Skip to main content
SpringerLink
Log in

The Immune Privilege of the Testis

  • Chapter
  • First Online:
Immune Infertility

Abstract

The onset of spermatogenesis at puberty represents unique challenges to the immune system as neoantigens of meiotic and haploid germ cells (GC) appear long after the formation of systemic self tolerance. The protection of GC from autoimmune attack, the “immune privilege” of the testis, was originally attributed both to the existence of the blood-testis barrier and to a failure of the testicular immune system to respond to antigens. Recent research has shown that the testis is by no means ignorant, and can mount a robust immune deviant response that can protect the gonad from damaging inflammatory responses to pathogens. Moreover, an excessive immune response can lead to inflammatory male factor infertility. The mechanisms controlling immune privilege seem to overlap with those controlling tolerance to transplantation antigens, autoantigens, and cancer cells. They appear to involve cellular processes, androgens, and a delicate balance of immunomodulatory molecules such as cytokines and chemokines.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.00
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Suescun MO, Calandra RS, Lustig L (1994) Alterations of testicular function after induced autoimmune orchitis in rats. J Androl 15:442–448

    CAS  PubMed  Google Scholar 

  2. Tung KS, Unanue ER, Dixon FJ (1971) Immunological events associated with immunization by sperm in incomplete Freund’s adjuvant. Int Arch Allergy Appl Immunol 41:565–574

    Article  CAS  PubMed  Google Scholar 

  3. Setchell BP (1990) The testis and tissue transplantation: historical aspects. J Reprod Immunol 18:1–8

    Article  CAS  PubMed  Google Scholar 

  4. Selawry HP, Cameron DF (1993) Sertoli cell-enriched fractions in successful islet cell transplantation. Cell Transplant 2:123–129

    CAS  PubMed  Google Scholar 

  5. Brinster RL (2002) Germline stem cell transplantation and transgenesis. Science 296:2174–2176

    Article  CAS  PubMed  Google Scholar 

  6. Filippini A, Riccioli A, Padula F et al (2001) Control and impairment of immune privilege in the testis and in semen. Hum Reprod Update 7:444–449

    Article  CAS  PubMed  Google Scholar 

  7. Setchell BP, Uksila J, Maddocks S, Pollanen P (1990) Testis physiology relevant to ­immunoregulation. J Reprod Immunol 18:19–32

    Article  CAS  PubMed  Google Scholar 

  8. Mahmoud A, Comhaire FH (2006) Immunological causes. In: Schill W-B, Comhaire FH, Hargreave TB (eds) Andrology for the clinician. Springer, Berlin, pp 47–52

    Chapter  Google Scholar 

  9. McLachlan RI (2002) Basis, diagnosis and treatment of immunological infertility in men. J Reprod Immunol 57:35–45

    Article  CAS  PubMed  Google Scholar 

  10. Naz RK (2004) Modalities for treatment of antisperm antibody mediated infertility: novel perspectives. Am J Reprod Immunol 51:390–397

    Article  PubMed  Google Scholar 

  11. Nieschlag E, Behre HM (2000) Andrology: male reproductive health and dysfunction, 2nd edn. Springer, Berlin

    Google Scholar 

  12. WHO (1987) Towards more objectivity in diagnosis and management of male infertility. Int J Androl (Suppl 7):1–53

    Google Scholar 

  13. Tung KS, Teuscher C (1995) Mechanisms of autoimmune disease in the testis and ovary. Hum Reprod Update 1:35–50

    Article  CAS  PubMed  Google Scholar 

  14. Schuppe HC, Meinhardt A (2005) Immune privilege and inflammation of the testis. Chem Immunol Allergy 88:1–14

    Article  CAS  PubMed  Google Scholar 

  15. Weidner W, Krause W, Ludwig M (1999) Relevance of male accessory gland infection for subsequent fertility with special focus on prostatitis. Hum Reprod Update 5:421–432

    Article  CAS  PubMed  Google Scholar 

  16. Jenkin GA, Choo M, Hosking P, Johnson PD (1998) Candidal epididymo-orchitis: case report and review. Clin Infect Dis 26:942–945

