Androgen-Induced Suppression of Autoimmune Disease in Lacrimal Glands of Mouse Models of Sjögren’s Syndrome

  • David A. Sullivan
  • Hiroko Ariga
  • Ana C. Vendramini
  • Flavio J. Rocha
  • Masafumi Ono
  • Elcio H. Sato
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 350)


Almost 2,000 years ago, Claudius Galen, the Greek physician and writer, proposed that the mental status of an individual may significantly influence one’s susceptibility to disease.1 This postulate serves as an historic landmark in the rapidly growing field of neuroendocrinimmunology, which was established through the recognition that the nervous, endocrine and immune systems control each other through bidirectional channels of communication, that employ both similar signals and receptors.2–7 At present, over 50 neurotransmitters, hormones and secretagogues are known that exert a profound impact on cellular, humoral and mucosal immunity.2–7 However, the exact nature of these interactions is extremely dependent upon the specific signal, target cell, and local microenvironment.8 Thus, depending upon the tissue, neuroendocrine action may result in stimulation, inhibition, or no effect, on immune expression.8 As an additional consideration, antigenic exposure to the immune system may lead to the generation of numerous lymphocytic cytokines (e.g. lymphokines, neuropeptides, hormones), that directly regulate neural and endocrine function.2–7 In consequence, an extensive, triangular interrelationship exists among the neural, endocrine and immune systems that acts to promote homeostasis and health.


Systemic Lupus Erythematosus Androgen Receptor Lacrimal Gland Androgen Therapy Androgen Treatment 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    N.R.S, Hall, and A.L. Goldstein, Thymosin modulation of the immune system, in: “The Neuro-Immune-Endocrine Connection,” C.W. Cotman, R.E. Brinton, A. Galaburda, B. McEwen, and D.M. Schneider, eds., Raven Press, New York, pp. 59–69 (1987).Google Scholar
  2. 2.
    S. Freier, ed., “The Neuroendocrine-Immune Network,” CRC Press, Boca Raton, FL (1989).Google Scholar
  3. 3.
    R. Ader, D. Felten, and N. Cohen, eds., “Psychoneuroimmunology,” Acad. Press, San Diego, CA (1991).Google Scholar
  4. 4.
    S. D’Orisio, and A. Panerai, eds., “Neuropeptides and Immunopeptides: Messengers in a Neuroimmune Axis,” Ann. N.Y. Acad. Sci. vol. 594 (1990).Google Scholar
  5. 5.
    R.H. Stead, M.H. Perdue, H. Cooke, D. Powell, and K. Barrett, eds., “Neuro-Immuno-Physiology of the Gastrointestinal Mucosa,” Ann. N.Y. Acad. Sci. vol. 664 (1992).Google Scholar
  6. 6.
    E.J. Goetzl, and S.P. Sreedharan, Mediators of communication and adaptation in the neuroendocrine and immune systems, FASEB J. 6:2646 (1992).PubMedGoogle Scholar
  7. 7.
    N. Fabris, B.D. Jancovic, B.M. Markovic, and N.H. Spector, eds., “Ontogenetic and Phylogenetic Mechanisms of Neuroimmunomodulation,” Ann. N.Y. Acad. Sci. vol. 650 (1992).Google Scholar
  8. 8.
    D.A. Sullivan, Hormonal influence on the secretory immune system of the eye, in: “The Neuroendocrine-Immune Network,” S. Freier, ed., CRC Press, Boca Raton, FL, p199–238 (1990).Google Scholar
  9. 9.
    S.A. Ahmed, W.J. Penhale, and N. Talal, Sex hormones, immune responses and autoimmune diseases, Am. J. Pathol. 121:531 (1985).Google Scholar
  10. 10.
    S.A. Ahmed, and N. Talal, Sex hormones and the immune system, Bailliere’s Clin. Rheum. 4:13 (1990).CrossRefGoogle Scholar
  11. 11.
    S.A. Ahmed, and N. Talal, Importance of sex hormones in systemic lupus erythematosus, in: “Dubois’ Lupus Erythematosus,” D. Wallace, and B. Hahn, eds.. Lea & Febiger, Philadelphia, p 148–156 (1993).Google Scholar
  12. 12.
