2 balance of peripheral T helper cells in systemic lupus erythematosus. Arthritis Rheum. 1999;42:1644–1648.
- Lit LC, Wong CK, Li EK, Tam LS, Lam CW, Lo YM. Elevated gene expression of Th1/Th2 associated transcription factors is correlated with disease activity in patients with systemic lupus erythematosus. J Rheumatol. 2007;34:89–96.
- Ronnblom L, Alm GV. Effector mechanisms of autoimmunity: antibodies and immune complexes. Rose NR, Mackay IR, editors. St. Louis: Elsevier Academic Press,; The Autoimmune Diseases. (ed 4) 2006:pp 203–215.
- Verthelyi D, Petri M, Ylamus M, Klinman DM. Disassociation of sex hormone levels and cytokine production in SLE patients. Lupus. 2001;10:352–358.
- Wang Y, Meng J, Wang X, Liu S, Shu Q, Gao L, Ju Y, Zhang L, Sun W, Ma C. Expression of human TIM-1 and TIM-3 on lymphocytes from systemic lupus erythematosus patients. Scand J Immunol. 2007;67:63–70.
- Subramanian S, Tovey M, Afentoulis M, Krogstad A, Vandenbark AA, Offner H. Ethinyl estradiol treats collagen-induced arthritis in DBA/1LacJ mice by inhibiting the production of TNF-alpha and IL-1beta. Clin Immunol. 2005;115:162–172.
- Nielsen RH, Christiansen C, Stolina M, Karsdal MA. Oestrogen exhibits type II collagen protective effects and attenuates collagen-inducted arthritis in rats. Clin Exp Immunol. 2008;152:21–27.
- Jansson L, Holmdahl R. Estrogen-mediated immunosuppression in autoimmune diseases. Inflamm Res. 1998;47:290–301.
- Bretano F, Ospelt C, Stanczyk J, Gay RE, Gay S, Kyburz D. Abundant expression of the IL-23 subunit p19, but low levels of bioactive IL-23 in the rheumatoid synovium. Ann Rheum Dis. 2008 DOI: 10.1136/ard.2007.082081.
- Yamada H, Nakashima Y, Okazaki K, Mawatari T, Fukushi JI, Kaibara N, Hori A, Iwamoto Y, Yoshikai Y. Th1 but not Th17 cells predominate in the joints of patients with rheumatoid arthritis. Ann Rheum Dis. 2007 DOI: 10.1136/ard.2007.080341.
- Castagnetta LA, Carruba G, Granata OM, Stefano R, Miele M, Schmidt M, Cutolo M, Straub RH. Increased estrogen formation and estrogen to androgen ration in the synovial fluid of patients with rheumatoid arthritis. J Rheumatol. 2003;30:2597–2605.
- Olsen NJ, Kovacs WJ. Hormones, pregnancy, and rheumatoid arthritis. J Gend Specif Med. 2002;5:28–37.
- Fairweather D, Rose NR. Type I diabetes: virus infection or autoimmune disease? Nat Immunol. 2002;3:338–340.
- Fujinami RS, von Herrath MG, Christen U, Whitton JL. Molecular mimicry, bystander activation, or viral persistence: infections and autoimmune disease. Clin Microbiol Rev. 2006;19:80–94.
- Lu FX, Ma Z, Moser S, Evans TG, Miller CJ. Effects of ovarian steroids on immunoglobulin-secreting cell function in healthy women. Clin Diagn Lab Immunol. 2003;10:944–949.
- Lassmann H, Bruck W, Lucchinetti C. Heterogeneity of multiple sclerosis pathogenesis: implications for diagnosis and therapy. Trends Mol Med. 2001;7:115–121.
- Bebo BF, Jr, Fyfe-Johnson A, Adlard K, Beam AG, Vandenbark AA, Offner H. Low dose estrogen therapy ameliorates experimental autoimmune encephalomyelitis in two different inbred mouse strains. J Immunol. 2001;166:2080–2089.
- Polanczyk MJ, Hopke C, Vandenbark AA, Offner H. Treg suppressive activity involves estrogen-dependent expression of programmed death-1 (PD-1). Intern Immunol. 2007;19:337–343.
- Panitch HS, Hirsch RL, Haley AS, Johnson KP. Exacerbations of multiple sclerosis in patients treated with gamma interferon. Lancet. 1987;1:893–895.