    Article  CAS  PubMed  Google Scholar 

  17. Wong EW, Mruk DD, Cheng CY (2008) Biology and regulation of ectoplasmic specialization, an atypical adherens junction type, in the testis. Biochim Biophys Acta 1778:692–708

    CAS  PubMed  Google Scholar 

  18. de Kretser DM, Kerr JB (1994) The cytology of the testis. In: Knobil E, Neill J (eds) Physiology of reproduction, 2nd edn. Raven, New York, pp 1177–1300

    Google Scholar 

  19. Comhaire FH, Mahmoud AM, Depuydt CE, Zalata AA, Christophe AB (1999) Mechanisms and effects of male genital tract infection on sperm quality and fertilizing potential: the andrologist’s viewpoint. Hum Reprod Update 5:393–398

    Article  CAS  PubMed  Google Scholar 

  20. Johnson MH (1970) Changes in the blood-testis barrier of the guinea-pig in relation to histological damage following iso-immunization with testis. J Reprod Fertil 22:119–127

    Article  CAS  PubMed  Google Scholar 

  21. Lewis-Jones DI, Richards RC, Lynch RV, Joughin EC (1987) Immunocytochemical localisation of the antibody which breaches the blood-testis barrier in sympathetic orchiopathia. Br J Urol 59:452–457

    Article  CAS  PubMed  Google Scholar 

  22. Hales DB, Diemer T, Hales KH (1999) Role of cytokines in testicular function. Endocrine 10:201–217

    Article  CAS  PubMed  Google Scholar 

  23. Hedger MP, Meinhardt A (2003) Cytokines and the immune-testicular axis. J Reprod Immunol 58:1–26

    Article  CAS  PubMed  Google Scholar 

  24. Huleihel M, Lunenfeld E (2004) Regulation of spermatogenesis by paracrine/autocrine testicular factors. Asian J Androl 6:259–268

    CAS  PubMed  Google Scholar 

  25. Iosub R, Klug J, Fijak M et al (2006) Development of testicular inflammation in the rat involves activation of proteinase-activated receptor-2. J Pathol 208:686–698

    Article  CAS  PubMed  Google Scholar 

  26. Mankertz J, Tavalali S, Schmitz H et al (2000) Expression from the human occludin promoter is affected by tumor necrosis factor alpha and interferon gamma. J Cell Sci 113(Pt 11):2085–2090

    CAS  PubMed  Google Scholar 

  27. Siu MK, Lee WM, Cheng CY (2003) The interplay of collagen IV, tumor necrosis factor-alpha, gelatinase B (matrix metalloprotease-9), and tissue inhibitor of metalloproteases-1 in the basal lamina regulates Sertoli cell-tight junction dynamics in the rat testis. Endocrinology 144: 371–387

    Article  CAS  PubMed  Google Scholar 

  28. Saari T, Jahnukainen K, Pollanen P (1996) Autoantigenicity of the basal compartment of seminiferous tubules in the rat. J Reprod Immunol 31:65–79

    Article  CAS  PubMed  Google Scholar 

  29. Yule TD, Montoya GD, Russell LD, Williams TM, Tung KS (1988) Autoantigenic germ cells exist outside the blood testis barrier. J Immunol 141:1161–1167

    CAS  PubMed  Google Scholar 

  30. Head JR, Billingham RE (1985) Immunologically privileged sites in transplantation ­immunology and oncology. Perspect Biol Med 29:115–131

    CAS  PubMed  Google Scholar 

  31. Gornstein RA, Lapp CA, Bustos-Valdes SM, Zamorano P (1999) Androgens modulate ­interleukin-6 production by gingival fibroblasts in vitro. J Periodontol 70:604–609

    Article  CAS  PubMed  Google Scholar 

  32. Hatakeyama H, Nishizawa M, Nakagawa A, Nakano S, Kigoshi T, Uchida K (2002) Testosterone inhibits tumor necrosis factor-alpha-induced vascular cell adhesion molecule-1 expression in human aortic endothelial cells. FEBS Lett 530:129–132

