Testicular immunology

Testicular immunology

Testicular Immunology is the study of the immune system within the testis. It includes an investigation of the effects of infection, inflammation and immune factors on testicular function. Two unique characteristics of testicular immunology are evident: (1) the testis is described as an immunologically privileged site, where suppression of immune responses occurs; and, (2) some factors which normally lead to inflammation are present at high levels in the testis, where they regulate the development of sperm instead of promoting inflammation.

History of testicular immunology

* 460-377 BC Hippocrates described testicular inflammation associated with mumps cite book | author = Hedger MP, Hales DB |title = Knobil and Neill's Physiology of Reproduction | editor = Neill JD | pages=1195-1286 | publisher = Elsevier | year = 2006 | chapter = Immunophysiology of the Male Reproductive Tract | id= ISBN 0-12-515401-7 ]

* 1785 Hunter and Michaelis performed transplant experiments in domestic chickens cite journal |author=Setchel BP |title=The testis and tissue transplantation: historical aspects. |journal=J Reprod Immunol. |volume=18 |pages=1–8 |year=1990 |pmid=2213727 |doi=10.1016/0165-0378(90)90020-7 ]

* 1849 Berthold transplanted testes between roosters and showed maintenance of male sex characteristics only in birds with successfully grafted testes cite journal |author=Setchel BP |title=The testis and tissue transplantation: historical aspects. |journal=J Reprod Immunol. |volume=18 |pages=1–8 |year=1990 |pmid=2213727 |doi=10.1016/0165-0378(90)90020-7 ]

* 1899-1900 Sperm recognized as immunogenic (will cause an autoimmune reaction if transplanted from the testis into a different area of the body) by Lansteiner (1899) and Metchinikoff, (1900)cite book | author = Hedger MP, Hales DB |title = Knobil and Neill's Physiology of Reproduction | editor = Neill JD | pages=1195-1286 | publisher = Elsevier | year = 2006 | chapter = Immunophysiology of the Male Reproductive Tract | id= ISBN 0-12-515401-7 ]

* 1913-1914 Human testis transplants performed by Lespinasse (1913), and Lydson (1914) who performed a graft on himself! cite journal |author=Setchel BP |title=The testis and tissue transplantation: historical aspects. |journal=J Reprod Immunol. |volume=18 |pages=1–8 |year=1990 |pmid=2213727 |doi=10.1016/0165-0378(90)90020-7 ]

* 1954 Discovery that sperm autoantibodies contribute to infertility, cite journal |author=Wilson L |title=Sperm agglutinins in human semen and blood. |journal= Proc Soc Exp Biol Med. |volume=85 |pages=952–655 |year=1954 |pmid=13167169]

* 1977 Billingham recognized that the testis is site of immune privilege cite journal |author=Barker CF, Billingham RE |title=Immunologically privileged sites. |journal=Adv Immunol. |volume=25 |pages=1–54 |year=1977 |pmid=345773 |doi=]

Immune cells found in the testis

Immune cells of the human testis are not as well characterized as those from rodents, due to the rarity of normal human testes available for experiment. The majority of experiments have studied the rat testis due to its convenience: it is a relatively large size and is easily extracted from experimental animals.

Macrophages

Macrophages are directly involved in the fight against invading micro-organisms as well as being antigen-presenting cells which activate lymphocytes. Testicular macrophages are the largest population of immune cells in the rodent testis cite journal |author=Hume DA, Halpin D, Charlton H, Gordon S |title=The mononuclear phagocyte system of the mouse defined by immunohistochemical localization of antigen F4/80: macrophages of endocrine organs. |journal=Proc Natl Acad Sci U S A. |volume=81 |pages=4174–4177 |year=1984 |pmid=6377311 |doi=10.1073/pnas.81.13.4174 ] cite journal |author=Niemi M, Sharpe RM, Brown WR |title=Macrophages in the interstitial tissue of the rat testis. |journal=Cell Tissue Res. |volume=243 |pages=337–344 |year=1986 |pmid=2418975 |doi=10.1007/BF00251049 ] . Macrophages have also been found in the testes of humans cite journal |author=Frungieri MB, Calandra RS, Lustig L, Meineke V, Köhn FM, Vogt HJ, Mayerhofer A |title=Number, distribution pattern, and identification of macrophages in the testes of infertile men. |journal=Fertil Steril. |volume=78 |pages=298–306 |year=2002 |pmid=12137866 |doi=10.1016/S0015-0282(02)03206-5 ] , guinea pigs, hamsters cite journal |author=Mendis-Handagama SM, Zirkin BR, Ewing LL |title=Comparison of components of the testis interstitium with testosterone secretion in hamster, rat, and guinea pig testes perfused "in vitro". |journal=Am J Anat. |volume=181 |pages=12–22 |year=1988 |pmid=3348144 |doi=10.1002/aja.1001810103 ] , boars cite journal |author=Sur JH, Doster AR, Christian JS, Galeota JA, Wills RW, Zimmerman JJ, Osorio FA |title=Porcine reproductive and respiratory syndrome virus replicates in testicular germ cells, alters spermatogenesis, and induces germ cell death by apoptosis. |journal=J Virol. |volume=71 |pages=9170–9179 |year=1997 |pmid=9371575 ] , horses cite journal |author=Clemmons AJ, Thompson DL Jr, Johnson L |title=Local initiation of spermatogenesis in the horse. |journal=Biol Reprod. |volume=52 |pages=1258–1267 |year=1995 |pmid=7632834 |doi=10.1095/biolreprod52.6.1258 ] and bulls cite journal |author=Wrobel KH, Dostal S, Schimmel M |title=Postnatal development of the tubular lamina propria and the intertubular tissue in the bovine testis. |journal=Cell Tissue Res. |volume=252 |pages=639–653 |year=1988 |pmid=3396061 |doi=10.1007/BF00216652 ] . They originate from blood monocytes which move into the testis then mature into macrophages. In the rat, testicular macrophages have been described as either “resident” or “newly arrived” from the blood supply cite journal |author=Wang J, Wreford NG, Lan HY, Atkins R, Hedger MP.
title=Leukocyte populations of the adult rat testis following removal of the Leydig cells by treatment with ethane dimethane sulfonate and subcutaneous testosterone implants. |journal=Biol Reprod. |volume=51 |pages=551–561 |year=1994 |pmid=7528551
doi=10.1095/biolreprod51.3.551
] cite journal |author=Meinhardt A, Bacher M, Metz C, Bucala R, Wreford N, Lan H, Atkins R, Hedger M. |title=Local regulation of macrophage subsets in the adult rat testis: examination of the roles of the seminiferous tubules, testosterone, and macrophage-migration inhibitory factor. |journal=Biol Reprod. |volume=59 |pages=371–378 |year=1998 |pmid=9687310 |doi=10.1095/biolreprod59.2.371] .

