Autoimmunity to Spermatozoa and the Testis

Tung, Kenneth S. K.; Teuscher, Cory; Meng, A.

doi:10.1111/j.1600-065x.1981.tb00344.x

Cited by 62 publications

(43 citation statements)

References 47 publications

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“…Thus, many sperm proteins represent "neoantigens" that could trigger autoimmune responses. Proof that neoantigens exist is the observation in many mammalian species that the injection of testicular homogenates into homologous species induces autoimmune orchitis directed against sperm antigens (38). On the other hand, allografts and even xenografts can be transplanted into the testis without rejection (39).…”

Section: Discussionmentioning

confidence: 99%

Expression of Bisecting Type and Lewisx/Lewisy Terminated N-Glycans on Human Sperm

Pang

Tissot

Drobnis

et al. 2007

Journal of Biological Chemistry

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Human sperm lack major histocompatibility class I molecules, making them susceptible to lysis by natural killer (NK) cells. Major histocompatibility class I negative tumor cells block NK cell lysis by expressing sufficient amounts of bisecting type N-glycans on their surfaces. Therefore, sperm could employ the same strategy to evade NK cell lysis. The total N-glycans derived from sperm were sequenced using ultrasensitive mass spectrometric and conventional approaches. Three major classes of N-glycans were detected, (i) high mannose, (ii) biantennary bisecting type, and (iii) biantennary, triantennary, and tetraantennary oligosaccharides terminated with Lewis x and Lewis y sequences. Immunostaining of normal sperm showed that glycoproteins bearing Lewis y sequences are localized to the acrosome and not the plasma membrane. In contrast, defective sperm showed distinct surface labeling with antiLewis y antibody. The substantial expression of high mannose and complex type N-glycans terminated with Lewis x and Lewis y sequences suggests that sperm glycoproteins are highly decorated with ligands for DC-SIGN. Based on previous studies, the addition of such carbohydrate signals should inhibit antigenspecific responses directed against sperm glycoproteins in both the male and female reproductive systems. Thus, the major N-glycans of human sperm are associated with the inhibition of both innate and adaptive immune responses. These results provide more support for the eutherian fetoembryonic defense system hypothesis that links the expression of carbohydrate functional groups to the protection of gametes and the developing human in utero. This study also highlights the usefulness of glycomic profiling for revealing potential physiological functions of glycans expressed in specific cell types.Studies performed over the past four decades indicate that conditions are not optimal for human sperm in the female reproductive system (1). Women release neutrophils, monocytes, and lymphocytes from the specialized mucosal surface of their cervix during the leukocyte reaction after coitus (2, 3). This sequestration occurs specifically in response to contact with sperm but not seminal plasma (2, 3). Increased immunological awareness related to histocompatibility and its implications for reproduction in eutherians initially raised concerns about how foreign human sperm are tolerated in the female reproductive system (4). Early studies suggested that human sperm express MHC 3 class I molecules that define self, suggesting the possibility that histocompatibility based responses must be suppressed in the female reproductive tract (5). However, more recent studies confirm that sperm precursors down-modulate their MHC class I molecules, yielding mature sperm that are MHC class I negative cells (5). This absence enables these gametes to evade histocompatibility based responses mediated by MHC class I-restricted cytotoxic T lymphocytes (6).This lack of MHC class I molecules does not make sperm completely invulnerable to cell mediated responses...