- Langer-Gould A, Garren H, Slansky A, Ruiz PJ, Steinman L. Late pregnancy suppresses relapses in experimental autoimmune encephalomyelitis: evidence for a suppressive pregnancy-related serum factor. J Immunol. 2002;169:1084–1091.
- Okayasu I, Kong YM, Rose NR. Effect of castration and sex hormones on experimental autoimmune thyroiditis. Clin Immunol Immunopathol. 1981;20:240–245.
- Liu PY, Death AK, Handelsman DJ. Androgens and cardiovascular disease. Endocr Rev. 2003;24:313–340.
- Schoub BD, Johnson S, McAnerney JM, Dos Santos IL, Klaassen KI. Epidemic Coxsackie B virus infection in Johannesburg. S Afr J Hyg (Lond) 1985;95:447–455.
- Dechkum N, Pangsawan Y, Jayavasu C, Saguanwongse S. Coxsackie B virus infection and myopericarditis in Thailand, 1987–1989. Southeast Asian J Trop Med Public Health. 1998;29:273–276.
- Fabre A, Sheppard MN. Sudden adult death syndrome and other non-ischaemic causes of sudden cardiac death. Heart. 2006;92:316–320.
- Rangachari M, Mauermann N, Marty RR, Dirnhofer S, Kurrer MO, Komnenovic V, Penninger JM, Eriksson U. T-bet negatively regulates autoimmune myocarditis by suppressing local production of interleukin 17. J Exp Med. 2006;203:2009–2019.
- Valaperti A, Marty RR, Kania G, Germano D, Mauermann N, Dirnhofer S, Leimenstoll B, Blyszczuk P, Dong C, Mueller C, Hunziker L, Eriksson U. CD11b+ monocytes abrogate Th17 CD4+ T cell-mediated experimental autoimmune myocarditis. J Immunol. 2008;180:2686–2695.
- Lima AP, Lunardi LO, Rosa e Silva AAM. Effects of castration and testosterone replacement on peritoneal histamine concentration and lung histamine concentration in pubertal male rats. J Endocrinol. 2000;167:71–75.
- Mahoney PM, Hurst PR, McLeod BJ, McConnell MA, Thompson EG. Effect of estradiol treatment on mast cell populations and microflora in the vaginal cul-de-sac of seasonally anestrous brushtail possums (Trichosurus vulpecula). Reproduction. 2003;125:733–741.
- Rossouw JE, Prentice RL, Manson JE, Wu L, Barad D, Barnabei VM, Ko M, LaCroix AZ, Margolis KL, Stefanick ML. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. J Am Med Assoc. 2007;297:1465–1477.
Why Women Are More Prone to Autoimmune Diseases
An estimated 75% of people with autoimmune diseases are female, according to the American Autoimmune Related Diseases Association. In the case of lupus, the gender difference is even more severe, as nine out of 10 of those afflicted are women.
What’s more, autoimmune diseases are among the leading causes of death and disability in girls and women 65 years of age and younger.
Asa Tivesten, MD, professor of medicine at Sahlgrenska Academy, Sweden, was part of a team of researchers who recently explored why women are more susceptible to these diseases, hoping to provide better treatment for the diseases in the future.
“We know testosterone reduces the number of B cells, a type of lymphocyte that releases harmful antibodies,” she says. “Our scientific question was we wanted to find out what the mechanism behind testosterone to the relation of the number of B cells in the spleen was. We wanted to understand what the connection actually looks like, mechanisms that have so far been unknown.”
The study, published in Nature Communications, provided findings on possible mechanisms behind gender differences in the occurrence of rheumatism and other autoimmune diseases.
Read: How Using DNA Banks Can Improve Autoimmune Disease Treatment
Tivesten and her research team began studying mice, as there are cell-specific knockouts and castration experiments where you take away the testes and thereby take away the testosterone production of the mouse. It next confirmed its results in a cohort of healthy men, studying blood samples from 128 males.
“We looked at the testosterone levels in these men and we defined a subpopulation of them as having low testosterone levels and we saw that those men with low testosterone levels had higher BAFF levels,” Tivesten says.
The data revealed that if you eliminate testosterone, you get more BAFF and thereby more B cells in the spleen because they survive to a greater extent. This recognition of a link between testosterone and BAFF is something that hasn’t been known before.
“What we have found is a physiological regulation, a hormone regulates an important factor in the immune system and that is actually physiology,” Tivesten says. “But the finding has implications for pathophysiology, we think, because BAFF is so tightly coupled to development of autoimmune disorders and especially SLE.”
