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1.
Membrane Fas ligand activates innate immunity and terminates ocular immune privilege 总被引:4,自引:0,他引:4
Gregory MS Repp AC Holhbaum AM Saff RR Marshak-Rothstein A Ksander BR 《Journal of immunology (Baltimore, Md. : 1950)》2002,169(5):2727-2735
It has been proposed that the constitutive expression of Fas ligand (FasL) in the eye maintains immune privilege, in part through inducing apoptosis of infiltrating Fas(+) T cells. However, the role of FasL in immune privilege remains controversial due to studies that indicate FasL is both pro- and anti-inflammatory. To elucidate the mechanism(s) by which FasL regulates immune privilege, we used an ocular tumor model and examined the individual roles of the membrane-bound and soluble form of FasL in regulating ocular inflammation. Following injection into the privileged eye, tumors expressing only soluble FasL failed to trigger inflammation and grew progressively. By contrast, tumors expressing only membrane FasL 1) initiated vigorous neutrophil-mediated inflammation, 2) terminated immune privilege, and 3) were completely rejected. Moreover, the rejection coincided with activation of both innate and adaptive immunity. Interestingly, a higher threshold level of membrane FasL on tumors is required to initiate inflammation within the immune privileged eye, as compared with nonprivileged sites. The higher threshold is due to the suppressive microenvironment found within aqueous humor that blocks membrane FasL activation of neutrophils. However, aqueous humor is unable to completely block the proinflammatory effects of tumor cells that express high levels of membrane FasL. In conclusion, our data indicate that the function of FasL on intraocular tumors is determined by the microenvironment in conjunction with the form and level of FasL expressed. 相似文献
2.
Ramhorst RE Giribaldi L Fraccaroli L Toscano MA Stupirski JC Romero MD Durand ES Rubinstein N Blaschitz A Sedlmayr P Genti-Raimondi S Fainboim L Rabinovich GA 《Glycobiology》2012,22(10):1374-1386
Mechanisms accounting for the protection of the fetal semi-allograft from maternal immune cells remain incompletely understood. In previous studies, we showed that galectin-1 (Gal1), an immunoregulatory glycan-binding protein, hierarchically triggers a cascade of tolerogenic events at the mouse fetomaternal interface. Here, we show that Gal1 confers immune privilege to human trophoblast cells through the modulation of a number of regulatory mechanisms. Gal1 was mainly expressed in invasive extravillous trophoblast cells of human first trimester and term placenta in direct contact with maternal tissue. Expression of Gal1 by the human trophoblast cell line JEG-3 was primarily controlled by progesterone and pro-inflammatory cytokines and impaired T-cell responses by limiting T cell viability, suppressing the secretion of Th1-type cytokines and favoring the expansion of CD4(+)CD25(+)FoxP3(+) regulatory T (T(reg)) cells. Targeted inhibition of Gal1 expression through antibody (Ab)-mediated blockade, addition of the specific disaccharide lactose or retroviral-mediated siRNA strategies prevented these immunoregulatory effects. Consistent with a homeostatic role of endogenous Gal1, patients with recurrent pregnancy loss showed considerably lower levels of circulating Gal1 and had higher frequency of anti-Gal1 auto-Abs in their sera compared with fertile women. Thus, endogenous Gal1 confers immune privilege to human trophoblast cells by triggering a broad tolerogenic program with potential implications in threatened pregnancies. 相似文献
3.
