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PubMed1994

Histological study in contralateral testis of prepubertal children following unilateral testicular torsion.

Histological changes in the contralateral testis in 8 prepubertal children whose ages ranged from 3 to 7.5 years with a history of testicular torsion and subsequent atrophy were studied. The following histological parameters were evaluated: fertility tubular index (FTI), Sertoli cell index (SCI) and minimum tubular diameter (MTD). According to our findings and following Nistal and Paniagua's classification (1984) for tubular alterations, we found 5 cases (62.5%) who present the following alterations. Type 1 (case 2): FTI was decreased above 50% corresponding to slight germinal hypoplasia with normal MTD and SCI. Type 2 (cases 3 and 5): testis with remarkable germinal hypoplasia; FTI was between 30 and 50% while MTD was below normal values. Type 3 (case 8): testis with diffuse tubular hypoplasia; FTI was below 30%, whereas MTD showed 33% decrease regarding normal values. Type 4 (case 6): testes with hyperplasia of Sertoli cells; SCI was increased one third with regard to that corresponding to his age; FTI showed severe hypoplasia of germ cells. No relationship between alterations in either the age of the patients or the time elapsed since the torsion was observed. Because of all these facts and the young age of our patients, we believe that the alterations found in the contralateral testis were due to congenital dysgenesia.

Atrophy↗
PubMed2000

Cathepsin A is expressed in a cell- and region-specific manner in the testis and epididymis and is not regulated by testicular or pituitary factors.

The epithelial cells of the testis are involved in the production, differentiation, and sustenance of sperm, and those of the epididymis play a major role in sperm maturation, protection, and storage. These tissues express various proteins that respond differently to androgens. Cathepsin A is a multifunctional lysosomal carboxypeptidase that also functions as a protective and an activator protein for neuraminidase and beta-galactosidase. In this study, cathepsin A was immunolocalized by light and electron microscopy using a polyclonal affinity-purified antibody on the testis and epididymis of normal, orchidectomized with or without testosterone supplementation, efferent duct-ligated, and hypophysectomized adult rats. In normal rats, cathepsin A expression was noted in lysosomes of Sertoli and Leydig cells but not in germ cells of the testis, as well as nonciliated cells of the efferent ducts. In the epididymis, a cell- and region-specific distribution of cathepsin A was noted. In experimentally treated animals, no changes were noted in the expression of cathepsin A. Immunolabeling of tissues examined at the electron microscopic level revealed that lysosomes were reactive. These data indicate cell- and region-specific expression of cathepsin A in cells of the testis and epididymis and also indicate that cathepsin A expression is not regulated by testicular or pituitary factors.

Animals↗
PubMed1998

Laparoscopy for the nonpalpable testis.

Cryptorchidism represents one of the most common childhood disorders with the incidence of testicular maldescent being 0.8% by 1 year of age. Nonpalpable testis occurs in approximately 20% of patients with cryptorchidism. Laparoscopy for diagnosis and management of nonpalpable testis has shown to be highly effective with few complications. This article reviews some of the special considerations in performing laparoscopy in children with descriptions about the unique features of a child's anatomy and physiology. The role of laparoscopy in the evaluation and management of nonpalpable testis is discussed, along with some of the controversies about how laparoscopy may be changing our approach to a child with a nonpalpable testis.

Cryptorchidism↗
PubMed2002

Characterization of rat100, a 300-kilodalton ubiquitin-protein ligase induced in germ cells of the rat testis and similar to the Drosophila hyperplastic discs gene.