    Article  CAS  PubMed  Google Scholar 

  33. Li ZG, Danis VA, Brooks PM (1993) Effect of gonadal steroids on the production of IL-1 and IL-6 by blood mononuclear cells in vitro. Clin Exp Rheumatol 11:157–162

    CAS  PubMed  Google Scholar 

  34. Liva SM, Voskuhl RR (2001) Testosterone acts directly on CD4+ T lymphocytes to increase IL-10 production. J Immunol 167:2060–2067

    CAS  PubMed  Google Scholar 

  35. McMurray RW, Suwannaroj S, Ndebele K, Jenkins JK (2001) Differential effects of sex steroids on T and B cells: modulation of cell cycle phase distribution, apoptosis and bcl-2 protein levels. Pathobiology 69:44–58

    Article  CAS  PubMed  Google Scholar 

  36. Head JR, Billingham RE (1985) Immune privilege in the testis. II. Evaluation of potential local factors. Transplantation 40:269–275

    Article  CAS  PubMed  Google Scholar 

  37. Benten WP, Lieberherr M, Stamm O, Wrehlke C, Guo Z, Wunderlich F (1999) Testosterone signaling through internalizable surface receptors in androgen receptor-free macrophages. Mol Biol Cell 10:3113–3123

    CAS  PubMed  Google Scholar 

  38. Hayes R, Chalmers SA, Nikolic-Paterson DJ, Atkins RC, Hedger MP (1996) Secretion of bioactive interleukin 1 by rat testicular macrophages in vitro. J Androl 17:41–49

    CAS  PubMed  Google Scholar 

  39. Kern S, Maddocks S (1995) Indomethacin blocks the immunosuppressive activity of rat testicular macrophages cultured in vitro. J Reprod Immunol 28:189–201

    Article  CAS  PubMed  Google Scholar 

  40. Kern S, Robertson SA, Mau VJ, Maddocks S (1995) Cytokine secretion by macrophages in the rat testis. Biol Reprod 53:1407–1416

    Article  CAS  PubMed  Google Scholar 

  41. Bryniarski K, Szczepanik M, Maresz K, Ptak M, Ptak W (2004) Subpopulations of mouse testicular macrophages and their immunoregulatory function. Am J Reprod Immunol 52:27–35

    Article  PubMed  Google Scholar 

  42. Gerdprasert O, O’Bryan MK, Muir JA et al (2002) The response of testicular leukocytes to lipopolysaccharide-induced inflammation: further evidence for heterogeneity of the testicular macrophage population. Cell Tissue Res 308:277–285

    Article  CAS  PubMed  Google Scholar 

  43. Gerdprasert O, O’Bryan MK, Nikolic-Paterson DJ, Sebire K, de Kretser DM, Hedger MP (2002) Expression of monocyte chemoattractant protein-1 and macrophage colony-stimulating factor in normal and inflamed rat testis. Mol Hum Reprod 8:518–524

    Article  CAS  PubMed  Google Scholar 

  44. Suescun MO, Rival C, Theas MS, Calandra RS, Lustig L (2003) Involvement of tumor necrosis factor-alpha in the pathogenesis of autoimmune orchitis in rats. Biol Reprod 68:2114–2121

    Article  CAS  PubMed  Google Scholar 

  45. Banchereau J, Steinman RM (1998) Dendritic cells and the control of immunity. Nature 392:245–252

    Article  CAS  PubMed  Google Scholar 

  46. Banchereau J, Briere F, Caux C et al (2000) Immunobiology of dendritic cells. Annu Rev Immunol 18:767–811

    Article  CAS  PubMed  Google Scholar 

  47. Hackstein H, Thomson AW (2004) Dendritic cells: emerging pharmacological targets of immunosuppressive drugs. Nat Rev Immunol 4:24–34

    Article  CAS  PubMed  Google Scholar 

  48. Haas GG Jr, D’Cruz OJ, De Bault LE (1988) Distribution of human leukocyte antigen-ABC and -D/DR antigens in the unfixed human testis. Am J Reprod Immunol Microbiol 18:47–51