Gamma delta T cells are needed for ocular immune privilege and corneal graft survival 总被引:8,自引:0,他引:8
Skelsey ME Mellon J Niederkorn JY 《Journal of immunology (Baltimore, Md. : 1950)》2001,166(7):4327-4333
It has been recognized for over a century that the anterior chamber of the eye is endowed with a remarkable immune privilege. One contributing component is the Ag-specific down-regulation of systemic delayed-type hypersensitivity (DTH) that is induced when Ags are introduced into the anterior chamber. This phenomenon, termed anterior chamber-associated immune deviation (ACAID), culminates in the generation of regulatory cells that inhibit the induction (afferent suppression) and expression (efferent suppression) of DTH. Since gamma delta T cells play a major role in other forms of immune regulation, we suspected they might contribute to the induction and expression of ACAID. Mice treated with anti-gamma delta Ab failed to develop ACAID following anterior chamber injection of either soluble Ag (OVA) or alloantigens (spleen cells). Additional experiments with knockout mice confirmed that mice lacking functional gamma delta T cells also fail to develop ACAID. Using a local adoptive transfer of DTH assay, we found that gamma delta T cells were required for the generation of regulatory T cells, but did not function as the efferent regulatory cells of ACAID. The importance of gamma delta T cells in corneal allograft survival was confirmed by blocking gamma delta T cells with GL3 Ab before corneal transplantation. While in vivo treatment with normal hamster serum had no effect on corneal graft survival, infusion of anti-gamma delta Ab resulted in a profound increase in corneal allograft rejection. Thus, gamma delta T cells are needed for sustaining at least one aspect of ocular immune privilege and for promoting corneal allograft survival. 相似文献
4.
Denniston AK Kottoor SH Khan I Oswal K Williams GP Abbott J Wallace GR Salmon M Rauz S Murray PI Curnow SJ 《Journal of immunology (Baltimore, Md. : 1950)》2011,186(1):305-311
Aqueous humor (AqH) has been shown to have significant immunosuppressive effects on APCs in animal models. We wanted to establish whether, in humans, AqH can regulate dendritic cell (DC) function and to identify the dominant mechanism involved. Human AqH inhibited the capacity of human peripheral blood monocyte-derived DC to induce naive CD4(+) T cell proliferation and cytokine production in vitro, associated with a reduction in DC expression of the costimulatory molecule CD86. This was seen both for DC cultured under noninflammatory conditions (immature DC) and for DC stimulated by proinflammatory cytokines (mature DC). DC expression of MHC classes I/II and CD83 was reduced (mature DC only). Myeloid DC from peripheral blood were similarly sensitive to the effects of human AqH, but only under inflammatory conditions. The addition of α-melanocyte stimulating hormone and vasoactive intestinal peptide did not cause significant inhibition at physiological levels. However, the addition of exogenous cortisol at physiological levels recapitulated the AqH-induced reduction in CD86 and inhibition of DC-induced T cell proliferation, and blockade of cortisol in AqH partially reversed its suppressive effects. TGF-β2 had an additional effect with cortisol, and although simultaneous blockade of cortisol and TGF-β2 in AqH reduced its effectiveness, there was still a cortisol- and TGF-β-independent component. In humans, AqH regulates DC maturation and function by the combined actions of cortisol and TGF-β2, a pathway that is likely to contribute to the maintenance of immune privilege in the eye. 相似文献
5.
The testis exhibits a distinctive form of immune privilege to protect the germ cells from the host immune attack. The property
of testicular immune privilege was originally attributed to the blood-testis barrier in the seminiferous epithelium, which
sequesters antigens. Recent studies have uncovered several levels of immune control besides the blood-testis barrier involved
in the privilege of the testis, including the mechanisms of immune tolerance, reduced immune activation, localized active
immunosuppression and antigen-specific immunoregulation. The somatic cells of the testis, especially Sertoli cells, play a
key role in regulating the testicular immune privileged status. The constitutive expression of anti-inflammatory factors in
the testis by somatic cells is essential for local immunosuppression. Growing evidence shows that androgens orchestrate the
inhibition of proinflammatory factors and shift cytokine balance toward a tolerogenic environment. Disruption of these protective
mechanisms, which may be caused by trauma, infection and genetic factors, can lead to orchitis and infertility. This review
article highlights the unique immune environment of the testis, particularly focuses on the regulation of testicular immune
privilege. 相似文献
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Species loss leads to community closure 总被引:1,自引:0,他引:1
Global extinction of a species is sadly irreversible. At a local scale, however, extinctions may be followed by re-invasion. We here show that this is not necessarily the case and that an ecological community may close its doors for re-invasion of species lost from it. Previous studies of how communities are assembled have shown that there may be rules for that process and that limitations are set to the order by which species are introduced and put together. Instead of focusing on the assembly process we randomly generated simple competitive model communities that were stable and allowed for two to 10 coexisting species. When a randomly selected single species was removed from the community, the cascading species loss was recorded and frequently the resulting community was more than halved. Cascading extinctions have previously been recorded, but we here show that the relative magnitude of the cascade is dependent on community size (and not only trophic structure) and that the reintroduction of the original species lost often is impossible. Hence, species loss does not simply leave a void potentially refilled, but permanently alters the entire community structure and consequently the adaptive landscape for potential re-invaders. 相似文献
8.