Conjugation of ubiquitin to proteins is activated during spermatogenesis. Ubiquitination is mediated by ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzymes (UBCs or E2s), and ubiquitin protein ligases (E3s). Since we previously showed that the activated ubiquitination is UBC4 dependent, we characterized Rat100, a UBC4-dependent E3 expressed in the testis. Analysis of expressed sequence tag sequences and immunoblotting showed that Rat100 is actually a 300-kDa protein expressed mainly in the brain and testis and is similar to the human E3 identified by differential display (EDD) protein and the Drosophila hyperplastic discs gene, mutants of which cause a defect in spermatogenesis. Rat100 is induced during postnatal development of the rat testis, peaking at d 25. It is localized only in germ cells and is highly expressed in spermatocytes, moderately in round and slightly in elongating spermatids. In contrast to UBC4 whose removal from a testis extract abrogates much of the conjugation activity, immmunodepletion of Rat100 from the extracts had little effect. Rat100 therefore has a limited subset of substrates, some of which appear associated with the E3 as the immunoprecipitate containing Rat100 supported incorporation of (125)I-ubiquitin into high molecular weight proteins. Thus, Rat100 is the homolog of human EDD and likely of Drosophila hyperplastic discs. This homology, together with our results, suggests that induction of this E3 results in ubiquitination of specific substrates, some of which are important in male germ cell development.

Aging↗
PubMed2004

Differential expression of steroidogenic factor-1/adrenal 4 binding protein and liver receptor homolog-1 (LRH-1)/fetoprotein transcription factor in the rat testis: LRH-1 as a potential regulator of testicular aromatase expression.

Aromatase converts testicular androgens to estrogens, which are essential for male fertility. Aromatase expression in testis occurs via transcription from promoter II, and requires the presence of a nuclear receptor half-site that binds the orphan receptor steroidogenic factor-1 [SF-1 (nuclear receptor 5A1)] to mediate basal and (in part) cAMP-induced transcription. We hypothesized that liver receptor homolog-1 (LRH-1) (nuclear receptor 5A2), a receptor closely related to SF-1, could also play a role in regulating aromatase expression in the testis. We demonstrate expression of LRH-1 in adult rat and immature mouse Leydig cells (LHR-1 > SF-1) as well as in pachytene spermatocytes and round spermatids but not in Sertoli cells, which in contrast, express high levels of SF-1. In transient transfection assays using TM3 Leydig cells and TM4 Sertoli cells, a rat promoter II luciferase reporter construct was stimulated by cotransfection of LRH-1 expression vector. Mutation analysis showed that induction by LRH-1 in TM3 and TM4 cells requires an AGGTCA motif at position -90, to which LRH-1 bound in gel shift analysis. We therefore provide evidence that LRH-1 plays an important role in the regulation of aromatase expression in Leydig cells. The colocalization of LRH-1 and aromatase to multiple testis cell types suggests that LRH-1 may have important effects on estrogen production, testis development, spermatogenesis, and testicular carcinogenesis.

Animals↗
PubMed2003

Di(n-butyl) phthalate impairs cholesterol transport and steroidogenesis in the fetal rat testis through a rapid and reversible mechanism.

In utero exposure to di(n-butyl) phthalate (DBP) leads to a variety of male reproductive abnormalities similar to those caused by androgen receptor antagonists. DBP demonstrates no affinity for the androgen receptor, but rather leads to diminished testosterone production by the fetal testis. The purpose of this study was to determine the onset and reversibility of DBP effects on the fetal testis and to determine at a functional level the points in the cholesterol transport and steroidogenesis pathways affected by DBP. Starting at gestational day (gd) 12, pregnant rats were gavaged daily with 500 mg/kg DBP or corn oil control. Significant decreases in testosterone production and mRNA expression of scavenger receptor B1, P450(SCC), steroidogenic acute regulatory protein, and cytochrome p450c17 were observed as early as gd 17. Testosterone, mRNA, and protein levels remained low 24 h after withdrawal of DBP treatment but increased 48 h after cessation of DBP exposure. In another experiment, pregnant dams were treated with DBP until gd 19, with the start of DBP treatment moved 1 d later into gestation for each treatment group, with the final group dosed only on gd 19. Significant decreases in testosterone, mRNA expression, and protein expression were evident as early as 3 h after treatment with DBP, with full repression apparent 24 h after treatment. Using a testis explant system, we determined that DBP treatment led to diminished transport of cholesterol across the mitochondrial membrane as well as diminished function at each point in the testosterone biosynthesis pathway except 17 beta-hydroxysteroid dehydrogenase. The transcriptional repression caused by DBP does not appear to be mediated via interference with steroidogenic factor-1 as determined by reporter assays. We conclude that high-dose DBP exposure leads to rapid and reversible diminution of the expression of several proteins required for cholesterol transport and steroidogenesis in the fetal testis, resulting in decreased testosterone synthesis and consequent male reproductive maldevelopment.

