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Dual role of immune cells in the testis: Protective or pathogenic for germ cells?

Pérez CV, Theas MS, Jacobo PV, Jarazo-Dietrich S, Guazzone VA, Lustig L - Spermatogenesis (2013)

Bottom Line: The purpose of this review is to describe how the immune cells present in the testis interact with the germinal epithelium contributing to survival or apoptosis of germ cells (GCs).Physiologically, the immunosuppressor testicular microenvironment protects GCs from immune attack, whereas in inflammatory conditions, tolerance is disrupted and immune cells and their mediators respond to GC self antigens, inducing damage of the germinal epithelium.Considering that experimental models of autoimmune orchitis have clarified the local immune mechanisms by which protection of the testis is compromised, we described the following topics in the testis of normal and orchitic rats: (1) cell adhesion molecule expression of seminiferous tubule specialized junctions and modulation of blood-testis barrier permeability by cytokines (2) phenotypic and functional characteristics of testicular dendritic cells, macrophages, effector and regulatory T cells and mast cells and (3) effects of pro-inflammatory cytokines (TNF-α, IL-6 and FasL) and the nitric oxide-nitric oxide synthase system on GC apoptosis.

View Article: PubMed Central - PubMed

Affiliation: Instituto de Investigaciones Biomédicas; UBA/CONICET; Facultad de Medicina; Universidad de Buenos Aires; Buenos Aires, Argentina.

ABSTRACT
The purpose of this review is to describe how the immune cells present in the testis interact with the germinal epithelium contributing to survival or apoptosis of germ cells (GCs). Physiologically, the immunosuppressor testicular microenvironment protects GCs from immune attack, whereas in inflammatory conditions, tolerance is disrupted and immune cells and their mediators respond to GC self antigens, inducing damage of the germinal epithelium. Considering that experimental models of autoimmune orchitis have clarified the local immune mechanisms by which protection of the testis is compromised, we described the following topics in the testis of normal and orchitic rats: (1) cell adhesion molecule expression of seminiferous tubule specialized junctions and modulation of blood-testis barrier permeability by cytokines (2) phenotypic and functional characteristics of testicular dendritic cells, macrophages, effector and regulatory T cells and mast cells and (3) effects of pro-inflammatory cytokines (TNF-α, IL-6 and FasL) and the nitric oxide-nitric oxide synthase system on GC apoptosis.

No MeSH data available.


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Figure 1. Schematic drawing illustrating the seminiferous epithelium and intestitium under normal (A) or inflammatory (B) conditions. (A) The seminiferous epithelium is composed of Sertoli cells and germ cells at different stages of development. The blood-testis barrier (BTB) is constituted by coexisting adherens, gap and tight junctions between adjacent Sertoli cells. As representative tight junction molecules, occludin and ZO-1 are shown. Macrophages close to Leydig cells and few immature dendritic cells (DCs), T cells and regulatory T cells (Treg) are present in the interstitium. (B) Spermatocytes and spermatids undergo apoptosis and sloughing in the lumen of the seminiferous tubule. Decreased occludin expression in Sertoli cell tight junctions associated to impairment of BTB is shown. An increased number of mature DCs, pro-inflammatory and intermediate type macrophages, CD4+ and CD8+ T cells and T regs are present in the interstitium. Pro-inflammatory cytokines (IL-6, TNF-α, FasL, IFN-γ, IL-17) and nitric oxide (NO) released by macrophages and T cells are involved in the induction of inflammation and germ cell apoptosis. Cytokines and other factors secreted by Sertoli, Leydig and peritubular cells are not illustrated.
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Figure 1: Figure 1. Schematic drawing illustrating the seminiferous epithelium and intestitium under normal (A) or inflammatory (B) conditions. (A) The seminiferous epithelium is composed of Sertoli cells and germ cells at different stages of development. The blood-testis barrier (BTB) is constituted by coexisting adherens, gap and tight junctions between adjacent Sertoli cells. As representative tight junction molecules, occludin and ZO-1 are shown. Macrophages close to Leydig cells and few immature dendritic cells (DCs), T cells and regulatory T cells (Treg) are present in the interstitium. (B) Spermatocytes and spermatids undergo apoptosis and sloughing in the lumen of the seminiferous tubule. Decreased occludin expression in Sertoli cell tight junctions associated to impairment of BTB is shown. An increased number of mature DCs, pro-inflammatory and intermediate type macrophages, CD4+ and CD8+ T cells and T regs are present in the interstitium. Pro-inflammatory cytokines (IL-6, TNF-α, FasL, IFN-γ, IL-17) and nitric oxide (NO) released by macrophages and T cells are involved in the induction of inflammation and germ cell apoptosis. Cytokines and other factors secreted by Sertoli, Leydig and peritubular cells are not illustrated.