Testicular macrophages can respond to infectious stimuli and become activated (undergo changes enabling the killing of the invading micro-organism), but do so to a lesser extent than other types of macrophages cite journal |author=Hedger MP |title=Macrophages and the immune responsiveness of the testis. |journal=J Reprod Immunol. |volume=57 |pages=19–34 |year=2002 |pmid=12385831 |doi=10.1016/S0165-0378(02)00016-5] cite journal |author=Kern S, Robertson SA, Mau VJ, Maddocks S |title=Cytokine secretion by macrophages in the rat testis. |journal=Biol Reprod. |volume=53 |pages=1407–1416 |year=1995 |pmid=8562698 |doi=10.1095/biolreprod53.6.1407] . An example is production of the inflammatory cytokines TNFα and IL-1β by activated rat testicular macrophages: these macrophages produce significantly less TNFα and IL-1β than activated rat peritoneal macrophages cite journal |author=Kern S, Robertson SA, Mau VJ, Maddocks S |title=Cytokine secretion by macrophages in the rat testis. |journal=Biol Reprod. |volume=53 |pages=1407–1416 |year=1995 |pmid=8562698 |doi=10.1095/biolreprod53.6.1407] cite journal |author=Hayes R, Chalmers SA, Nikolic-Paterson DJ, Atkins RC, Hedger MP |title=Secretion of bioactive interleukin 1 by rat testicular macrophages "in vitro". |journal=J Androl. |volume=17 |pages=41–49 |year=1996 |pmid=8833740] . Aside from responding to infectious stimuli, testicular macrophages are also involved in maintaining normal testis function. Their presence is necessary for the normal development and function of the Leydig cells cite journal |author=Gaytan F, Bellido C, Aguilar E, van Rooijen N. |title=Requirement for testicular macrophages in Leydig cell proliferation and differentiation during prepubertal development in rats. |journal=J Reprod Fertil. |volume=102 |pages=393–399 |year=1994 |pmid=7861393] cite journal |author=Gaytan F, Bellido C, Morales C, García M, van Rooijen N, Aguilar E |title="In vivo" manipulation (depletion versus activation) of testicular macrophages: central and local effects. |journal=J Endocrinol. |volume=150 |pages=57–65 |year=1996 |pmid=8708563 |doi=10.1677/joe.0.1500057] cite journal |author=Bergh A, Damber JE, van Rooijen N |title=Liposome-mediated macrophage depletion: an experimental approach to study the role of testicular macrophages in the rat. |journal=J Endocrinol. |volume=136 |pages=407–413 |year=1993 |pmid=8473830] , which are the testosterone-producing cells of the testis.

B-Lymphocytes

B-lymphocytes take part in the adaptive immune response and produce antibodies. These cells are not normally found in the testis, even during inflammatory conditions. The lack of B-lymphocytes in the testis is significant, since these are the antibody-producing cells of the immune system. Since anti-sperm antibodies can cause infertility, it is important that antibody-producing B-lymphocytes are kept separated from the testis.

T-lymphocytes

T-lymphocytes (T-cells) are white blood cells which take part in cell-mediated immunity. They are often found within tissues where they can be activated by antigen-presenting cells upon infection. They are present in rat cite journal |author=Hedger MP, Meinhardt A |title=Local regulation of T cell numbers and lymphocyte-inhibiting activity in the interstitial tissue of the adult rat testis. |journal=J Reprod Immunol. |volume=48 |pages=69–80 |year=2000 |pmid=11011073 |doi=10.1016/S0165-0378(00)00071-1] cite journal |author=Pöllänen P, Maddocks S|title=Macrophages, lymphocytes and MHC II antigen in the ram and the rat testis. |journal=J Reprod Fertil. |volume=82 |pages=437–445 |year=1988 |pmid=3163001] and human testes cite journal |author=Pöllänen P, Niemi M |title=Immunohistochemical identification of macrophages, lymphoid cells and HLA antigens in the human testis. |journal=Int J Androl. |volume=10 |pages=37–42 |year=1987 |pmid=3294605 |doi=10.1111/j.1365-2605.1987.tb00163.x] , where they constitute approximately 10 to 20% of the immune cells present, as well as mouse cite journal |author=el-Demiry M, James K |title=Lymphocyte subsets and macrophages in the male genital tract in health and disease. A monoclonal antibody-based study. |journal=Eur Urol. |volume=14 |pages=226–235 |year=1988 |pmid=3289938] and ram cite journal |author=Pöllänen P, Maddocks S|title=Macrophages, lymphocytes and MHC II antigen in the ram and the rat testis. |journal=J Reprod Fertil. |volume=82 |pages=437–445 |year=1988 |pmid=3163001] testes. Both cytotoxic T-cells and helper T-cells are found in the testes of rats cite journal |author=Tompkins AB, Hutchinson P, de Kretser DM, Hedger MP |title=Characterization of lymphocytes in the adult rat testis by flow cytometry: effects of activin and transforming growth factor beta on lymphocyte subsets "in vitro". |journal=Biol Reprod. |volume=58 |pages=943–951 |year=1998 |pmid=9546724 |doi=10.1095/biolreprod58.4.943] . Also present in the testes of rats and humans are natural killer cells cite journal |author=Tompkins AB, Hutchinson P, de Kretser DM, Hedger MP |title=Characterization of lymphocytes in the adult rat testis by flow cytometry: effects of activin and transforming growth factor beta on lymphocyte subsets "in vitro". |journal=Biol Reprod. |volume=58 |pages=943–951 |year=1998 |pmid=9546724 |doi=10.1095/biolreprod58.4.943] cite book | author = Hedger MP, Hales DB |title = Knobil and Neill's Physiology of Reproduction | editor = Neill JD | pages=1195-1286 | publisher = Elsevier | year = 2006 | chapter = Immunophysiology of the Male Reproductive Tract | id= ISBN 0-12-515401-7 ] and natural killer T-cells have been found in rats and mice.