Animals↗
PubMed2005

The liver X receptor-{beta} is essential for maintaining cholesterol homeostasis in the testis.

The liver X receptor (LXR)alpha and -beta has been found to play a central role in maintaining cellular cholesterol homeostasis. In this study we comprehensively investigated the effect of deleting LXRalpha and -beta on testicular morphology and function. In the absence of LXRbeta, excessive cholesterol accumulated in the Sertoli cells from 2.5 months, resulting in severe cellular disruption and dysregulation of spermatogenesis by 10 months of age. This correlated with gene expression analyses that clearly indicated that LXRbeta was the dominant transcript in the testis Although the LXRalpha(-/-) testis was normal, the LXRalpha(-/-)beta(-/-) testis presented with a more severe phenotype than the LXRbeta(-/-) mice, and males were infertile by 4 months of age, indicating LXRalpha may partially rescue the testicular phenotype. Although Leydig cells did not accumulate excessive cholesterol, declining serum and intratesticular androgen levels with age suggested that these cells were in fact less functional. Treatment of a Sertoli cell line with the LXR agonist T0901317 led to increased expression of known LXR target genes like ATP binding cassette-G1 and sterol regulatory binding protein-1c; similar results were observed in wild-type testis after in vivo administration, suggesting the LXR is functioning in the same way as in other tissues. Ordinarily increased levels of cholesterol activate intracellular sensors to decrease these levels; however, the increasing amount of cholesterol in the Sertoli cells indicates improper control of cholesterol metabolism when LXRbeta is absent. Although the precise molecular mechanism at this time remains unclear, our study highlights the crucial role for LXRbeta in retaining cholesterol homeostasis in Sertoli cells.

Animals↗
PubMed2005

Pattern of orexin expression and direct biological actions of orexin-a in rat testis.

Orexins, hypothalamic neuropeptides initially involved in the control of food intake and sleep-wake cycle, have recently emerged as pleiotropic regulators of different biological systems, including the reproductive axis. Besides central actions, peripheral expression and functions of orexins have been reported, and prepro-orexin and orexin type-1 receptor mRNAs have been detected in the testis. However, the pattern of expression and biological actions of orexin in the male gonad remain mostly unexplored. In this study, we report analyses on testicular prepro-orexin mRNA expression and orexin-A immunoreactivity in different experimental settings, and on direct effects of orexin-A on seminiferous tubule functions. Expression of prepro-orexin mRNA was demonstrated in the rat testis at different stages of postnatal development, with negligible levels at early juvenile period and maximum values in adulthood. Likewise, orexin-A immunoreactivity was demonstrated along postnatal maturation, with strong peptide signal in Leydig cells and spermatocytes at specific stages of meiosis. Testicular expression of prepro-orexin mRNA appeared hormonally regulated; its levels decreased after hypophysectomy and increased after gonadotropin replacement and ghrelin stimulation. Finally, orexin-A suppressed the expression of key Sertoli cell genes, such as Müllerian-inhibiting substance and stem cell factor, and inhibited DNA synthesis in specific stages of the seminiferous epithelium. In conclusion, we provide evidence for the regulated expression of orexin in the rat testis and its potential involvement in the control of seminiferous tubule functions. Together with our recent results on the expression of orexin type-1 receptor in the rat testis, our data further document a novel testicular site of action of orexins in the control of male reproductive axis.

Aging↗
PubMed1985

The distribution of serum albumin in the rat testis, studied by electron microscope immunocytochemistry on ultrathin frozen sections.

The distribution of serum albumin is of interest in the rat testis because this protein is the principal carrier for testosterone in the plasma and interstitial fluid of this species. We have localized extravascular serum albumin in the rat testis at the electron microscope level, using gold particle immunocytochemistry on ultrathin frozen sections of tissue fixed lightly by perfusion. The same localization was obtained with three different antisera. Preabsorption and normal rabbit serum controls were negative, and Western blots of testis extracts showed major activity only at the molecular weight of albumin. Serum albumin occurred in substantial concentration throughout extracellular space in the interstitial tissue, as well as in the space between the boundary layer and the base of the seminiferous epithelium. Immunoreactivity extended between Sertoli cells, as well as around spermatogonia and early primary spermatocytes (to stage 11), but did not traverse the Sertoli-Sertoli junctions that comprise the blood-testis barrier. Macrophages in the interstitial tissue showed some endocytic activity. If perfusion fixation was carried out in a manner that flushed most of the albumin from the interstitial space, then a layer of albumin remained on the surface of Leydig cells and many macrophages but was minimal or absent on the surface of other cell types that are normally in contact with albumin, such as Sertoli cells, spermatogonia, myoid cells, lymphatic endothelium, fibroblasts, or cells of blood vessels.

Animals↗
PubMed1986

Expression and regulation of proopiomelanocortin-like gene in the ovary and placenta: comparison with the testis.

Proopiomelanocortin (POMC), a precursor protein for ACTH, beta-endorphin, and the MSHs, has been identified in the reproductive tracts of both male and female. With rat pituitary POMC complementary DNA (cDNA) as a hybridization probe, POMC-like messenger RNA (mRNA) was identified in the ovaries of rat, mouse, and monkey. The molecular size of POMC-like mRNA in the ovary was 150-200 bases smaller than in the pituitary and hypothalamus but identical to that in the testis and epididymis. The size heterogeneity of POMC mRNA observed in various tissues is not due to differences in the lengths of the poly(A) tail, as measured by RNase H digestion. S1 nuclease mapping analysis revealed that POMC mRNAs isolated from pituitary, testis, or ovary share the nucleotide sequences coding for ACTH, beta-lipotropin, and the 3'-untranslated region. The regulation of ovarian POMC-like mRNA was also investigated. Treatment of 25-day-old immature female rats with PMSG resulted in profound increases in the ovarian content of total RNA, poly(A) RNA, and POMC-like mRNA. The concentration of ovarian POMC-like mRNA during pregnancy increased increased to 3-4 times that in immature or normally cycling animals. POMC-derived peptides are present in the human placenta and are synthesized de novo in cultured placental cells. In this report we also demonstrate POMC-like mRNA in the placenta of rat, mouse, and human. The size of POMC-like mRNA in the placenta was similar to that observed in the testis, epididymis, and ovary and different from that found in the pituitary or hypothalamus. The concentration of placental POMC-like mRNA did not change throughout pregnancy. In conclusion, we have demonstrated that 1) POMC-like mRNA is present in the ovary and placenta of rodents and primates; 2) the size of POMC-like mRNA in the ovary and placenta, like that in the testis and epididymis, is smaller than that in the pituitary and hypothalamus, probably owing to a shortening of the 5'-ends; and 3) the expression of this gene is regulated by gonadotropins in the ovary but probably not in the placenta.

Animals↗
PubMed1990

Differential response of luteinizing hormone receptor and steroidogenic enzyme gene expression to human chorionic gonadotropin stimulation in the neonatal and adult rat testis.

To study further the functional differences of the fetal-neonatal and adult growth phases of Leydig cells, neonatal (5-day-old) and adult (60-day-old) male rats were challenged with a 600 IU/kg injection of human CG (hCG). Certain Leydig cell responses were monitored 1, 2, and 3 days after the hCG injection. The down-regulation of LH receptors and blockage of the 17-hydroxylase/C17-20 lyase step in adult testis, and the absence of these responses in neonatal testis were confirmed. Novel data were obtained on concomitant responses of LH receptor and steroidogenic enzyme messenger RNAs (mRNAs). The LH receptor mRNA was increased 4-5-fold by 2 days after hCG injection in the neonatal testis (P less than 0.05), but in the adult was decreased during all 3 days by 50% (P less than 0.05). The mRNA level of the cytochrome P450 for cholesterol side chain cleavage responded similarly at both ages, with a 180-260% increase during 2 and 3 days (P less than 0.05-0.01). In contrast, the 17-hydroxylase/17,20-lyase cytochrome P450 mRNAs displayed opposite responses, increasing 4.5-fold in 2 days (P less than 0.01) in the neonates, but decreasing by 80% in 1 day in the adults (P less than 0.01). No response of the aromatase cytochrome P450 mRNA to hCG stimulation was found at either age studied. These results demonstrate that the functional differences of the neonatal and adult Leydig cells to high gonadotropic stimulation occur at the level of expression of specific genes, including those of the LH receptor and the 17-hydroxylase/17,20-lyase cytochrome P450. Although aromatization of testicular androgens has been suggested to mediate the blockade of the 17-hydroxylase/C17-20 lyase step in adult testes, altered steady state levels of aromatase mRNA are not involved in this response. LH receptor mRNA decreases in adult rat testis in response to treatment with high levels of hCG. Thus, this phenomenon of down-regulation of membrane receptors includes a decreased LH receptor mRNA as well as cellular internalization of the existing receptors.

Animals↗
PubMed1991

Alpha 2-macroglobulin is not an acute-phase protein in the rat testis.

Earlier studies from this laboratory have shown that Sertoli cells actively synthesize and secrete a nonspecific protease inhibitor in vitro; N-terminal sequence analysis, subunit structural analysis, and other biological studies revealed that this protein is the homolog of serum alpha 2-macroglobulin. We have now quantified the relative distribution of alpha 2-macroglobulin in the reproductive compartments and their comparison with nonreproductive organs. In serum and all nonreproductive tissues examined, the concentration of alpha 2-macroglobulin progressively decreased with advancing age. However, in both the testis and epididymis, the levels of this protein increased with the age of the animals. Serum alpha 2-macroglobulin levels were consistently higher than those in any other tissues until 60 days when the concentrations of this protein were the highest in the epididymis. The distribution of alpha 2-macroglobulin in various nonreproductive tissues from female rats was similar to that observed for male rats in that its levels tended to decrease with age. However, uterine levels of alpha 2-macroglobulin increased progressively with advancing age, whereas ovarian levels of alpha 2-macroglobulin remained relatively stable with an increase in animal age. As serum alpha 2-macroglobulin is an acute-phase protein in the rat, the response of this protein in the testis to induced inflammation was examined. The concentration of alpha 2-macroglobulin in serum rose about 150-fold after injection of fermented yeast. By contrast, the levels of this protein in rete testis fluid, which is derived exclusively from seminiferous fluid, did not change in response to inflammation. These results suggest that there might be distinctive mechanisms that regulate this protein in the systemic circulation vs. the microenvironment behind the blood-testis barrier in the seminiferous epithelium.

Acute-Phase Proteins↗
PubMed1975

The intratesticular localization of cytochrome P-450 and cytochrome P-450-dependent enzymes in the rat testis.

Following separation of the seminiferous tubules from the interstitial cells in the rat testis, the amount of cytochrome P-450 and the activities of the cytochrome P-450-dependent enzymes, the 17alpha-hydroxylase and the C17-C20 lyase, were measured in the microsomes of the separated fractions. The amount of cytochrome P-450-dependent enzymes recovered in the microsomal fraction of the interstitial cells ranged from 71 to 86% of the whole testis. However, in some experiments lower recoveries of the activities of the enzymes were attributed to the breakdown of cytochrome P-450 to cytochrome P-420. In all cases, less than 10% of the testicular cytochrome P-450 and the cytochrome P-450-dependent steroidogenic enzymes were found in the tubular microsomes. Moreover, the specific activities of the 17 alpha-hydroxylase and the C17-C20 lyase were found to be 10 to 30 times higher in the interstitial tissue than in the seminiferous tubules of the rat testis. From these results, we have concluded that cytochrome P-450 and the activities of the cytochrome P-450-dependent enzymes in the rat testis are predominantly, if not sole, located in the interstitial cells.

Animals↗
PubMed1992

Regulation of beta-endorphin secretion by corticotropin-releasing factor in the intact rat testis.

CRF stimulates beta-endorphin (beta EP) secretion from adult rat Leydig cells in vitro. To evaluate the relevance of this action of CRF in a physiological context, we studied the effect of CRF on beta EP secretion in the testis in whole animals. In the pubertal rat, intratesticular infusion of CRF resulted in a 3-fold stimulation of immunoreactive beta EP (ir beta EP) levels in testicular interstitial fluid (TIF) compared with levels in contralateral saline-infused testes. Coadministration of the antagonist CRF-(12-41) resulted in TIF ir beta EP concentrations that were reduced compared to levels in paired saline controls. Infusion of the competitive antagonist CRF-(9-41) alone slightly stimulated ir beta EP concentrations in TIF. In adult animals, all of the peptides tested were without effect. These results suggest a developmental regulation of the action of CRF on beta EP levels in the pubertal rat testis. Our studies in conjunction with documented results demonstrate that in the testis, beta EP is actively secreted. These results imply that testicular ir beta EP is derived from a POMC mRNA that encodes a signal peptide containing preprohormone similar or identical to pituitary POMC. Previous studies of rodent testicular mRNA have found only 5'-truncated forms of POMC message. The current study provides direct evidence for a low abundance POMC transcript that could encode the preprohormone. Therefore, the major components of a pituitary-like CRF/POMC stimulus/secretion system appear to be present in the rat testis, including the full-length POMC mRNA and release of POMC-derived beta EP that is stimulated by CRF.

Animals↗
PubMed1992

Expression of diazepam binding inhibitor-like immunoreactivity in rat testis is dependent on pituitary hormones.

Diazepam binding inhibitor-like immunoreactivity (DBI-LI) in normal and hypophysectomized (HPX) rat testis was studied by light and electron microscopic immunohistochemistry. In normal testis DBI-LI was observed in interstitial Leydig cells and Sertoli cells of most seminiferous tubules. At the electron microscopic level, DBI-LI was distributed throughout the cytoplasm of labeled cells; a concentration of the labeling product was observed in the smooth endoplasmic reticulum, Golgi apparati, and the outer membrane of the mitochondria. In the seminiferous epithelium, labeled processes of Sertoli cells could be traced among developing germ cells. After HPX a gradual disappearance of DBI-LI was observed in all Leydig cells. The number of labeled Sertoli cells was reduced in the majority of tubules after HPX, whereas in some tubules the staining was only slightly reduced. Replacement therapy of the HPX animals with human CG prevented the disappearance of DBI-LI from Leydig cells, whereas replacement with FSH did not prevent the disappearance of DBI-LI in Leydig cells. In Sertoli cells replacement therapies were not effective in restoring DBI-LI. In rat testis DBI and mitochondrial benzodiazepine binding sites are highly concentrated in the Leydig cells. Mitochondrial benzodiazepine binding sites and DBI are involved in the regulation of steroid production. As the expression of DBI-LI is under the control of pituitary hormones, DBI may play a role as an endogenous regulator of intracellular metabolic functions, such as steroidogenesis, in rat testis.

Animals↗
PubMed1993

Germ cells of the mouse testis express P450 aromatase.