BAFF inhibitors is the first drug that has become registered for SLE in more than 30 years, which Tivesten notes is an extremely long time without any new medications for this very serious disease. And yet in her clinic, these BAFF inhibitors have been a little bit of a disappointment and haven’t lived up to expectations.
“So, there has been a question of how well is BAFF coupled to autoimmune pathophysiology?” she says. “There was a very important paper in the New England Journal of Medicine last summer where they looked at genetic variations in the BAFF gene and they could see that people with genetic variants that resulted in higher BAFF levels are more prone to develop SLE and multiple sclerosis. I think those were the major diseases that could be coupled to BAFF.”
Additionally, the findings compare closely to a previous study showing that genetic variations in BAFF could be connected to the risk of diseases such as lupus.
“That’s why understanding how the body regulates the levels of BAFF is so important, so we’re able to continue to put the pieces together and try to understand which patients should have BAFF inhibitors and which should not,” Tivesten says. “Our study serves as a basis for further research on how the medicine can be used in a better way. I think this information is important for those that treat and form and design clinical studies with BAFF inhibitors and it will be interesting to see if the findings will lead to any new study schemes or stratifications of patients.”
Keith Loria is an award-winning journalist who has been writing for major newspapers and magazines for close to 20 years, on topics as diverse as sports, business, and healthcare.
Why do autoimmune diseases affect women more often than men?
My sister-in-law, Donna Cimons, 77, a retired nurse anesthetist who lives on a farm near Cambridge, Ohio, began losing her hair as a teenager. She woke up each morning to find tufts of hair scattered across her pillow. By age 50, she was bald. She knew this problem ran in her family — her mother had it, too — but not much else.
“It had a name, alopecia areata, but that was all,” she says, speaking of the scant knowledge 60 or more years ago. “We really didn’t know what it was.”
Today we know that it is one of more than 80 autoimmune diseases that can be life-altering, even life-threatening. These occur when the immune system goes awry and mistakenly attacks healthy parts of the body rather than infectious invaders such as bacteria and viruses. It’s often described as the body’s inability to distinguish “self” from “non-self.”
Autoimmune diseases afflict 23.5 million Americans, according to the Department of Health and Human Services, although the American Autoimmune Related Diseases Association estimates the number at more than twice that.
These disorders disproportionately strike women — who account for nearly 80 percent of all cases — for reasons not well understood. Most often, they hit women in their reproductive years, often complicating pregnancy.
“Autoimmune diseases carry a huge burden for affected individuals and their families because of their devastating and chronic nature,” says Daniel Rotrosen, director of the division of allergy, immunology and transplantation at the National Institute of Allergy and Infectious Diseases. “They can require a lifetime of treatment, often with potent immunosuppressive medications that can have worrisome side effects,” such as raising the risk of osteoporosis.
A malfunctioning process
The immune system produces a type of B cell that secretes autoantibodies. These substances can bind to the body’s cells and tissues. In people with healthy immune systems, several mechanisms keep these B cells in check and purge them from the body. However, the process can malfunction. When this happens, these B cells proliferate, producing autoantibodies that go on the attack — and an autoimmune disease results.
Autoantibodies can damage joints, the digestive system, the heart, lungs, kidneys and other organs, the nerves, hair follicles and the connective tissue in the skin and blood vessels. Although each disorder is distinct, they frequently share such symptoms as fatigue, dizziness and low-grade fever. Inflammation is a hallmark of all of them, both at the target site, such as the joints, as well as in the blood.
Among the more common autoimmune diseases are rheumatoid arthritis, which attacks the lining of the joints; Type 1 diabetes, which destroys cells needed to make blood-sugar-controlling insulin; multiple sclerosis, which damages linings around the nerves, affecting the brain and spinal cord; Crohn’s disease and irritable bowel syndrome, which harm the gastrointestinal tract; scleroderma, which causes abnormal growth of connective tissue in the skin and blood vessels; psoriasis, in which new skin cells rise up too fast, resulting in thick red patches and scales; Hashimoto’s disease, which attacks the thyroid gland; and systemic lupus erythematosus, often just called lupus, which can hurt the joints, skin, heart, lungs and kidneys. Lupus is especially prevalent in African American women, who are two to three times as likely to develop it as are Caucasians.
Many of these diseases can be debilitating.
“If you tell your friends and teachers that you have cancer, they understand it, but if you tell them you have lupus, they don’t understand that it took you three hours to get out of bed because your joints were so sore and inflamed,” says Judith James, chair of the Oklahoma Medical Research Foundation. “Lupus can also affect your brain and cause depression, and affect your ability to think. It’s a terrible disease.’’