Mast cells

Mast cells are regulators of immune responses, particularly those against parasites. They are also involved in the development of autoimmune diseases and allergies. Mast cells have been found in relatively low numbers in the testes of humans, rats, mice, dogs, cats, bulls, boars and deer cite journal |author=Anton F, Morales C, Aguilar R, Bellido C, Aguilar E, Gaytán F |title=A comparative study of mast cells and eosinophil leukocytes in the mammalian testis. |journal= Zentralbl Veterinarmed A. |volume=45 |pages=209–218 |year=1998 |pmid=9697421 ] cite journal |author=Fijak M, Meinhardt A |title=The testis in immune privilege. |journal= Immunol Rev. |volume=213 |pages=66–81 |year=2006 |pmid=16972897 |doi=10.1111/j.1600-065X.2006.00438.x ] . In the mammalian testis mast cells regulate testosterone production cite journal |author=Fijak M, Meinhardt A |title=The testis in immune privilege. |journal= Immunol Rev. |volume=213 |pages=66–81 |year=2006 |pmid=16972897 |doi=10.1111/j.1600-065X.2006.00438.x ] . There are two lines of evidence that restriction of mast cell activation in the testis could be beneficial during treatment of inflammatory conditions; (1) In experimental models of testicular inflammation, mast cells were present in 10-fold greater numbers and showed signs of activation cite journal |author=Iosub R, Klug J, Fijak M, Schneider E, Fröhlich S, Blumbach K, Wennemuth G, Sommerhoff CP, Steinhoff M, Meinhardt A |title=Development of testicular inflammation in the rat involves activation of proteinase-activated receptor-2. |journal= J Pathol. |volume=208 |pages=686–698 |year=2006 |pmid=16450334 |doi=10.1002/path.1938 ] , and (2) Treatment with drugs which stabilize mast cell activation has proved beneficial in treating some types of male infertility cite journal |author=Yamamoto M, Hibi H, Miyake K |title=New treatment of idiopathic severe oligozoospermia with mast cell blocker: results of a single-blind study. |journal= Fertil Steril. |volume=64 |pages=1221–1223 |year=1995 |pmid=7589684 ] cite journal |author=Hibi H, Kato K, Mitsui K, Taki T, Yamada Y, Honda N, Fukatsu H, Yamamoto M |title=Treatment of oligoasthenozoospermia with tranilast, a mast cell blocker, after long-term administration. |journal= Arch Androl. |volume=48 |pages=415–419 |year=2002 |pmid=12425762 ] cite journal |author=Matsuki S, Sasagawa I, Suzuki Y, Yazawa H, Tateno T, Hashimoto T, Nakada T, Saito H, Hiroi M. |title=The use of ebastine, a mast cell blocker, for treatment of oligozoospermia. |journal= Arch Androl. |volume=44 |pages=129–132 |year=2000 |pmid=16450334 |doi=10.1080/014850100262290 ] .

Eosinophils

Eosinophils directly fight parasitic infections and are involved in allergic reactions. They have been found in relatively low numbers in the rat, mouse, dog, cat, bull and deer testes cite journal |author=Anton F, Morales C, Aguilar R, Bellido C, Aguilar E, Gaytán F |title=A comparative study of mast cells and eosinophil leukocytes in the mammalian testis. |journal= Zentralbl Veterinarmed A. |volume=45 |pages=209–218 |year=1998 |pmid=9697421 ] . Almost nothing is known about their significance or function in the testis.

Dendritic cells

Dendritic cells initiate adaptive immune responses. Relatively small amounts of dendritic cells have been found in the testes of humans cite journal |author=Derrick EK, Barker JN, Khan A, Price ML, Macdonald DM |title=A comparative study of mast cells and eosinophil leukocytes in the mammalian testis. |journal= Histopathology |volume=22 |pages=157–162 |year=1993 |pmid=8095915 ] , rats cite journal |author=Rival C, Lustig L, Iosub R, Guazzone VA, Schneider E, Meinhardt A, Fijak M |title=Identification of a dendritic cell population in normal testis and in chronically inflamed testis of rats with autoimmune orchitis. |journal= Cell Tiss Res. |volume=324 |pages=311–318 |year=2006 |pmid=16432710 |doi=10.1007/s00441-005-0129-5 ] and mice cite journal |author=Itoh M, De Rooij DG, Jansen A, Drexhage HA |title=Phenotypical heterogeneity of testicular macrophages/dendritic cells in normal adult mice: an immunohistochemical study. |journal= J Reprod Immunol. |volume=28 |pages=217–232 |year=1995 |pmid=7473432 |doi=10.1016/0165-0378(95)00923-9 ] cite journal |author=Hoek A, Allaerts AW, Leenen PJ, Schoemaker J, and Drexhage HA |title=Dendritic cells and macrophages in the pituitary and the gonads. Evidence for their role in the fine regulation of the reproductive endocrine response. |journal= Eur J Endocrinol. |volume=126 |pages=8–24 |year=19987 |pmid=9037117 ] . The functional role of dendritic cells in the testis is not well understood, although they have been shown to be involved in autoimmune orchitis during animal experiments cite journal |author=Anton F, Morales C, Aguilar R, Bellido C, Aguilar E, Gaytán F |title=A comparative study of mast cells and eosinophil leukocytes in the mammalian testis. |journal= Zentralbl Veterinarmed A. |volume=45 |pages=209–218 |year=1998 |pmid=9697421 ] cite journal |author=Rival C, Lustig L, Iosub R, Guazzone VA, Schneider E, Meinhardt A, Fijak M |title=Identification of a dendritic cell population in normal testis and in chronically inflamed testis of rats with autoimmune orchitis. |journal= Cell Tiss Res. |volume=324 |pages=311–318 |year=2006 |pmid=16432710 |doi=10.1007/s00441-005-0129-5 ] . When autoimmune orchitis is induced in rats, the dendritic cell population of the testis greatly increases cite journal |author=Rival C, Lustig L, Iosub R, Guazzone VA, Schneider E, Meinhardt A, Fijak M |title=Identification of a dendritic cell population in normal testis and in chronically inflamed testis of rats with autoimmune orchitis. |journal= Cell Tiss Res. |volume=324 |pages=311–318 |year=2006 |pmid=16432710 |doi=10.1007/s00441-005-0129-5 ] . This is likely to contribute to testicular inflammation, considering the well-established role of dendritic cells in other types of autoimmune inflammation cite journal |author=Manuel SL, Rahman S, Wigdahl B, Khan ZK, Jain P |title=Dendritic cells in autoimmune diseases and neuroinflammatory disorders. |journal= Front Biosci. |volume=12 |pages=4315–4335 |year=2007 |pmid=17485377 |doi=10.2741/2390 ] .