    F. Homo-Delarche, F. Fitzpatrick, N. Christeff, E.A. Nunez, J.F. Bach, and M. Dardenne, Sex steroids, glucocorticoids, stress and autoimmunity, J. Ster. Biochem. Mol. Biol. 40:619 (1991).CrossRefGoogle Scholar
  13. 13.
    H. Carlsten, A. Tarkowski, R. Holmdahl, and L.A. Nilsson, Oestrogen is a potent disease accelerator in SLE-prone MRL lpr/lpr mice, Clin. exp. Immunol. 80:467 (1990).PubMedCrossRefGoogle Scholar
  14. 14.
    S.A. Ahmed, T.B. Aufdemorte, J.R. Chen, A.I. Montoya, D. Olive, and N. Talal, Estrogen induces the development of autoantibodies and promotes salivary gland lymphoid infiltrates in normal mice, J. Autoimmunity 2:543 (1989).CrossRefGoogle Scholar
  15. 15.
    D.A. Sullivan, and E.H. Sato, Potential therapeutic approach for the hormonal treatment of lacrimal gland dysfunction in Sjögren’s syndrome, Clin. Immunol. Immunopath. 64:9 (1992).CrossRefGoogle Scholar
  16. 16.
    R.I. Fox, ed., “Sjögren’s Syndrome,” Rheum. Dis. Clin. N.A. vol. 18 (3) (1992).Google Scholar
  17. 17.
    N. Talal, H.M. Moutsopoulos, and S.S. Kassan, eds., “Sjögren’s Syndrome. Clinical and Immunological Aspects,” Springer Verlag, Berlin (1987).Google Scholar
  18. 18.
    H. Carlsten, R. Holmdahl, and A. Tarkowski, Analysis of the genetic encoding of oestradiol suppression of delayed-type hypersensitivity in (NZB/NZW) F1 mice, Immunol. 73:186 (1991).Google Scholar
  19. 19.
    R.I. Fox, M. Luppi, H.I. Kang, and P. Pisa, Reactivation of Epstein-Barr virus in Sjögren’s syndrome, Springer Semin. Immunopathol. 13:217 (1991).PubMedCrossRefGoogle Scholar
  20. 20.
    R. MeMurray, D. Keisler, K. Kanuckel, S. Izui, and S.E. Walker, Prolactin influences autoimmune disease activity in the female B/W mouse. J. Immunol. 147:3780 (1991).Google Scholar
  21. 21.
    R.W. Hoffman, M.A. Alspaugh, K.S. Waggie, J.B. Durham, J.B., and S.E. Walker, Sjögren’s syndrome in MRL/1 and MRL/n mice. Arthritis Rheum. 27:157 (1984).Google Scholar
  22. 22.
    J.D. Mountz, W.C. Gause, and R. Jonsson, Murine models for systemic lupus erythematosus and Sjögren’s syndrome, Curr. Opin. Rheumatol. 3:738 (1991).PubMedCrossRefGoogle Scholar
  23. 23.
    D.A. Jabs, E.L. Alexander, and W.R. Green, Ocular inflammation in autoimmune MRL/Mp mice, Invest. Ophthalmol. Vis. Sci. 26:1223 (1985).PubMedGoogle Scholar
  24. 24.
    H. Ariga, J. Edwards, and D.A. Sullivan, Androgen control of autoimmune expression in lacrimal glands of MRL/Mp-lpr/lpr mice, Clin. Immunol, Immunopath. 53:499 (1989).CrossRefGoogle Scholar
  25. 25.
    H.S. Kessler, A laboratory model for Sjögren’s syndrome, Am. J. Pathol. 52:671 (1968).PubMedGoogle Scholar
  26. 26.
    D.A. Jabs, and R.A. Prendergast, Murine models of Sjögren’s syndrome. Invest. Ophthalmol. Vis. Sci. 29:1437 (1988).PubMedGoogle Scholar
  27. 27.