Sarah Feinberg, 42, of Silver Spring, Md., a planner at the U.S. Holocaust Memorial Museum, has lived with Crohn’s disease for nine years, although it wasn’t clear what was wrong with her when she began having symptoms at age 33.
Crohn’s, an inflammatory bowel disorder, also can affect the eyes, skin and joints — which is what happened to Feinberg initially. Her first symptom was an inflammation in the iris of one eye, followed by a painful rash under the skin, then temporary arthritis in her hips, knees and ankles.
“Then my stomach kicked in, and I started having to go to the bathroom eight, 10, 12 times a day,” she says. “Anything I ate went right through me. I was constantly excusing myself from meetings and going to the bathroom. I also couldn’t walk because of the arthritis, so I was hobbling to the bathroom.”
Finally, she underwent a colonoscopy — “which you don’t do for an eye problem,’’ she says — and was diagnosed with Crohn’s. She’s lucky, however. Her disease is mild and responds well to medication.
Researchers believe that gene mutations, the environment and even the human microbiome are involved in autoimmune diseases, citing such environmental stimuli as smoking, obesity, sun exposure and infection with the Epstein-Barr virus. These diseases often run in familiesand, while rare, some people can suffer from more than one at the same time, known as polyautoimmunity.
While my sister-in-law’s mother had alopecia, her daughter — my niece — developed a different autoimmune disorder, Hashimoto’s disease, when she was 10.
Smoking gun remains hidden
“Autoimmune diseases appear to be a mismatch between genes and the environment,” says David Hafler, chairman of the department of neurology at the Yale School of Medicine. “It’s not one gene; there are hundreds of common genetic variants which together lead to disease. But all this also raises the question of why we have not found the smoking gun that defines the gender risk.”
Women typically mount a more vigorous immune response than men to infections and vaccinations, producing higher levels of antibodies. In the case of autoimmune disorders, this trait seems to backfire. “Robust immunity in females can be good evolutionarily, but too much immunity can be bad if directed toward self,” says Rhonda Voskuhl, a professor of neurology at UCLA who studies multiple sclerosis.
Scientists believe that sex hormones also may play a role, because many autoimmune disorders occur in women soon after puberty. Some studies, in fact, suggest that the female hormones estrogen and prolactin stimulate the growth of B cell autoantibodies.
Scientists also think that sex chromosomes, specifically the X chromosome, may have an influence. (Everyone normally has one pair of sex chromosomes in each cell; women have two X chromosomes, while men have one X and one Y chromosome.)
The symptoms of some autoimmune diseases, including lupus, often worsen during pregnancy, while in others, such as rheumatoid arthritis, they may improve. “We’re trying to figure out why two diseases with a lot of similarities behave differently during pregnancy,” says Eliza Chakravarty, a rheumatologist at the Oklahoma Medical Research Foundation. “It’s not uncommon for women to have their first episode of lupus during pregnancy. It probably would have developed anyway, but it tends to come on during pregnancy.”
A murky relationship
The relationship between autoimmune diseases and menopause is even murkier. “It used to be said that some of these diseases burn out with time,” says Betty Diamond, director of the Center for Autoimmune and Musculoskeletal Diseases at the Feinstein Institute for Medical Research in Manhasset, N.Y. “If you manage to have the kind of autoimmune disease that doesn’t kill you, it may smolder a little less by then. On the other hand, there is a certain incidence of women who get an autoimmune disease after menopause, which tells you the whole problem is not hormones.”
Interestingly, men who develop these diseases often experience worse symptoms than women, probably because they lack “whatever factors protect men or make it easier for women to get these diseases,” Hafler says.
These are chronic diseases; there are no cures, only medications to treat the symptoms, some of them with serious side effects.But the drugs are getting better. More than 300 medicines for autoimmune diseases are in the research pipeline.
Nothing, however, has helped my sister-in-law restore her hair. “I’m resigned to it,” she says. “I kept hoping something would happen, that they would make some kind of discovery that would get my hair back, but they didn’t.”
She copes. She owns three wigs, each of a different length. “Real hair grows, so I pretend,” she says. “I wear the short one for a while, then the medium one and then the longer one. And then I get a ‘haircut’ and start all over again.’’
She knows things could be worse. While alopecia has drastically affected her appearance, it won’t kill her. “I know I’m not going to die from this disease,” she says. “But it would be nice to have hair.”
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