Neutrophils

Neutrophils are white blood cells which are present in the blood but not normally in tissues. They move out from the blood into tissues and organs upon infection or damage. They directly fight invading pathogens such as bacteria. Neutrophils are not found in the rodent testis under normal conditions but can enter from the blood supply upon infection or inflammatory stimulus. This has been demonstrated in the rat after injection with bacterial cell wall components to produce an immune reaction cite journal |author=O'Bryan MK, Schlatt S, Phillips DJ, de Kretser DM, Hedger MP. |title= Bacterial lipopolysaccharide-induced inflammation compromises testicular function at multiple levels "in vivo". |journal= Endocrinology |volume=141 |pages=238–246 |year=2000 |pmid=10614644 |doi= 10.1210/en.141.1.238 ] . Neutrophils also enter the rat testis after treatment with hormones that increase the permeability of blood vessels cite journal |author=Bergh A, Widmark A, Damber JE, Cajander S.|title= Are leukocytes involved in the human chorionic gonadotropin-induced increase in testicular vascular permeability? |journal= Endocrinology |volume=119 |pages=589–590 |year=1986 |pmid=3732138 ] . In humans, neutrophils have been found in the testis when associated with some tumors cite journal |author=Akhtar M, al-Dayel F, Siegrist K, Ezzat A |title=Neutrophil-rich Ki-1-positive anaplastic large cell lymphoma presenting as a testicular mass. |journal= Mol Pathol |volume=9 |pages=812–815 |year=1996 |pmid=8871921 ] . In rat experiments, testicular torsion leads to neutrophil entry into the testis cite journal |author=Lysiak JJ |title= The role of tumor necrosis factor-alpha and interleukin-1 in the mammalian testis and their involvement in testicular torsion and autoimmune orchitis. |journal= Reprod Biol Endocrinol |volume=2 |pages=9 |year=2004 |pmid=15012831 |doi= 10.1186/1477-7827-2-9 ] . Neutrophil activity in the testis is an inflammatory response which needs to be tightly regulated by the body, since inflammation-induced damage to the testis can lead to infertility cite journal |author=Adamopoulos DA, Lawrence DM, Vassilopoulos P, Contoyiannis PA, Swyer GI |title= Pituitary-testicular interrelationships in mumps orchitis and other viral infections. |journal= Histopathology |volume=6 |pages=1177–1180 |year=1978 |pmid=346165 ] cite journal |author=Wallgren M, Kindahl H, Larsson K |title= Clinical, endocrinological and spermatological studies after endotoxin in the ram. |journal= Zentralbl Veterinarmed A. |volume=36 |pages=90–103 |year=1989 |pmid=2501956 ] . It is assumed that the role of the immunosuppressive environment of the testis is to protect developing sperm from inflammation.

Immune privilege in the testis

Sperm are immunogenic - that is they will cause an autoimmune reaction if transplanted from the testis into a different part of the body. This has been demonstrated in experiments using rats by Lansteiner (1899) and Metchinikoff (1900)cite book | author = Hedger MP, Hales DB |title = Knobil and Neill's Physiology of Reproduction | editor = Neill JD | pages=1195-1286 | publisher = Elsevier | year = 2006 | chapter = Immunophysiology of the Male Reproductive Tract | id= ISBN 0-12-515401-7 ] cite journal |author=Fijak M, Meinhardt A |title=The testis in immune privilege. |journal= Immunol Rev. |volume=213 |pages=66–81 |year=2006 |pmid=16972897 |doi=10.1111/j.1600-065X.2006.00438.x ] , mice cite journal |author=Kohno S, Munoz JA, Williams TM, Teuscher C, Bernard CC, Tung KS. |title=Immunopathology of murine experimental allergic orchitis. |journal= J Immunol. |volume=130 |pages=2675–2682 |year=1983 |pmid=6682874 ] and guinea pigs cite journal |author=Teuscher C, Wild GC, Tung KS |title=Immunochemical analysis of guinea pig sperm autoantigens. |journal= Biol reprod. |volume=26 |pages=218–229 |year=1982 |pmid=7039703 |doi=10.1095/biolreprod26.2.218 ] . The likely reason for this is that sperm first mature at puberty, after immune tolerance is established, therefore the body recognizes them as foreign and mounts an immune reaction against them. Since sperm do not die in the testis, mechanisms for their protection must exist in this organ. The blood-testis barrier is likely to contribute to the survival of sperm. However, it is believed in the field of testicular immunology that the blood-testis barrier cannot account for all immune suppression in the testis, due to (1) its incompleteness at a region called the rete testis cite journal |author=Fijak M, Meinhardt A |title=The testis in immune privilege. |journal= Immunol Rev. |volume=213 |pages=66–81 |year=2006 |pmid=16972897 |doi=10.1111/j.1600-065X.2006.00438.x ] and (2) the presence of immunogenic molecules outside the blood-testis barrier, on the surface of spermatogonia cite journal |author=Fijak M, Meinhardt A |title=The testis in immune privilege. |journal= Immunol Rev. |volume=213 |pages=66–81 |year=2006 |pmid=16972897 |doi=10.1111/j.1600-065X.2006.00438.x ] cite book | author = Hedger MP, Hales DB |title = Knobil and Neill's Physiology of Reproduction | editor = Neill JD | pages=1195-1286 | publisher = Elsevier | year = 2006 | chapter = Immunophysiology of the Male Reproductive Tract | id= ISBN 0-12-515401-7 ] . Another mechanism which is likely to protect sperm is the suppression of immune responses in the testis cite journal |author=Kern S, Robertson SA, Mau VJ, Maddocks S |title=Cytokine secretion by macrophages in the rat testis. |journal=Biol Reprod. |volume=53 |pages=1407–1416 |year=1995 |pmid=8562698 |doi=10.1095/biolreprod53.6.1407] cite journal |author=O'Bryan MK, Gerdprasert O, Nikolic-Paterson DJ, Meinhardt A, Muir JA, Foulds LM, Phillips DJ, de Kretser DM, Hedger MP |title=Cytokine profiles in the testes of rats treated with lipopolysaccharide reveal localized suppression of inflammatory responses. |journal=Am J Physiol Regul Integr Comp Physiol. |volume=288 |pages=R1744–R1755 |year=2005 |pmid=15661966] . Both the suppression of immune responses and the increased survival of grafts in the testis have led to its recognition as an immunologically privileged site. Other immunologically privileged sites include the eye, brain and uterus cite journal |author=Streilein, JW |title=Unravelling immune privilege. |journal=Science |volume=270 |pages=1158–1159 |year=1995 |pmid=7502038 |doi=10.1126/science.270.5239.1158] .