Estrogen production within the testis has been a subject of considerable controversy for many years. Several studies have shown that both Sertoli and Leydig cells produce estrogen during different stages of development. Therefore, we have conducted experiments to localize aromatase, a cytochrome P450 enzyme that converts androgen to estrogen, within the testis. First, P450 aromatase (P450arom) was localized in germ cells of the adult mouse testis by immunocytochemistry, using an antiserum generated against purified human placental cytochrome P450arom. In the germinal epithelium, P450arom was located primarily in the Golgi region of round spermatids, throughout the cytoplasm of elongating spermatids, and along the flagella of late spermatids. Second, localization of P450arom within the germinal epithelium was supported by Western blot analysis of isolated germ cells. Third, Northern blot analysis using a mouse P450arom cDNA probe indicated that the mRNA for the mouse P450arom was present in testicular germ cells. Fourth, P450arom activity was measured in germ cells by the 3H2O water assay. Based upon these observations, we conclude that germ cells are a site of estrogen synthesis in the adult mouse testis.

Animals↗
PubMed1993

Early thyroid hormone treatment in rats increases testis size and germ cell number.

By means of in vivo and in vitro approaches, we studied the effect of thyroid hormone on postnatal development of rat testis. T3 treatment in neonatal rats is associated with an increase of testis size of about 60%, compared to coeval controls. Increased number of both Sertoli and germ cells and enlarged diameter of seminiferous cords were found in hyperplastic testes. In the T3-treated group, TSH serum levels were low and a slight increase of FSH was found. In vitro treatment of neonatal testis fragments by 10(-7) M T3 for 3 days increased the number of gonocytes (P < 0.001 vs control) and decreased the percentage of degenerating germ cells (P < 0.001 vs control). In the adult testis, both in vivo and in vitro treatments with thyroid hormone did not induce morphological modifications, thus demonstrating that the critical window of thyroid hormone effectiveness coincides with the prepuberal period. Since thyroid hormone stimulates Sertoli cells to secrete growth factors and nutrients for germ cell development, we suggest that the increased testicular size and germ cell number following the T3 treatment is mediated by a direct hormonal effect on the somatic cell of the seminiferous epithelium.

Animals↗
PubMed1993

Experimental autoimmune orchitis induced by testis and sperm antigen-specific T cell clones: an important pathogenic cytokine is tumor necrosis factor.

Testicular autoimmune disease (autoimmune orchitis) develops in mice immunized with testis antigen in adjuvant, occurs spontaneously in dogs, mink, and horses, and is a potential cause of human infertility. This is the first study to investigate autoimmune orchitis using monoclonal T cells. Despite the use of crude tissue antigens, 100% of the T cell lines/clones transferred autoimmune disease of the male gonad to normal syngeneic mice, with pathology that affected the testis, the epididymis and/or the vas deferens. Thus orchitogenic peptides are likely of restricted number and/or of dominant immunogenicity. Upon transfer to normal mice, the mildest and earliest pathology elicited by the cloned T cells invariably occurred in a specific region, the testicular straight tubules. Although testis antigen-derived T cell clones responded preferentially to testis antigen, and sperm antigen-derived clones responded more to sperm antigens, each of the 16 clones respond to both antigens. Thus common orchitogenic antigens exist in these germ cell populations though their quantity may differ in distribution. All orchitogenic T cell lines and clones expressed CD4 and the alpha beta T cell receptor; and when activated, they produced interleukin 2, interferon gamma, and tumor necrosis factor (TNF), but not interleukin 4. This cytokine profile characterizes the Th1 CD4+ T cell subset, known to be responsible for the delayed type immunological reaction. Importantly, since disease transfer was significantly and reproducibly attenuated when recipients were injected with neutralizing antibody to TNF, but not neutralizing antibody to interferon gamma, TNF has been defined as a cytokine important in the pathogenesis of this autoimmune disease.

Animals↗