Mentions: The data reviewed here show that testicular immunoregulation depends on a delicate equilibrium between immunoprivilege and inflammation and is modulated by the dual role played by tolerogenic or pathogenic cells of the immune system and by cytokines acting as immunosuppressors or pro-inflammatory mediators. Under physiological conditions, antigen-specific auto immune responses are prevented by systemic and local tolerance mechanisms. In the testis (Fig. 1A), tolerogenic DCs and Treg subsets allow the survival of GCs expressing auto-antigens and the normal completion of spermatogenesis. Under inflammatory conditions (Fig. 1B), mature DCs and macrophages secreting high levels of NO, IL-6 and TNF-α, infiltrate the testicular interstitium. TNF-α and IFN-γ-producing Th1 cells and IL-17-producing Th17 cells increase in number in association with testicular damage. With the action of pro-inflammatory cytokines (e.g., IL-6) on tight junction molecule expression and distribution, BTB permeability increases. Cytokines entering the ST adluminal compartment induce apoptosis of GCs expressing death receptors TNFR1, Fas and IL-6R. NO is another relevant factor contributing to GC apoptosis; however, the chronology of GC sloughing and apoptosis remains incompletely understood. Spermatic antigens released during GC apoptosis interacting with immune cells amplify the autoimmune response. Although Tregs increase in the testicular interstitium, they fail to effectively suppress inflammation. All these events contribute to GC sloughing and infertility.


Dual role of immune cells in the testis: Protective or pathogenic for germ cells?

Pérez CV, Theas MS, Jacobo PV, Jarazo-Dietrich S, Guazzone VA, Lustig L - Spermatogenesis (2013)

Figure 1. Schematic drawing illustrating the seminiferous epithelium and intestitium under normal (A) or inflammatory (B) conditions. (A) The seminiferous epithelium is composed of Sertoli cells and germ cells at different stages of development. The blood-testis barrier (BTB) is constituted by coexisting adherens, gap and tight junctions between adjacent Sertoli cells. As representative tight junction molecules, occludin and ZO-1 are shown. Macrophages close to Leydig cells and few immature dendritic cells (DCs), T cells and regulatory T cells (Treg) are present in the interstitium. (B) Spermatocytes and spermatids undergo apoptosis and sloughing in the lumen of the seminiferous tubule. Decreased occludin expression in Sertoli cell tight junctions associated to impairment of BTB is shown. An increased number of mature DCs, pro-inflammatory and intermediate type macrophages, CD4+ and CD8+ T cells and T regs are present in the interstitium. Pro-inflammatory cytokines (IL-6, TNF-α, FasL, IFN-γ, IL-17) and nitric oxide (NO) released by macrophages and T cells are involved in the induction of inflammation and germ cell apoptosis. Cytokines and other factors secreted by Sertoli, Leydig and peritubular cells are not illustrated.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3644047&req=5