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Section: Discussionmentioning

confidence: 99%

Expression of Bisecting Type and Lewisx/Lewisy Terminated N-Glycans on Human Sperm

Pang

Tissot

Drobnis

et al. 2007

Journal of Biological Chemistry

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“…Testicular immune privilege seems logical, as the first appearance of a large number of neoantigens in developing germ cells occurs only after establishment of self-tolerance and thus requires special adaptations of the immune system to avoid rejection and ultimately infertility by chronic orchitis. Tolerance is conferred by the testis itself, as autoimmunity is rapidly elicited when testicular autoantigens are injected under the skin (4). Data accumulated during the last decade now imply that local active immunosuppression rather than simple sequestration of autoantigens by the blood/testis barrier is central in the establishment and maintenance of testicular immune privilege.…”

mentioning

confidence: 99%

Differential Activation of Inflammatory Pathways in Testicular Macrophages Provides a Rationale for Their Subdued Inflammatory Capacity

Bhushan

Tchatalbachev

et al. 2015

The Journal of Immunology

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Spermatogenic cells express cell-specific molecules with the potential to be seen as “foreign” by the immune system. Owing to the time difference between their appearance in puberty and the editing of the lymphocyte repertoire around birth, local adaptations of the immune system coined immune privilege are required to confer protection from autoattack. Testicular macrophages (TM) play an important role in maintaining testicular immune privilege and display reduced proinflammatory capacity compared with other macrophages. However, the molecular mechanism underlying this macrophage phenotype remained elusive. We demonstrate that TM have a lower constitutive expression of TLR pathway–specific genes compared with peritoneal macrophages. Moreover, in TM stimulated with LPS, the NF-κB signaling pathway is blocked due to lack of IκBα ubiquitination and, hence, degradation. Instead, challenge of TM with LPS or polyinosinic-polycytidylic acid induces MAPK, AP-1, and CREB signaling pathways, which leads to production of proinflammatory cytokines such as TNF-α, although at much lower levels than in peritoneal macrophages. Pretreatment of TM with inhibitors for MAPKs p38 and ERK1/2 suppresses activation of AP-1 and CREB signaling pathways and attenuates LPS-induced TNF-α and IL-10 secretion. High levels of IL-10 production and activation of STAT3 by LPS stimulation in TM indicate a regulatory macrophage phenotype. Our results suggest that TM maintain testicular immune privilege by inhibiting NF-κB signaling through impairment of IκBα ubiquitination and a general reduction of TLR cascade gene expression. However, TM do maintain some capacity for innate immune responses through AP-1 and CREB signaling pathways.

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“…This could be the result of a rising interstitial pressure and a breakdown of the blood-testis barrier 11 followed by exposure of testicular antigens to the circulating antibodies. This mechanism has previously been evoked to explain immune complexes 12 seen in patients and in animals after ligation of the vas. 11 Our findings, however, differ from those of Pousset et al 13 who, in a study of 52 infertile males, found immunofluorescence in only 1 of the 22 patients with a varicocele.…”

Section: Discussionmentioning

confidence: 99%

Testicular Immunoglobulin Deposition as a Possible Cause of Male Infertility

et al. 1983

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The possibility that infertility might result from deposition of immunoglobulin (Ig) within the testis was investigated in 30 consecutive male patients. Testicular tissue was examined by direct immunofluorescent techniques to demonstrate IgG, A and M, complement (C3), and fibrinogen. IgG was seen in 13 patients (43 percent) localized to the basement membrane of seminiferous tubules. Varicoceles were more common (7 v 2, P < 0.02) in the IgG-positive patients and a history of testicular swelling, probably due to mumps, was more common (5 v 0, P < 0.05) in the IgG-negative group. The percentage of nonmotile sperms was high in both groups (73 v 77). We conclude that IgG deposition is a common finding in the Saudi male, may be one cause of male infertility, and suggest that the testicular damage is caused by an antibody directed against specific antigens within the seminiferous tubular basement membrane.

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Autoimmunity to Spermatozoa and the Testis

Cited by 62 publications

References 47 publications

Expression of Bisecting Type and Lewisx/Lewisy Terminated N-Glycans on Human Sperm

Expression of Bisecting Type and Lewisx/Lewisy Terminated N-Glycans on Human Sperm

Differential Activation of Inflammatory Pathways in Testicular Macrophages Provides a Rationale for Their Subdued Inflammatory Capacity

Testicular Immunoglobulin Deposition as a Possible Cause of Male Infertility

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