Despite high bacterial colonization and frequent allergen contact, acute inflammatory and allergic reactions are rarely seen in the oral mucosa. Therefore we assert that immune tolerance predominates at this site and antigen presenting cells, such as dendritic cells and different T cell subtypes, serve as key players in oral mucosal tolerance induction. In this article we describe the mechanisms that lead to tolerance induced in the oral mucosa and how they differ from tolerance induced in the lower gastrointestinal tract. Furthermore we discuss ways in which novel nonparenteral approaches for immune intervention, such as allergen-specific immunotherapy applied by way of the sublingual route, might be improved to target the tolerogenic properties of the sophisticated oral mucosal immune network. 相似文献
9.
Trex1, a major 3' DNA exonuclease in mammalian cells, has been thought to act primarily in DNA replication or repair. Surprisingly, the major phenotype resulting from Trex1 deficiency in humans and mice is a chronic inflammatory disease. In this issue, Yang et al. (2007) report that Trex1 deficiency causes chronic activation of the ATM-dependent DNA-damage checkpoint and accumulation of a discrete single-stranded DNA species in the cytoplasm, either of which could contribute to chronic inflammation. 相似文献
10.
The neuropeptide substance P is a critical mediator of burn-induced acute lung injury 总被引:1,自引:0,他引:1
Sio SW Puthia MK Lu J Moochhala S Bhatia M 《Journal of immunology (Baltimore, Md. : 1950)》2008,180(12):8333-8341
The classical tachykinin substance P (SP) has numerous potent neuroimmunomodulatory effects on all kinds of airway functions. Belonging to a class of neuromediators targeting not only residential cells but also inflammatory cells, studying SP provides important information on the bidirectional linkage between how neural function affects inflammatory events and, in turn, how inflammatory responses alter neural activity. Therefore, this study aimed to investigate the effect of local burn injury on inducing distant organ pulmonary SP release and its relevance to lung injury. Our results show that burn injury in male BALB/c mice subjected to 30% total body surface area full thickness burn augments significant production of SP, preprotachykinin-A gene expression, which encodes for SP, and biological activity of SP-neurokinin-1 receptor (NK1R) signaling. Furthermore, the enhanced SP-NK1R response correlates with exacerbated lung damage after burn as evidenced by increased microvascular permeability, edema, and neutrophil accumulation. The development of heightened inflammation and lung damage was observed along with increased proinflammatory IL-1beta, TNF-alpha, and IL-6 mRNA and protein production after injury in lung. Chemokines MIP-2 and MIP-1alpha were markedly increased, suggesting the active role of SP-induced chemoattractants production in trafficking inflammatory cells. More importantly, administration of L703606, a specific NK1R antagonist, 1 h before burn injury significantly disrupted the SP-NK1R signaling and reversed pulmonary inflammation and injury. The present findings show for the first time the role of SP in contributing to exaggerated pulmonary inflammatory damage after burn injury via activation of NK1R signaling. 相似文献
11.