The two main features of immune privilege in the rat testis are;
* a diminishment in the activation of testicular macrophages by infections such as bacteria cite journal |author=Kern S, Robertson SA, Mau VJ, Maddocks S |title=Cytokine secretion by macrophages in the rat testis. |journal=Biol Reprod. |volume=53 |pages=1407–1416 |year=1995 |pmid=8562698 |doi=10.1095/biolreprod53.6.1407] , and
* a defect in the activation of T-cells when antigen is presented to them, leading to the absence of an adaptive immune response to sperm in the testis cite journal |author=Fijak M, Meinhardt A |title=The testis in immune privilege. |journal= Immunol Rev. |volume=213 |pages=66–81 |year=2006 |pmid=16972897 |doi=10.1111/j.1600-065X.2006.00438.x ] (more citations needed). It is also predicted that the high level of inflammatory cytokines in the testis contributes to immune privilege cite journal |author=Fijak M, Meinhardt A |title=The testis in immune privilege. |journal= Immunol Rev. |volume=213 |pages=66–81 |year=2006 |pmid=16972897 |doi=10.1111/j.1600-065X.2006.00438.x ] .

Immune privilege in rodents and other experimental animals

The existence of immune privilege in the testes of rodents is well accepted, due to many experiments demonstrating prolonged, and sometimes indefinite, survival of tissue transplanted into the testis cite journal |author=Brinster RL, Avarbock MR |title=Germline transmission of donor haplotype following spermatogonial transplantation. |journal= Proc Natl Acad Sci U S A. |volume=22 |pages=11303–11307 |year=1994 |pmid=7972054 |doi=10.1073/pnas.91.24.11303 ] cite journal |author=Clouthier DE, Avarbock MR, Maika SD, Hammer RE, Brinster RL. |title=Rat spermatogenesis in mouse testis. |journal= Nature |volume=381 |pages=418–421 |year=1996 |pmid=8632797 |doi=10.1038/381418a0 ] , or testicular tissue transplanted elsewhere cite journal |author=Honaramooz A, Snedaker A, Boiani M, Schöler H, Dobrinski I, Schlatt S. |title=The testis in immune privilege.|journal= Nature |volume=418 |pages=778–781 |year=2002 |pmid=12181567 ] cite journal |author=Oatley JM, de Avila DM, Reeves JJ, McLean DJ. |title= Testis tissue explant culture supports survival and proliferation of bovine spermatogonial stem cells. |journal= Biol Reprod. |volume=70 |pages=625–631 |year=2004 |pmid=14585812 |doi= 10.1095/biolreprod.103.022483 ] . Evidence includes the tolerance of testicular grafts in mice and rats, as well as the increased survival of transplants of pancreatic insulin-producing cells in rats, when cells from the testes (Sertoli Cells) are added to the transplanted material cite journal |author=Selawry HP, Cameron DF.|title=Sertoli cell-enriched fractions in successful islet cell transplantation. |journal= Cell Transplant |volume=2 |pages=123–129 |year=1993 |pmid=8143079 ] . Complete spermatogenesis, forming functional pig or goat sperm, can be established by the grafting of pig or goat testicular tissue onto the backs of mice - however, immunodeficient mice needed to be used cite journal |author=Honaramooz A, Snedaker A, Boiani M, Schöler H, Dobrinski I, Schlatt S. |title=The testis in immune privilege.|journal= Nature |volume=418 |pages=778–781 |year=2002 |pmid=12181567 ] .

Immune privilege in humans

The presence of immune-privilege in the human testis is controversial and insufficient evidence exists to either confirm or rule out this phenomenon.
* Evidence for human/primate testicular immune privilege:Sperm are protected from autoimmune attack, which when it occurs in humans leads to infertility cite journal |author=McLachlan RI. |title=Basis, diagnosis and treatment of immunological infertility in men. |journal= J Reprod Immunol. |volume=57 |pages=35–45 |year=2002 |pmid=12385832 |doi=10.1016/S0165-0378(02)00014-1] . Local injury of seminiferous tubules caused by fine-needle biopsies in humans does not cause testicular inflammation (orchitis) cite journal |author=Mallidis C, Baker HW. |title=Fine needle tissue aspiration biopsy of the testis. |journal= Fertil Steril. |volume=61 |pages=367–375 |year=1994 |pmid=8299798 ] . Furthermore, human testis cells tolerate early HIV infection with little response cite journal |author=Muciaccia B, Filippini A, Ziparo E, Colelli F, Baroni CD, Stefanini M|title=Testicular germ cells of HIV-seropositive asymptomatic men are infected by the virus. |journal= J Reprod Immunol. |volume=41 |pages=81–93 |year=1998 |pmid=10213302|doi=10.1016/S0165-0378(98)00050-3 ] .
* Evidence against human/primate testicular immune-privilege:In transplant experiments, primate testes fail to support grafts of monkey thyroid tissue cite journal |author=Setchell BP, Granholm T, Ritzén EM. |title=Failure of thyroid allografts to function in the testes of cynomolgous monkeys. |journal= JU Reprod Immunol |volume=28 |pages=75–80 |year=1995 |pmid=7738917 |doi=10.1016/0165-0378(94)00897-G ] . Human testis tissue transplanted into the mouse elicited an immune response and was rejected, however, this immune response was not as extensive as that against other types of grafted tissue cite journal |author=Kimmel SG, Ohbatake M, Kushida M, Merguerian P, Clarke ID, Kim PC. |title=Murine xenogeneic immune responses to the human testis: a presumed immune-privileged tissue. |journal= Transplantation |volume=69 |pages=1075–1084 |year=2000 |pmid=7972054 |doi=10.1097/00007890-200003270-00010 ] .

How does the testis suppress immune responses?