    B. Lieberum, and K.U. Hartmann, Successive changes of the cellular composition in lymphoid organs of MRL-Mp/lpr/lpr mice during the development of lymphoproliferative disease as investigated in cryoscctions, Clin. Immunol. Immunopathol. 46:421 (1988).PubMedCrossRefGoogle Scholar
  28. 28.
    A.C. Vendramini, C.H. Soo, and D.A. Sullivan, Testosterone-induced suppression of autoimmune disease in lacrimal tissue of a mouse model (NZB/NZW Fl) of Sjögren’s syndrome, Invest. Ophthalmol. Vis. Sci. 32:3002 (1991).PubMedGoogle Scholar
  29. 29.
    E.H. Sato, H. Ariga H, and D.A. Sullivan, Impact of androgen therapy in Sjögren’s syndrome: Hormonal influence on lymphocyte populations and la expression in lacrimal glands of MRL/Mp-lpr/lpr mice, Invest. Ophthalmol. Vis. Sci. 33:2537 (1992).PubMedGoogle Scholar
  30. 30.
    E.H. Sato, and D.A. Sullivan, Comparative influence of steroid hormones and immunosuppressive agents on autoimmune expression in lacrimal glands of a female mouse model (MRL/Mp-lpr/lpr) of Sjögren’s syndrome, submitted (1993).Google Scholar
  31. 31.
    D.A. Sullivan, J. Edwards, C. Soo, A.C. Vendramini, H. Ariga, and E.H. Sato, article submitted (1993).Google Scholar
  32. 32.
    R.G. Lahita, H.L. Bradlow, E. Ginzler, S. Pang, and M. New, Low plasma androgens in women with systemic lupus erythematosus, Arth. Rheum. 30:241 (1987).CrossRefGoogle Scholar
  33. 33.
    C. Lavalle, E. Loyo, R. Paniagua, J.A. Bermudez, J. Herrera, A. Graef, D. Gonzalez-Barcena, and A. Fraga, Correlation study between prolactin and androgens in male patients with Systemic Lupus Erythematosus, J. Rheum. 14:268 (1987).PubMedGoogle Scholar
  34. 34.
    R.G. Lahita, The importance of estrogens in SLE, Clin. Immunol. Immunopath. 63:17 (1992).CrossRefGoogle Scholar
  35. 35.
    R. Bruckner, Uber einem erfolgreich mit perandren behandelten fall von Sjogren’schem symptomen komplex, Ophthalmologica 110:37 (1945).PubMedCrossRefGoogle Scholar
  36. 36.
    M. Appelmans, La Keratoconjonctivite seche de Gougerot-Sjogren, Arch. ‘Ophtalmologie 81:577 (1948).Google Scholar
  37. 37.
    A. Bizzarro, G. Valentini, G. Di Marinto, A. Daponte, A. De Bellis, and G. Iacono, Influence of testosterone therapy on clinincal and immunological features of autoimmune diseases associated with Klinefelter’s syndrome, J. Clin. End. Metab. 64:32 (1987).CrossRefGoogle Scholar
  38. 38.
    R. Lahita, Sex hormones, Sjögren’s syndrome and the immune response. The Moisture Seekers Newsletter 8:1(1991).Google Scholar
  39. 39.
    J. Comsa, H. Leonhardt, and H. Wekerle H, Hormonal coordination of the immune response, Rev. Physiol. Biochem. Pharmacol. 92:115 (1982).PubMedCrossRefGoogle Scholar
  40. 40.
    N. Talal, and S.A. Ahmed, Sex hormones and autoimmune disease, Int. J. Immunotherapy 3:65 (1987).Google Scholar
  41. 41.
    C.J. Grossman, Are there underlying immune-neuroendocrine interactions responsible for immunological sexual dimorphism?, Prog. NeuroEndocrinlmmunology 3:75 (1990).Google Scholar
  42. 42.
    E.J. Goldsteyn, and M J.L. Fritzler, The role of the thymus-hypothalamus-pituitary-gonadal axis in normal immune processes and autoimmunity, J. Rheumatol. 14:982 (1987).Google Scholar
  43. 43.
    A.H.W.M. Shuurs, and H.A.M. Verheul, Effect of gender and sex steroids on the immune response, J. Steroid Biochem. 35:157 (1990).CrossRefGoogle Scholar
  44. 44.
