Egress of sperm autoantigen from seminiferous tubules maintains systemic tolerance

Tung, Kenneth S. K.; Harakal, Jessica; Qiao, Hui; Rival, Claudia; Li, Jonathan C. H.; Paul, Alberta; Wheeler, Krista K.; Pramoonjago, Patcharin; Grafer, Constance M.; Sun, Wei; Sampson, Robert D.; Wong, Elissa W.P.; Reddi, Prabhakara P.; Deshmukh, Umesh S.; Hardy, Daniel M.; Tang, Huanghui; Cheng, C. Yan; Goldberg, Erwin

doi:10.1172/jci89927

Cited by 107 publications

(112 citation statements)

References 90 publications

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“…Despite these immune biological exceptions, testicular tissue possesses an effective innate immune response (Zhao et al ., ). While the testicular microenvironment was previously believed to be completely privileged from immune system, recent work has shown there are certain connections through the Sertoli cell barrier allowing for the introduction of some testis antigens to the immunity (Tung et al ., ). The consequences of such interactions are not clear; however, the hypothesis of infertility in some men driven by autoimmunity arises (Tung et al ., ).…”

Section: Testicular Immune Privilegementioning

confidence: 97%

Immune mechanisms and possible immune therapy in testicular germ cell tumours

2019

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Background: Testicular germ cell tumours (GCTs) are the only universally curable solid malignancy. The long-term cure rate of >95% is attributed to the extraordinary sensitivity to cisplatin-based treatment but a proportion of patients die due to a progression of the chemotherapy-refractory disease. While treatment of a variety of solid cancers was significantly improved with recent immune therapies, the immunology and immunotherapy remained underinvestigated in GCTs. Objectives: In this narrative review, we summarize evidence about immune-related mechanisms and possible immune therapies in GCTs and provide insights and implications for future research and clinical practice. Materials and methods: We performed a comprehensive search of PubMed/MEDLINE to identify original and review articles reporting on immune mechanisms and immunotherapy in GCTs. Review articles were further searched for additional original articles. Results: Clear link of immune surveillance and the presence of GCT have been identified with several novel immune-related prognostic biomarkers published recently. Several case reports, case series, and preliminary results from phase I-II studies are emerging to report on the efficacy of immune checkpoint inhibitors. Discussion: Newly discovered immune biomarkers provide an evidence supporting the role of immune environment in the GCT biology. While these discoveries provide only an initial insight into the immunobiology, strong correlation with prognosis is evident. This provided a premise to investigate the treatment efficacy of novel immunotherapy. Some efficacy of these treatments has been reported in clinical setting; however, the results of published studies with immune checkpoint inhibitor monotherapy seem to be disappointing. Conclusion: Immune-related mechanisms and efficacy of immune checkpoint blockade in GCTs should be further investigated in preclinical and clinical studies.

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Section: Testicular Immune Privilegementioning

confidence: 97%

Immune mechanisms and possible immune therapy in testicular germ cell tumours

2019

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“…LDH3 passes as cargo through the SC, and egress basally, thus circumventing the BTB by intracellular transport. Egressed Ags then cause and maintain systemic tolerance in a regulatory T cell (Treg) dependent mechanism …”

Section: The Testis Is An Immune‐privileged Organmentioning

confidence: 99%

“…The alternative immunosuppressive phenotype of TM was characterized by the production of high amounts of the anti‐inflammatory cytokine IL‐10, and simultaneous low levels of NO and TNF‐α following stimulation with inflammatory stimuli, such as LPS . This balance in cytokine response is important, as a high secretion of TNF‐α by TM (and other testicular somatic cells) can inhibit LC steroidogenesis and more seriously impair the BTB, which ultimately can lead to chronic orchitis . Similarly, excessive production of NO can also impair LC function and hence steroidogenesis …”

Section: Role Of Tm In the Immune Privilege Of The Testismentioning

confidence: 99%

“…Egressed Ags then cause and maintain systemic tolerance in a regulatory T cell (Treg) dependent mechanism. 12 The term immune privilege, as applied to the testis, originated from studies on prolonged allograft (e.g., parathyroid) and xenograft survival, placed experimentally in the testicular interstitium. 13 This implies that, apart from specific systemic tolerance against germ cell Ags, more general local mechanisms must exist that create a unique immunosuppressed microenvironment, providing protection for a wide array of different Ags.…”

Section: The Testis Is An Immune-privileged Organmentioning

confidence: 99%

“…42,52,55,61 This balance in cytokine response is important, as a high secretion of TNF-by TM (and other testicular somatic cells) can inhibit LC steroidogenesis and more seriously impair the BTB, which ultimately can lead to chronic orchitis. 12,62 Similarly, excessive production of NO can also impair LC function and hence steroidogenesis. 63 Synthesis of low levels of proinflammatory cytokines by TM may also, at least partially, be influenced by the release of high amounts of IL-10, possibly by intracrine mechanisms.…”

Section: Role Of Tm In the Immune Privilege Of The Testismentioning

confidence: 99%

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Microenvironmental signals govern the cellular identity of testicular macrophages

Meinhardt

Wang

Schulz³

et al. 2018

Journal of Leukocyte Biology

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Testicular macrophages (TM) comprise the largest immune cell population in the mammalian testis. They are characterized by a subdued proinflammatory response upon adequate stimulation, and a polarization toward the immunoregulatory and immunotolerant M2 phenotype. This enables them to play a relevant role in supporting the archetypical functions of the testis, namely spermatogenesis and steroidogenesis. During infection, the characteristic blunted immune response of TM reflects the need for a delicate balance between a sufficiently strong reaction to counteract invading pathogens, and the prevention of excessive proinflammatory cytokine levels with the potential to disturb or destroy spermatogenesis. Local microenvironmental factors that determine the special phenotype of TM have just begun to be unraveled, and are discussed in this review.

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