How the testicular environment suppresses the immune response is only partially understood. Recent experiments have uncovered a number of biological processes that most likely contribute to immune privilege in the testes of rodents:
* 1. Experiments in the rat have shown that Sertoli cells can help protect from graft rejection. These cells were isolated from the testis, then added to transplants of the insulin-producing cells of the pancreas (islets of Langerhans), resulting in increased graft survival cite journal |author=Korbutt GS, Elliott JF, Rajotte RV |title=Cotransplantation of allogeneic islets with allogeneic testicular cell aggregates allows long-term graft survival without systemic immunosuppression. |journal= Diabetes |volume=46 |pages=317–322 |year=1997 |pmid=9000711 |doi=10.2337/diabetes.46.2.317 ] . Molecules released by the Sertoli cells are predicted to protect the graft cite journal |author=Selawry HP, Cameron DF.|title=Sertoli cell-enriched fractions in successful islet cell transplantation. |journal= Cell Transplant |volume=2 |pages=123–129 |year=1993 |pmid=8143079 ] .
* 2. It is likely that the testicular environment itself is inhibiting the activation of T-cells, in order to protect the developing sperm which are immunogenic cite journal |author=Hedger, MP, Meinhardt, A |title=Local regulation of T cell numbers and lymphocyte-inhibiting activity in the interstitial tissue of the adult rat testis. |journal= J Reprod Immunol. |volume=48 |pages=69–80 |year=2000 |pmid=11011073 |doi=10.1016/S0165-0378(00)00071-1] cite journal |author=Kern S, Maddocks S. |title=Indomethacin blocks the immunosuppressive activity of rat testicular macrophages cultured in vitro. |journal= J Reprod Immunol. |volume=28 |pages=189–201 |year=1995 |pmid=7473430 |doi=10.1016/0165-0378(95)91391-Q] . The fluid present in the testis is a potent inhibitor of the activation of T-cells under laboratory conditions cite journal |author=Hedger, MP, Meinhardt, A |title=Local regulation of T cell numbers and lymphocyte-inhibiting activity in the interstitial tissue of the adult rat testis. |journal= J Reprod Immunol. |volume=48 |pages=69–80 |year=2000 |pmid=11011073 |doi=10.1016/S0165-0378(00)00071-1] .
* 3. The diminishment of the testis inflammatory response is likely to result from relatively low levels of inflammatory cytokines released by activated testicular macrophages cite journal |author=Kern S, Robertson SA, Mau VJ, Maddocks S |title=Cytokine secretion by macrophages in the rat testis. |journal=Biol Reprod. |volume=53 |pages=1407–1416 |year=1995 |pmid=8562698 |doi=10.1095/biolreprod53.6.1407] .

Since protection of developing sperm is so important to the survival of a species, it would not be surprising if more than one mechanism were in use.

Immune factors regulate normal testis function

Curiously, the testis contains factors such as cytokines, which are usually only produced upon infections and tissue damage. The cytokines interleukin-1α (IL-1α), IL-6 and Activin A are found in the testis, often at high levelscite journal |author=Gustafsson K, Sultana T, Zetterström CK, Setchell BP, Siddiqui A, Weber G, Söder O |title=Production and secretion of interleukin-1alpha proteins by rat testis.|journal= Biochem Biophys Res Commun. |volume=297 |pages=492–497 |year=2002 |pmid=12270120 |doi=10.1016/S0006-291X(02)02239-8 ] cite journal |author=Syed V, Gérard N, Kaipia A, Bardin CW, Parvinen M, Jégou B |title=Identification, ontogeny, and regulation of an interleukin-6-like factor in the rat seminiferous tubule. |journal= Endocrinology |volume=132 |pages=293–299 |year=1993 |pmid=8380379 |doi=10.1210/en.132.1.293 ] cite journal |author=Gérard N, Syed V, Bardin W, Genetet N, Jégou B. |title=Sertoli cells are the site of interleukin-1 alpha synthesis in rat testis. |journal= Mol Cell Endocrinol. |volume=82 |pages=R13–R16 |year=1991 |pmid=1761160 |doi=10.1016/0303-7207(91)90019-O] cite journal |author=Lee W, Mason AJ, Schwall R, Szonyi E, Mather JP |title=Secretion of activin by interstitial cells in the testis. |journal= Science |volume=243 |pages=396–398 |year=1989 |pmid=2492117 |doi=10.1126/science.2492117] cite journal |author=de Kretser DM, Robertson DM |title=The isolation and physiology of inhibin and related proteins. |journal= Biol Reprod. |volume=40 |pages=33–47 |year=1989 |pmid=2493821 |doi=10.1095/biolreprod40.1.33 ] . In other tissues, these cytokine would promote inflammation, but here they control testis function. They regulate the development of sperm by controlling their cell division and survival cite journal |author=Mather JP, Attie KM, Woodruff TK, Rice GC, Phillips DM |title=Activin stimulates spermatogonial proliferation in germ-Sertoli cell cocultures from immature rat testis. |journal= Endocrinology |volume=127 |pages=3206–3214 |year=1990 |pmid=2249646] cite journal |author=Boitani C, Stefanini M, Fragale A, Morena AR |title=Activin stimulates Sertoli cell proliferation in a defined period of rat testis development. |journal= Endocrinology |volume=136 |pages=5538–5444 |year=1995 |pmid=1761160 |doi=10.1210/en.136.12.5438 ] cite journal |author=Petersen C, Svechnikov K, Fröysa B, Söder O |title=The p38 MAPK pathway mediates interleukin-1-induced Sertoli cell proliferation. |journal= Cytokine |volume=32 |pages=51–59 |year=2005 |pmid=16181786 |doi=10.1016/j.cyto.2005.07.014 ] cite journal |author=Petersen C, Fröysa B, Söder O |title=Endotoxin and proinflammatory cytokines modulate Sertoli cell proliferation "in vitro". |journal= J Reprod Immunol. |volume=61 |pages=13–30 |year=2004 |pmid=15027475 |doi=10.1016/j.jri.2003.10.003 ] cite journal |author=Hakovirta H, Syed V, Jégou B, Parvinen M |title=Function of interleukin-6 as an inhibitor of meiotic DNA synthesis in the rat seminiferous epithelium. |journal= Mol Cell Endocrinol. |volume=108 |pages=193–198 |year=1995 |pmid=7758835 |doi=10.1016/0303-7207(95)03475-M] .

Other immune factors found in the testis include the enzyme inducible nitric oxide synthase (iNOS), and its product nitric oxide (NO) cite journal |author=Bauché F, Stéphan JP, Touzalin AM, Jégou B|title=In vitro regulation of an inducible-type NO synthase in the rat seminiferous tubule cells. |journal= Biol Reprod. |volume=58 |pages=431–438 |year=1995 |pmid=9475399|doi=10.1095/biolreprod58.2.431] cite journal |author=Tatsumi N, Fujisawa M, Kanzaki M, Okuda Y, Okada H, Arakawa S, Kamidono S. |title=Nitric oxide production by cultured rat Leydig cells. |journal= Endocrinology |volume=138 |pages=994–998 |year=1997 |pmid=9048600 |doi=10.1210/en.138.3.994] cite journal |author=O'Bryan MK, Schlatt S, Gerdprasert O, Phillips DJ, de Kretser DM, Hedger MP |title=Inducible nitric oxide synthase in the rat testis: evidence for potential roles in both normal function and inflammation-mediated infertility. |journal= Biol Reprod. |volume=63 |pages=1285–1293 |year=2000 |pmid=11058531 |doi=10.1095/biolreprod63.5.1285] , transforming growth factor beta (TGFβ)cite journal |author=Pöllänen P, von Euler M, Jahnukainen K, Saari T, Parvinen M, Sainio-Pöllänen S, Söder O |title=Role of transforming growth factor beta in testicular immunosuppression. |journal= Reprod Immunol. |volume=24 |pages=1213–137 |year=1993 |pmid=7901411] , the enzyme cyclooxygenase-2 (COX-2) and its product prostaglandin E2 cite journal |author=Winnall WR, Ali U, O'Bryan MK, Hirst JJ, Whiley PA, Muir JA, Hedger MP |title=Constitutive expression of prostaglandin-endoperoxide synthase 2 by somatic and spermatogenic cells is responsible for prostaglandin E2 production in the adult rat testis. |journal= Biol Reprod |volume=76 |pages=759–768 |year=2007 |pmid=17251525 |doi=10.1095/biolreprod.106.053124 ] , and many others. Further research is required to define the functional roles of these immune factors in the testis.

The effects of infections and immune responses on the testis

Mumps

Mumps is a viral disease which causes swelling of the salivary glands and testes. The mumps virus lives in the upper respiratory tract and spreads through direct contact with saliva [ [http://www.cdc.gov/vaccines/vpd-vac/mumps/in-short-adult.htm] "Mumps In-Short".] . Prior to widespread vaccination programs, it was a common childhood disease. Mumps is generally not serious in children, but in adults, where sperm have matured in the testis, it can cause more severe complications, such as infertility.

exually transmitted diseases:

Gonorrhea is a sexually transmitted disease caused by the bacteria "Niesseria gonorrhea" which can lead to testicular pain and swelling. Gonorrhea also infects the female reproductive system around the cervix and uterus, and can grow in the mouth, throat, eyes and anus [ [http://www.cdc.gov/std/Gonorrhea/STDFact-gonorrhea.htm] "Gonorrhea - CDC Fact Sheet".] . It can be effectively treated with antibiotics, however, if untreated, gonorrhea can cause infertility in men. Chlamydia is caused by the sexually transmitted bacteria "Chlamydia trachomatis" which infects the genitals. It more commonly affects women, and if untreated, can lead to pelvic inflammatory disease and infertility [ [http://www.cdc.gov/std/chlamydia/STDFact-Chlamydia.htm] "Chlamydia - CDC Fact Sheet".] . Serious symptoms in men are rare, but include swollen testicles and an unusual discharge from the penis. It is effectively treated with antibiotics.

Anti-sperm antibodies

Anti-sperm antibodies are produced by cells of the adaptive immune system and are the cause of approximately 7% of male infertility incidences. They can bind to sperm, inhibiting their movement, stopping recognition and entry into the egg, or targeting sperm for destruction when they reach the female reproductive tract cite journal |author=Hendry, WF |title=Detection and treatment of antispermatozoal antibodies in men.|journal= Reprod Fertil Dev. |volume=1 |pages=205–220 |year=1989 |pmid=2682806 |doi=10.1071/RD9890205] cite journal |author=Kremer J, Jager S.|title=The significance of antisperm antibodies for sperm-cervical mucus interaction.|journal= Autoimmunity |volume=7 |pages=781–784 |year=1992 |pmid=1500475]

Testicular torsion

Testicular torsion is a condition of physical twisting of the testis which results in cutting off the blood supply. It leads to damage that, if not treated within a few hours, causes the death of testicular tissue, and requires removal of the testis to prevent gangrene, and therefore can cause infertility cite journal |author= Ringdahl E, Teague L.|title=Testicular torsion. |journal= Am Fam Physician. |volume=74 |pages=1739–1743 |year=2006 |pmid=17137004] .

Autoimmune orchitis

Orchitis is a condition of testicular pain involving swelling, inflammation and possibly infection. Orchitis can be caused by an autoimmune reaction (autoimmune orchitis) leading to a reduction in fertility. Autoimmune orchitis is rare in humans, compared to anti-sperm antibodies cite book | author = Hedger MP, Hales DB |title = Knobil and Neill's Physiology of Reproduction | editor = Neill JD | pages=1195-1286 | publisher = Elsevier | year = 2006 | chapter = Immunophysiology of the Male Reproductive Tract | id= ISBN 0-12-515401-7 ] . To study orchitis in the testis, autoimmune orchitis has been induced in the rodent testis. The disease starts with the appearance of testicular antibodies, then movement of macrophages and lymphocytes from the blood stream into the testis, breaking of the physical interactions between the developing sperm and Sertoli cells, entry of neutrophils or eosinophils, and finally death of the developing sperm, leading to infertility cite journal |author= Doncel GF, Di Paola JA, Lustig L |title=Sequential study of the histopathology and cellular and humoral immune response during the development of an autoimmune orchitis in Wistar rats. |journal= Am J Reprod Immunol |volume=20 |pages=44–51 |year=1989 |pmid=2803528 ] cite journal |author=Kohno S, Munoz JA, Williams TM, Teuscher C, Bernard CC, Tung KS |title= Immunopathology of murine experimental allergic orchitis.|journal= J Immunol. |volume=130 |pages=2675–2682 |year=1983 |pmid=6682874 ] cite journal |author=Zhou ZZ, Zheng Y, Steenstra R, Hickey WF, Teuscher C |title=Actively-induced experimental allergic orchitis (EAO) in Lewis/NCR rats: sequential histo- and immunopathologic analysis.|journal= Autoimmunity |volume=3 |pages=125–134 |year=1989 |pmid=2491624 |doi=10.3109/08916938909019961 ] .

Inflammation models in the rodent

Experiments in rats have examined, in fine detail, the course of testicular events during a bacterial infection. In the short term (3 hours) multiple inflammatory factors are produced and released by testicular macrophages. Examples are prostaglandin E2cite journal |author=Kern S, Maddocks S |title=Indomethacin blocks the immunosuppressive activity of rat testicular macrophages cultured "in vitro". |journal= J Reprod Immunol. |volume=28 |pages=189–201 |year=1995 |pmid=7473430 |doi=10.1016/0165-0378(95)91391-Q ] cite journal |author=Winnall WR, Ali U, O'Bryan MK, Hirst JJ, Whiley PA, Muir JA, Hedger MP |title=Constitutive expression of prostaglandin-endoperoxide synthase 2 by somatic and spermatogenic cells is responsible for prostaglandin E2 production in the adult rat testis. |journal= Biol Reprod |volume=76 |pages=759–768 |year=2007 |pmid=17251525 |doi=10.1095/biolreprod.106.053124 ] , inducible nitric oxide synthase (iNOS) cite journal |author=Gerdprasert O, O'Bryan MK, Muir JA, Caldwell AM, Schlatt S, de Kretser DM, Hedger MP |title= The response of testicular leukocytes to lipopolysaccharide-induced inflammation: further evidence for heterogeneity of the testicular macrophage population. |journal= Cell Tiss Res. |volume=308 |pages=277–285 |year=2002 |pmid=12037584 |doi= 10.1007/s00441-002-0547-6 ] , TNFαcite journal |author=Hutson JC |title= Secretion of tumor necrosis factor alpha by testicular macrophages. |journal= J Reprod Immunol. |volume=23 |pages=63–72 |year=1993 |pmid=8429525 |doi= 10.1016/0165-0378(93)90027-F ] and IL-1β, although at lower levels than other tissuescite journal |author=Kern S, Robertson SA, Mau VJ, Maddocks S |title=Cytokine secretion by macrophages in the rat testis. |journal=Biol Reprod. |volume=53 |pages=1407–1416 |year=1995 |pmid=8562698 |doi=10.1095/biolreprod53.6.1407] . Non-immune cells of the testis such as Sertoli cells and Leydig cells also able to respond to bacteriacite journal |author=Syed V, Gérard N, Kaipia A, Bardin CW, Parvinen M, Jégou B |title=Identification, ontogeny, and regulation of an interleukin-6-like factor in the rat seminiferous tubule. |journal= Endocrinology |volume=132 |pages=293–299 |year=1993 |pmid=8380379 |doi=10.1210/en.132.1.293 ] cite journal |author=Gérard N, Syed V, Jégou B |title=Lipopolysaccharide, latex beads and residual bodies are potent activators of Sertoli cell interleukin-1 alpha production. |journal= Biochem Biophys Res Commun. |volume=185 |pages=154–161 |year=1992 |pmid=1599451 |doi=10.1016/S0006-291X(05)80969-6 ] . During a bacterial infection, testosterone levels and the amount of testicular interstitial fluid are reduced. Neutrophils enter the testis about 12 hours after infection. Importantly, there is damage to the developing sperm, which start to die under severe infectionscite journal |author= Liew SH, Meachem SJ, Hedger MP |title= A stereological analysis of the response of spermatogenesis to an acute inflammatory episode in adult rats. |journal= J Androl |volume=28 |pages=176–185 |year=2007 |pmid=16988326 |doi= 10.2164/jandrol.106.000752 ] . Despite all the data on the effects of bacteria on normal testis parameters, there is little experimental data regarding its effect on rodent fertility.

Other diseases where testicular inflammation can be a symptom:

Testicular inflammation can be a symptom of the following diseases: Coxsackie A virus [ [http://www.emedicine.com/EMERG/topic344.htm] "eMedicine - Orchitis"] cite journal |author=Willems WR, Hornig C, Bauer H, Klingmüller V.|title=A case of Coxsackie A9 virus infection with orchitis. |journal= J Med Virol. |volume=3 |pages=137–140 |year=1978 |pmid=8095915|doi=10.1002/jmv.1890030207 ] , varicella (chicken pox) [ [http://www.emedicine.com/EMERG/topic344.htm] "eMedicine - Orchitis"] cite journal |author=Liu HC, Tsai TC, Chang PY, Shih BF |title= Varicella orchitis: report of two cases and review of the literature. |journal= Pediatr Infect Dis J. |volume=13 |pages=748–750 |year=1994 |pmid=7970981 ] human immunodeficiency virus (HIV)cite journal |author=Pudney J, Anderson D |title= Orchitis and human immunodeficiency virus type 1 infected cells in reproductive tissues from men with the acquired immune deficiency syndrome. |journal= Am J Pathol. |volume=139 |pages=149–160 |year=1991 |pmid=1853930 ] , dengue fever [ [http://history.amedd.army.mil/booksdocs/wwii/infectiousdisvolii/chapter3.htm] "Internal Medicine in World War II - Dengue" by Richard B. Capps, M.D."] , Epstein Barr virus-associated infectious mononucleosiscite journal |author=Weiner RL |title=Orchitis: a rare complication of infectious mononucleosis. |journal= Pediatr Infect Dis J. |volume=16 |pages=1008–1009 |year=1997 |pmid=9380458 |doi=10.1097/00006454-199710000-00024 ] [ [http://www.emedicine.com/EMERG/topic344.htm] "eMedicine - Orchitis"] , syphiliscite journal |author= Singh R, Kaur D, Parameswaran M |title= Infantile congenital syphilis. Presenting with bilateral orchitis. |journal= Br J Vener Dis. |volume=47 |pages=206–208 |year=1971 |pmid=5090747 ] , leprosycite journal |author= Akhtar M, Ali MA, Mackey DM |title= Lepromatous leprosy presenting as orchitis. |journal= Am J Clin Pathol. |volume=73 |pages=712–715 |year=1980 |pmid=7377141 ] , tuberculosiscite journal |author= Kisbenedek L, Németh A |title= Granulomatous orchitis and spermatic granuloma.|journal= Int Urol Nephrol. |volume=7 |pages=141–148 |year=1975 |pmid=1184304 |doi= 10.1007/BF02085434 ] .

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