    Olsen NJ, Watson MB and Kovacs WJ: Studies of immunological function in mice with defective androgen action. Immunology 73: 52, 1991.PubMedGoogle Scholar
  45. 45.
    Y. Weinstein, and Z. Berkovich, Testosterone effect on bone marrow, thymus and suppressor T cells in the (NZB/NZW) F1 mice: its relevance to autoimmunity, J. Immunol. 126:998 (1981).PubMedGoogle Scholar
  46. 46.
    N. Talal, H. Dang, S.A. Ahmed, E. Kraig, and M. Fischbach, Interleukin 2, T cell receptor and sex hormone studies in autoimmune mice, J. Rheum. (suppl. 13) 14:21 (1987).Google Scholar
  47. 47.
    K.A. Melez, W.A. Boegel, and A.D. Steinberg, Therapeutic studies in New Zealand mice. VII. Successful androgen treatment of NZB/NZW Fl females of different ages, Arthritis Rheum. 23:41 (1980).PubMedCrossRefGoogle Scholar
  48. 48.
    J.R. Roubinian, N. Talal, J.S. Greenspan, J.R. Goodman, and P.K. Siiteri, Effect of castration and sex hormone treatment on survival, anti-nucleic acid antibodies, and glomerulonephritis in NZB/NZW F1 mice, J. Exp. Med. 147:1568 (1978).PubMedCrossRefGoogle Scholar
  49. 49.
    J.B. Allen, D. Blatter, G.B. Calandra, and R.L. Wilder, Sex hormonal effects on the severity of streptococcal cell wall-induced polyarthritis in the rat, Arthritis Rheum. 26:560 (1983).PubMedCrossRefGoogle Scholar
  50. 50.
    N. Talal, S.A. Ahmed, and M. Dauphinee, Hormonal approaches to immunotherapy of autoimmune diseases, N.Y. Acad. Sci. 475:320 (1986).CrossRefGoogle Scholar
  51. 51.
    H. Carlsten, R. Holmdahl, A. Tarkowski, and L.A. Nilsson, Oestradiol- and testosterone-mediated effects on the immune system in normal and autoimmune mice are genetically linked and inherited as dominant traits, Immunology 68:209 (1989).PubMedGoogle Scholar
  52. 52.
    M. Ono, F.J. Rocha and D.A. Sullivan, Cellular distribution and hormonal control of androgen receptors in lacrimal tissue of the MRL/Mp-lpr/lpr mouse model of Sjögren’s syndrome, submitted (1993).Google Scholar
  53. 53.
    M. Ota, S. Kyakumoto, and T. Nemoto, Demonstration and characterization of cytosol androgen receptor in rat exorbital lacrimal gland, Biochem. Internat. 10:129 (1985).Google Scholar
  54. 54.
    D.A. Sullivan, J. A. Edwards, and R.S. Kellcher, Analysis of androgen binding sites in the rat lacrimal gland, submitted (1993).Google Scholar
  55. 55.
    F J. Rocha, L.A. Wickham, J.D.O. Pena, J. Gao, M. Ono, R.W. Lambert, R.S. Kelleher, and D.A. Sullivan, Influence of gender and the endocrine environment on the distribution of androgen receptors in the lacrimal gland, submitted (1993).Google Scholar
  56. 56.
    L. Dancl, M. Menouni, J. Cohen, J. Magaud, G. Lenoir, J. Revillard, and S. Saez, Distribution of androgen and estrogen receptors among lymphoid and haemopoietic cell lines, Leukemia Res. 9:1373 (1985).CrossRefGoogle Scholar
  57. 57.
    H. Takeda, G. Chodak, S. Mutchnik, T. Nakamoto, and C. Chang, Immunohistochemical localization of androgen receptors with mono- and polyclonal antibodies to androgen receptor, J. Endocr. 126:17 (1990).PubMedCrossRefGoogle Scholar
  58. 58.
    D.A. Sullivan, R.S. Kelleher, J.P. Vaerman, and L.E. Hann, Androgen regulation of secretory component synthesis by lacrimal gland acinar cells in vitro, J. Immunol. 145:4238 (1990).PubMedGoogle Scholar
  59. 59.