    PubMed  Google Scholar 

  49. Lustig L, Lourtau L, Perez R, Doncel GF (1993) Phenotypic characterization of lymphocytic cell infiltrates into the testes of rats undergoing autoimmune orchitis. Int J Androl 16:279–284

    Article  CAS  PubMed  Google Scholar 

  50. Pollanen P, Jahnukainen K, Punnonen J, Sainio-Pollanen S (1992) Ontogeny of immunosuppressive activity, MHC antigens and leukocytes in the rat testis. J Reprod Immunol 21:257–274

    Article  CAS  PubMed  Google Scholar 

  51. Pollanen P, Maddocks S (1988) Macrophages, lymphocytes and MHC II antigen in the ram and the rat testis. J Reprod Fertil 82:437–445

    Article  CAS  PubMed  Google Scholar 

  52. Pollanen P, Niemi M (1987) Immunohistochemical identification of macrophages, lymphoid cells and HLA antigens in the human testis. Int J Androl 10:37–42

    Article  CAS  PubMed  Google Scholar 

  53. Tung KS, Yule TD, Mahi-Brown CA, Listrom MB (1987) Distribution of histopathology and Ia positive cells in actively induced and passively transferred experimental autoimmune orchitis. J Immunol 138:752–759

    CAS  PubMed  Google Scholar 

  54. Rival C, Lustig L, Iosub R et al (2006) Identification of a dendritic cell population in normal testis and in chronically inflamed testis of rats with autoimmune orchitis. Cell Tissue Res 324(2):311–318

    Article  PubMed  Google Scholar 

  55. Meinhardt A, Bacher M, Metz C et al (1998) Local regulation of macrophage subsets in the adult rat testis: examination of the roles of the seminiferous tubules, testosterone, and ­macrophage-migration inhibitory factor. Biol Reprod 59:371–378

    Article  CAS  PubMed  Google Scholar 

  56. Rival C, Theas MS, Suescun MO et al (2008) Functional and phenotypic characteristics of testicular macrophages in experimental autoimmune orchitis. J Pathol 215:108–117

    Article  CAS  PubMed  Google Scholar 

  57. Wang J, Wreford NG, Lan HY, Atkins R, Hedger MP (1994) Leukocyte populations of the adult rat testis following removal of the Leydig cells by treatment with ethane dimethane sulfonate and subcutaneous testosterone implants. Biol Reprod 51:551–561

    Article  CAS  PubMed  Google Scholar 

  58. Rival C, Guazzone VA, von Wulffen W et al (2007) Expression of co-stimulatory molecules, chemokine receptors and proinflammatory cytokines in dendritic cells from normal and chronically inflamed rat testis. Mol Hum Reprod 13:853–861

    Article  CAS  PubMed  Google Scholar 

  59. Fijak M, Iosub R, Schneider E et al (2005) Identification of immunodominant autoantigens in rat autoimmune orchitis. J Pathol 207:127–138

    Article  CAS  PubMed  Google Scholar 

  60. Millar DG, Garza KM, Odermatt B et al (2003) Hsp70 promotes antigen-presenting cell function and converts T-cell tolerance to autoimmunity in vivo. Nat Med 9:1469–1476

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Anatomy and Cell Biology, Justus-Liebig-University of Giessen, Giessen, 35385, Germany

    Monika Fijak

Authors
  1. Monika Fijak
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sudhanshu Bhushan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Andreas Meinhardt
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Monika Fijak .

Editor information

Editors and Affiliations

  1. Klinik für Andrologie und Venerologie, Universitätsklinikum Marburg, Deutschhausstr. 9, Marburg, 35033, Germany

    Walter K.H. Krause

  2. School of Medicine, West Virginia University, Morgantown, 26506, U.S.A.

    Rajesh K. Naz

Rights and permissions

Reprints and permissions

Copyright information

© 2009 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Fijak, M., Bhushan, S., Meinhardt, A. (2009). The Immune Privilege of the Testis. In: Krause, W., Naz, R. (eds) Immune Infertility. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-01379-9_5

Download citation

  • DOI: https://doi.org/10.1007/978-3-642-01379-9_5

  • Published:

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-01378-2

  • Online ISBN: 978-3-642-01379-9

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation