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Egress of sperm autoantigen from seminiferous tubules maintains systemic tolerance.

ABSTRACT: Autoimmune responses to meiotic germ cell antigens (MGCA) that are expressed on sperm and testis occur in human infertility and after vasectomy. Many MGCA are also expressed as cancer/testis antigens (CTA) in human cancers, but the tolerance status of MGCA has not been investigated. MGCA are considered to be uniformly immunogenic and nontolerogenic, and the prevailing view posits that MGCA are sequestered behind the Sertoli cell barrier in seminiferous tubules. Here, we have shown that only some murine MGCA are sequestered. Nonsequestered MCGA (NS-MGCA) egressed from normal tubules, as evidenced by their ability to interact with systemically injected antibodies and form localized immune complexes outside the Sertoli cell barrier. NS-MGCA derived from cell fragments that were discarded by spermatids during spermiation. They egressed as cargo in residual bodies and maintained Treg-dependent physiological tolerance. In contrast, sequestered MGCA (S-MGCA) were undetectable in residual bodies and were nontolerogenic. Unlike postvasectomy autoantibodies, which have been shown to mainly target S-MGCA, autoantibodies produced by normal mice with transient Treg depletion that developed autoimmune orchitis exclusively targeted NS-MGCA. We conclude that spermiation, a physiological checkpoint in spermatogenesis, determines the egress and tolerogenicity of MGCA. Our findings will affect target antigen selection in testis and sperm autoimmunity and the immune responses to CTA in male cancer patients.

SUBMITTER: Tung KS

PROVIDER: S-EPMC5330742 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Egress of sperm autoantigen from seminiferous tubules maintains systemic tolerance.

Tung Kenneth S K KS Harakal Jessica J Qiao Hui H Rival Claudia C Li Jonathan C H JC Paul Alberta G A AG Wheeler Karen K Pramoonjago Patcharin P Grafer Constance M CM Sun Wei W Sampson Robert D RD Wong Elissa W P EW Reddi Prabhakara P PP Deshmukh Umesh S US Hardy Daniel M DM Tang Huanghui H Cheng C Yan CY Goldberg Erwin E

The Journal of clinical investigation 20170220 3

Autoimmune responses to meiotic germ cell antigens (MGCA) that are expressed on sperm and testis occur in human infertility and after vasectomy. Many MGCA are also expressed as cancer/testis antigens (CTA) in human cancers, but the tolerance status of MGCA has not been investigated. MGCA are considered to be uniformly immunogenic and nontolerogenic, and the prevailing view posits that MGCA are sequestered behind the Sertoli cell barrier in seminiferous tubules. Here, we have shown that only some ...[more]

PMID: 28218625

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Project description:Objectives:Spermatogenesis is a regular and lengthy process in which the function of testicular cells may potentially be influenced by several extrinsic and intrinsic stressors, including environmental factors such as magnetic resonance imaging (MRI) waves and radiation. Our study aimed to investigate the effects of MRI waves and fields on the testicular histology and morphometry of seminiferous tubules in mice. Methods:The experiment was conducted on 40 adult Naval Medical Research Institute mice. The control group was located in the center of the MRI bore while it was turned off, while the exposed group was exposed to the active scanner for 36 minutes once a week for three weeks. Our study included four groups: group I (control group at one hour after last exposure), group II (experimental group at one hour after last exposure), group III (control group at 35 days after last virtual exposure), and group IV (experimental group at 35 days after last exposure). We then assessed the tube and lumen diameters, as well as epithelium thickness of the seminiferous tubules. Results:Our data showed that MRI waves partially reduced testicular weight one hour after the last exposure (group II) compared to group I (p = 0.240). On the other hand, in group II the Johnson's score (score 10, complete spermatogenesis and perfect tubules) was 87.5% which was slightly less than recorded in groups I, III, and IV (91.4%, 92.2%, and 90.5%, respectively). Furthermore, the MRI in group II revealed induces vacuolization in the epithelium, arrest in primary spermatocytes in the pachytene stage as well as disruption in the testicular parenchyma. Conclusions:Long-term exposure to MRI waves has deleterious effects on the male reproductive system, fertility parameters, and the quantity of germ cells in the seminiferous tubules with the exception of the number of round spermatid cells and epithelial thickness. All these effects were reversible after a new period of spermatogenesis.