    E. Nagy, I. Berczi, and E. Sabbadini, Endocrine control of an immunoregulatory cytokine of the submandibular gland, Hans Selye Symp. in Neuroendocrinology, Budapest, Hungary, p. 51 (1992).Google Scholar
  60. 60.
    W.L. Sibbitt, Oncogenes, growth factors and autoimmune diseases, Antican. Res. 11:97 (1991).Google Scholar
  61. 61.
    A. Mantovan, F. Bussolino, E. Dejana, Cytokine regulation of endothelial cell function, FASEB J. 6:2591 (1992).Google Scholar
  62. 62.
    S.A. Robertson, M. Brannstrom, and R.F. Seamark, Cytokines in rodent reproduction and the cytokine-endocrine interaction, Curr. Opin. Rheumatol. 4:585 (1992).Google Scholar
  63. 63.
    J.D. Mountz, and C. Edwards, Murine models of autoimmune disease, Curr. Opin. Rheum. 4:621 (1992).Google Scholar
  64. 64.
    N. Sarvetnick, and H.S. Fox, Interferon-gamma and the sexual dimorphism of autoimmunity, Mol. Biol. Med. 7:323 (1990).PubMedGoogle Scholar
  65. 65.
    G. Kroemer, and A. Martinez, Cytokines and autoimmune diseases, Clin. Immunol. Immunopath. 61:275 (1991).CrossRefGoogle Scholar
  66. 66.
    A.D. Steinberg, Concepts of pathogenesis of systemic lupus erythematosus. Clin. Immunol. Immunopathol. 63:19 (1992).CrossRefGoogle Scholar
  67. 67.
    R.P. Wuthrich, A.M. Jevnikar, F. Takei, L.H. Glimcher, and V.E. Kelley, Intercellular adhesion molecule-1 (ICAM-1) expression is upregulated in autoimmune murine lupus nephritis, A. J. Path. 136:441 (1990).Google Scholar
  68. 68.
    G.S. Firestein, Cytokines in autoimmune diseases, Clin. Mol. Asp. Autoimmune. Dis. 8:129 (1992).Google Scholar
  69. 69.
    R.L. Deem, F. Shanahan, and S.R. Targan, Triggered human mucosal T cells release tumour necrosis factor-α and interferon-γ which kill human colonic epithelial cells, Clin. exp. Immunol. 83:79 (1991).PubMedCrossRefGoogle Scholar
  70. 70.
    S.M. Collins, S.M. Hurst, C. Main, E. Stanley, I. Khan, P. Blennerhassett, and M. Swain, Effect of inflammation of enteric nerves. Cytokine-induced changes in neurotransmitter content and release, Ann. N.Y. Acad. Sci. 664:415 (1992).PubMedCrossRefGoogle Scholar
  71. 71.
    D. Wakefield, and A. Lloyd, The role of cytokines in the pathogenesis of inflammatory eye disease, Cytokine 4:1 (1992).PubMedCrossRefGoogle Scholar
  72. 72.
    F.N. Skopouli, E. Kousvelari, P. Mertz, E.S. Jaffe, P.C. Fox, and H.M. Moutsopoulos, c-myc mRNA expression in minor salivary glands of patients with Sjögren’s syndrome, J. Rheumatol. 19:693 (1992).PubMedGoogle Scholar
  73. 73.
    R.I. Fox, and H.I. Kang, Pathogenesis of Sjögren’s syndrome, Rheum. Dis. Clin. N.A. 18:517 (1992).Google Scholar

Copyright information

© Springer Science+Business Media New York 1994

Authors and Affiliations

  • David A. Sullivan
    • 1
    • 2
  • Hiroko Ariga
    • 1
    • 2
  • Ana C. Vendramini
    • 1
    • 2
  • Flavio J. Rocha
    • 1
    • 2
  • Masafumi Ono
    • 1
    • 2
  • Elcio H. Sato
    • 1
    • 2
  1. 1.Department of OphthalmologyHarvard Medical SchoolBostonUSA
  2. 2.Immunology UnitSchepens Eye Research InstituteBostonUSA

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