Immune privilege, a characteristic of the internal compartments of the eye, is a physiologic mechanism that is designed to provide the eye with protection against pathogens while protecting the delicate visual axis from the sight-destroying potential of immunogenic inflammation. It is assumed that the presence of intraocular inflammation is incompatible with the existence of immune privilege. The validity of this assumption has been tested in four animal models of intraocular inflammation-systemic and local endotoxin-induced uveitis (EIU), mycobacterial adjuvant-induced uveitis (MAIU), and experimental autoimmune uveitis (EAU). Immune privilege was assessed in inflamed eyes by growth of intracamerally injected allogeneic tumor cells, by the capacity to support immune deviation following intracameral injection of antigen (ovalbumin, OVA), by assaying protein, leukocyte, and selected cytokine content of aqueous humor (AqH), and by capacity of inflamed AqH to suppress T cell activation in vitro. The results indicate that, irrespective of the type of inflammation, tumor cells formed progressively growing tumors in inflamed eyes. Moreover, OVA injected into the anterior chamber of eyes inflamed by MAIU and EAU failed to induce immune deviation. AqH from inflamed eyes reflected breakdown of the blood:ocular barrier as well as transient loss of its immunosuppressive properties. Immunosuppressive microenvironments routinely reemerged in inflamed eyes, and the immunosuppressive agent present under these circumstances in AqH was active TGF beta2. It is concluded that immune privilege is surprisingly resistant to abolition by intraocular inflammation, and that maintenance of immune privilege in the face of ongoing inflammation depends upon the emergence of progressive and partially different immunosuppressive mechanisms. 相似文献
12.
Pituitary tumors are the third most common intracranial tumor in humans and can cause altered hormone secretions leading to hypercortisolism, acromegaly, and infertility. Reduced expression of the cell adhesion molecule N-cadherin has been linked with the formation of pituitary tumors, but its role in normal pituitary gland physiology or tumor initiation is unknown. In the murine pituitary, N-cadherin expression is detected in virtually all cells of the posterior, intermediate, and anterior lobes. N-cadherin may function to initiate important cues such as controlling proliferation, directing cell placement, and promoting formation of cell networks that coordinately release hormones into the bloodstream. To address this, we generated mice lacking N-cadherin in proopiomelanocortin-expressing melanotrope and corticotrope cells of the intermediate and anterior lobes of the pituitary. We observed that intermediate lobe cells can aberrantly displace SOX2-containing progenitor cells in the N-cadherin conditional knockout mice at postnatal d 1. By postnatal d 30, although a reduction in α- and β-catenin membrane staining occurs, there is little effect on intermediate lobe architecture with N-cadherin loss. Also, despite these changes in adherens junction molecules, no alterations in cell proliferation occur. In contrast, loss of N-cadherin in the corticotropes leads to aberrant cell clustering and a reduction in Pomc mRNA. Taken together, our data reveal important roles of N-cadherin in pituitary cell placement and that loss of N-cadherin alone does not lead to pituitary tumor formation. 相似文献
13.
Gerda Saxer Michael Doebeli Michael Travisano 《Proceedings. Biological sciences / The Royal Society》2009,276(1664):2065-2070
Spatial structure has been identified as a major contributor to the maintenance of diversity. Here, we show that the impact of spatial structure on diversity is strongly affected by the ecological mechanisms maintaining diversity. In well-mixed, unstructured environments, microbial populations can diversify by production of metabolites during growth, providing additional resources for novel specialists. By contrast, spatially structured environments potentially limit such facilitation due to reduced metabolite diffusion. Using replicate microcosms containing the bacterium Escherichia coli, we predicted the loss of diversity during an environmental shift from a spatially unstructured environment to spatially structured conditions. Although spatial structure is frequently observed to be a major promoter of diversity, our results indicate that it can also have negative impacts on diversity. 相似文献
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The phylogenetic clustering of extinction may jeopardize the existence of entire families and genera, which can result in elevated reductions of evolutionary history (EH), trait diversity, and ecosystem functioning. Analyses of globally threatened birds and mammals suggest current extinction threats will result in a much higher loss of EH than random extinction scenarios, while the analyses of the taxonomical distribution of regionally rare plants find the opposite pattern. The disproportionately high number of rare plant species within species-rich families potentially suggests that lower losses of plant EH will be sustained than expected under random extinction. We show that at a global scale, this is not the case. Species-poor (especially monotypic) angiosperm families are more often at risk of extinction than expected. Because these high-risk species-poor families are as evolutionarily distinct as other families, the expected family-level EH plausibly lost in the next 100 years exceeds that predicted from random extinction by up to approximately 1165 million years. 相似文献
16.