Figure 1: Figure 1. Schematic drawing illustrating the seminiferous epithelium and intestitium under normal (A) or inflammatory (B) conditions. (A) The seminiferous epithelium is composed of Sertoli cells and germ cells at different stages of development. The blood-testis barrier (BTB) is constituted by coexisting adherens, gap and tight junctions between adjacent Sertoli cells. As representative tight junction molecules, occludin and ZO-1 are shown. Macrophages close to Leydig cells and few immature dendritic cells (DCs), T cells and regulatory T cells (Treg) are present in the interstitium. (B) Spermatocytes and spermatids undergo apoptosis and sloughing in the lumen of the seminiferous tubule. Decreased occludin expression in Sertoli cell tight junctions associated to impairment of BTB is shown. An increased number of mature DCs, pro-inflammatory and intermediate type macrophages, CD4+ and CD8+ T cells and T regs are present in the interstitium. Pro-inflammatory cytokines (IL-6, TNF-α, FasL, IFN-γ, IL-17) and nitric oxide (NO) released by macrophages and T cells are involved in the induction of inflammation and germ cell apoptosis. Cytokines and other factors secreted by Sertoli, Leydig and peritubular cells are not illustrated.
Mentions: The data reviewed here show that testicular immunoregulation depends on a delicate equilibrium between immunoprivilege and inflammation and is modulated by the dual role played by tolerogenic or pathogenic cells of the immune system and by cytokines acting as immunosuppressors or pro-inflammatory mediators. Under physiological conditions, antigen-specific auto immune responses are prevented by systemic and local tolerance mechanisms. In the testis (Fig. 1A), tolerogenic DCs and Treg subsets allow the survival of GCs expressing auto-antigens and the normal completion of spermatogenesis. Under inflammatory conditions (Fig. 1B), mature DCs and macrophages secreting high levels of NO, IL-6 and TNF-α, infiltrate the testicular interstitium. TNF-α and IFN-γ-producing Th1 cells and IL-17-producing Th17 cells increase in number in association with testicular damage. With the action of pro-inflammatory cytokines (e.g., IL-6) on tight junction molecule expression and distribution, BTB permeability increases. Cytokines entering the ST adluminal compartment induce apoptosis of GCs expressing death receptors TNFR1, Fas and IL-6R. NO is another relevant factor contributing to GC apoptosis; however, the chronology of GC sloughing and apoptosis remains incompletely understood. Spermatic antigens released during GC apoptosis interacting with immune cells amplify the autoimmune response. Although Tregs increase in the testicular interstitium, they fail to effectively suppress inflammation. All these events contribute to GC sloughing and infertility.

Bottom Line: The purpose of this review is to describe how the immune cells present in the testis interact with the germinal epithelium contributing to survival or apoptosis of germ cells (GCs).Physiologically, the immunosuppressor testicular microenvironment protects GCs from immune attack, whereas in inflammatory conditions, tolerance is disrupted and immune cells and their mediators respond to GC self antigens, inducing damage of the germinal epithelium.Considering that experimental models of autoimmune orchitis have clarified the local immune mechanisms by which protection of the testis is compromised, we described the following topics in the testis of normal and orchitic rats: (1) cell adhesion molecule expression of seminiferous tubule specialized junctions and modulation of blood-testis barrier permeability by cytokines (2) phenotypic and functional characteristics of testicular dendritic cells, macrophages, effector and regulatory T cells and mast cells and (3) effects of pro-inflammatory cytokines (TNF-α, IL-6 and FasL) and the nitric oxide-nitric oxide synthase system on GC apoptosis.

View Article: PubMed Central - PubMed

Affiliation: Instituto de Investigaciones Biomédicas; UBA/CONICET; Facultad de Medicina; Universidad de Buenos Aires; Buenos Aires, Argentina.

ABSTRACT
The purpose of this review is to describe how the immune cells present in the testis interact with the germinal epithelium contributing to survival or apoptosis of germ cells (GCs). Physiologically, the immunosuppressor testicular microenvironment protects GCs from immune attack, whereas in inflammatory conditions, tolerance is disrupted and immune cells and their mediators respond to GC self antigens, inducing damage of the germinal epithelium. Considering that experimental models of autoimmune orchitis have clarified the local immune mechanisms by which protection of the testis is compromised, we described the following topics in the testis of normal and orchitic rats: (1) cell adhesion molecule expression of seminiferous tubule specialized junctions and modulation of blood-testis barrier permeability by cytokines (2) phenotypic and functional characteristics of testicular dendritic cells, macrophages, effector and regulatory T cells and mast cells and (3) effects of pro-inflammatory cytokines (TNF-α, IL-6 and FasL) and the nitric oxide-nitric oxide synthase system on GC apoptosis.

No MeSH data available.


Related in: MedlinePlus