Project description:BackgroundInfertile men with non-obstructive azoospermia (NOA) have impaired spermatogenesis. Dilated and un-dilated atrophic seminiferous tubules are often present in the testes of these patients, with the highest likelihood of active spermatogenesis in the dilated tubules. Little is known about the un-dilated tubules, which in NOA patients constitute the majority. To advance therapeutic strategies for men with NOA who fail surgical sperm retrieval we aimed to characterize the spermatogonial stem cell microenvironment in atrophic un-dilated tubules.MethodsTestis biopsies approximately 3x3x3 mm3 were obtained from un-dilated areas from 34 patients. They were classified as hypospermatogenesis (HS) (n=5), maturation arrest (MA) (n=14), and Sertoli cell only (SCO) (n= 15). Testis samples from five fertile men were included as controls. Biopsies were used for histological analysis, RT-PCR analysis and immunofluorescence of germ and Sertoli cell markers.ResultsAnti-Müllerian hormone mRNA and protein expression was increased in un-dilated tubules in all three NOA subtypes, compared to the control, showing an immature state of Sertoli cells (p<0.05). The GDNF mRNA expression was significantly increased in MA (P=0.0003). The BMP4 mRNA expression showed a significant increase in HS, MA, and SCO (P=0.02, P=0.0005, P=0.02, respectively). The thickness of the tubule wall was increased 2.2-fold in the SCO-NOA compared to the control (p<0.05). In germ cells, we found the DEAD-box helicase 4 (DDX4) and melanoma-associated antigen A4 (MAGE-A4) mRNA and protein expression reduced in NOA (MAGE-A: 46% decrease in HS, 53% decrease in MA, absent in SCO). In HS-NOA, the number of androgen receptor positive Sertoli cells was reduced 30% with a similar pattern in mRNA expression. The γH2AX expression was increased in SCO as compared to HS and MA. However, none of these differences reached statistical significance probably due to low number of samples.ConclusionsSertoli cells were shown to be immature in un-dilated tubules of three NOA subtypes. The increased DNA damage in Sertoli cells and thicker tubule wall in SCO suggested a different mechanism for the absence of spermatogenesis from SCO to HS and MA. These results expand insight into the differences in un-dilated tubules from the different types of NOA patients.

Project description:Hypercholesterolemia is a marker for several adult chronic diseases. Recently we demonstrated that sub/infertility is also associated to Hypercholesterolemia in rabbits. Seminal alterations included: abnormal sperm morphology, decreased sperm number and declined percentage of motile sperm, among others. In this work, our objective was to evaluate the effects of hypercholesterolemia on testicular efficiency and spermiogenesis, as the latter are directly related to sperm number and morphology respectively. Tubular efficiency was determined by comparing total number of spermatogenic cells with each cell type within the proliferation/differentiation compartments. We found lower testicular efficiency related to both a decrease in spermatogonial cells and an increase in germ cell apoptosis in hypercholesterolemic rabbits. On the other hand, spermiogenesis-the last step of spermatogenesis involved in sperm shaping-was detaily analyzed, particularly the acrosome-nucleus-manchette complex. The manchette is a microtubular-based temporary structure responsible in sperm cell elongation. We analyzed the contribution of actin filaments and raft microdomains in the arrangement of the manchette. Under fluorescence microscopy, spermatocyte to sperm cell development was followed in cells isolated from V to VIII tubular stages. In cells from hypercholesterolemic rabbits, abnormal development of acrosome, nucleus and inaccurate tail implantation were associated with actin-alpha-tubulin-GM1 sphingolipid altered distribution. Morphological alterations were also observed at electron microscopy. We demonstrated for the first time that GM1-enriched microdomains together with actin filaments and microtubules are involved in allowing the correct anchoring of the manchette complex. In conclusion, cholesterol enriched diets promote male fertility alterations by affecting critical steps in sperm development: spermatogenesis and spermiogenesis. It was also demonstrated that hypercholesterolemic rabbit model is a useful tool to study serum cholesterol increment linked to sub/infertility.

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Egress of sperm autoantigen from seminiferous tubules maintains systemic tolerance.

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Egress of sperm autoantigen from seminiferous tubules maintains systemic tolerance.

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