Species extinctions are biased towards higher trophic levels, and primary extinctions are often followed by unexpected secondary extinctions. Currently, predictions on the vulnerability of ecological communities to extinction cascades are based on models that focus on bottom‐up effects, which cannot capture the effects of extinctions at higher trophic levels. We show, in experimental insect communities, that harvesting of single carnivorous parasitoid species led to a significant increase in extinction rate of other parasitoid species, separated by four trophic links. Harvesting resulted in the release of prey from top‐down control, leading to increased interspecific competition at the herbivore trophic level. This resulted in increased extinction rates of non‐harvested parasitoid species when their host had become rare relative to other herbivores. The results demonstrate a mechanism for horizontal extinction cascades, and illustrate that altering the relationship between a predator and its prey can cause wide‐ranging ripple effects through ecosystems, including unexpected extinctions. 相似文献
17.
Campbell Rolian 《Evolution; international journal of organic evolution》2020,74(4):702-715
Primate limb morphology is often described as either generalized, that is, suited to a range of locomotor and positional behaviors, or specialized for unique locomotor behaviors such as brachiation or bipedalism. The evolution of highly specialized limb morphology may result in loss of evolvability, that is, in a decreased capacity of the locomotor skeleton to evolve in response to selection towards alternative ecomorphological niches. Using evolutionary simulations, I show that the highly specialized limb anatomy of hominoids is associated with a significant loss of evolvability, defined as the number of generations to reach alternative adaptive peaks, and in parallel an increased risk of extinction, particularly in simulated evolution toward generalized quadrupedal limb proportions. Loss of evolvability in apes and humans correlates with three factors: (1) decreased correlation among limb bone lengths (i.e., integration), which slows the rate of change along lines of least evolutionary resistance; (2) limb specialization, which places apes and humans in relatively remote areas of morphospace; and (3) increased skeletal size as a proxy for body size. Thus, locomotor over-specialization can lead to evolutionary dead-ends that significantly increase the probability of hominoid populations going extinct before evolving new adaptive morphologies. 相似文献
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Atrophy of skeletal muscle leads to decreases in myofiber size and nuclear number; however, the effects of atrophic conditions on muscle precursor cells (MPC) are largely unknown. MPC lie outside myofibers and represent the main source of additional myonuclei necessary for muscle growth and repair. In the present study, we examined the properties of MPC after hindlimb suspension (HS)-induced atrophy and subsequent recovery of the mouse hindlimb muscles. We demonstrated that the number of MPC in atrophied muscles was decreased. RT-PCR analysis of cells isolated from atrophied muscles indicated that several mRNA characteristic of the myogenic program in MPC were absent. Cells isolated from atrophied muscles failed to properly proliferate and undergo differentiation into multinucleated myotubes. Thus atrophy led to a decrease in MPC and caused dysfunction in those MPC that remained. Upon regrowth of the atrophied muscles, these deleterious effects were reversed. Our data suggest that preventing loss or dysfunction of MPC may be a new pharmacological target during muscle atrophy. satellite cells; hindlimb suspension; proliferation; differentiation; myotubes 相似文献