Immunogenic Inflammation Research Articles

THE MI GRAI NE- VERTI GO- PERI ODONTAL DI SEASE CONNECTION: EVIDENCE-BASED CASE AND VERIFICATION IN AN ANIMAL STUDY

Recently, two CNS disorders, migraine and anxiety have been recognized as being commonly associated with dizziness (Vertigo).These associations may be an expression of an etiological relationship, for example, dizziness caused by migraine, or dizziness causedby anxiety and termed as MARD. Chronic dizziness may become more disabling during the added stress of a migraine headache orpanic attack. In addition, dizziness occurred comorbidly with both migraine headache and anxiety disorders. Even though the etiologyof migraine had been suggested from trigeminal nerve sensitivity and neurogenic inflammation, its linking to periodontal disease thatinnervated by the same nerve was still uncertain. However, an animal study revealed that Porphyromonas gingivalis lipopolysaccharidestimulation was able to increase neurogenic inflammation. A male patient suffered with symptoms mimicking MARD for years andconcomitantly had chronic periodontitis. Scaling and root planning combined with the assisted drainage therapy resulted in instantdisappearing of most of the symptoms. This case report is to propose the mechanism of periodontal disease involvement in theetiopathogenesis of migraine and vertigo which could be treated with periodontal treatment. Regarding to remarkable result, it wasconcluded that periodontal disease could be a source of neurogenic and immunogenic inflammation which if not treated periodicallycould perpetuate symptoms mimicking MARD.

Aqueous Humor Induces Transforming Growth Factor-β (TGF-β)-Producing Regulatory T-Cells

Purpose: The intraocular microenvironment is an immuneprivileged site where immunogenic inflammation is suppressed. Suppression of immunogenic inflammation has been associated with immunosuppressive factors found in aqueous humor produced by ocular tissues. To further understand the mechanisms suppressing immunogenic inflammation in the eye, we have examined the production of lymphokines by primed T-cells activated in the presence of aqueous humor. Methods: Enriched in vivo primed T-cells were T-cell receptor-stimulated in the presence of fresh aqueous humor. The culture supernatant was assayed for IFN-γ and IL-4 by sandwich ELISA. TGF-β production by T-cells stimulated in the presence of aqueous humor was assayed by a TGF-β bioassay of the culture supernatant and by quantitative RT-PCR for TGF-β1 mRNA expression. Aqueous humor-treated T-cells were assayed for their capacity to suppress IFN-γ production by stimulated, primed T-cells. Results: Aqueous humor-enhanced proliferation but irreversibly suppressed production of both IFN-γ and IL-4 by in vitro-activated, in vivo-primed T-cells. Aqueous humor induced in vivo primed T-cells to produce TGF-β in vitro, and these TGF-β-producing T-cells suppressed IFN-γ production by other T-cells activated in co-cultures. Conclusions: Aqueous humor alters the functional program of TCR-ligand-activated, primed T-cells, converting the cells to TGF-β-producing regulatory cells. Curr. Eye Res. 16: 900–908, 1997.

Angiogenesis and Lymphangiogenesis—Implications for Corneal Immunity

It is now widely acknowledged that vasculogenesis and immunogenic inflammation are intricately related in many tissues. However, less understood is to what extent blood (heme) angiogenesis (HA) and lymphangiogenesis (LG) are differentially regulated, and in turn contribute potentially to different aspects of adaptive immunity generated to corneal antigens. Herein, we will provide a brief synopsis of relevant work in this field by focusing particularly on the differential regulation of immunity by these two distinct vasculogenic processes in the cornea, illustrating that in spite of significant redundancies in the mechanisms that induce these vascular processes in the cornea, there are also important distinctions in what aspects of immunity are promoted by them.keywords

565. Modulation of the Acute Phase Response by Recombinant Adeno-Associated Viral Expression of the IL-1 Type 1 Soluble Receptor

Acute rejection is a leading cause of graft loss in transplant recipients. Studies on the pathogenesis of acute rejection have suggested a major contributory role for certain cytokines and acute phase proteins. Interleukin (IL)-1 is a potent proinflammatory cytokine that plays a critical role in initiating and maintaining immunogenic inflammation associated with acute rejection. Previous experiments have shown that IL-1 antagonists can help reduce acute inflammation associated with allograft rejection. We performed a series of experiments to determine whether administration of a recombinant adeno-associated viral (rAAV) vector expressing the soluble extracellular domains of type I receptor for IL-1B can reduce inflammation in a turpentine induced murine inflammation model. METHODS: Experimental wt B6/129 mice were injected intramuscular using 2109 IU with either rAAV2-CMV-sIL-1r or rAAV2-CMV-LacZ. Saline injected B6/129 mice served as negative controls and B6/129 IL-1 receptor KO mice served as the positive control for these experiments. Four weeks after rAAV injection, both experimental and control mice underwent induction of inflammation by subcutaneous administration of 100 microliters sterile turpentine. Mice were followed for 6 days following turpentine injection. Blood samples were taken at 12 hours, three days, and six days pre- and post-turpentine administration. Sera samples were used to measure cytokine and acute phase protein levels. Body weight and food intake were measured daily during the course of the study. RESULTS: Following subcutaneous injection into the left hindlimb with sterile turpentine, the mice previously injected with saline or control rAAV2-CMV-LacZ began to lose weight, while those injected previously with rAAV2-CMV-sIL-1r did not experience as significant (P < 0.12) a loss in weight and the IL-1r KO mice gained weight. The amount of food intake showed a reduction in the mice that were administered saline, LacZ virus, and the IL-1r KO mice over those that were injected with rAAV2-CMV-sIL-1r. Serum levels of proinflammatory cytokines and acute phase proteins such as IL-6, Serum Amyloid A, and Serum Amyloid P showed a significant increase (P < 0.05) in the saline and LacZ injected mice over the KO and experimental mice. CONCLUSIONS: Based on the experimental results, mice that were administered rAAV expressing soluble IL-1 receptor were able to withstand the inflammatory reaction from subcutaneous turpentine injection better than the saline and LacZ controls. The reduced proinflammatory cytokine and acute phase proteins correlated to a reduced weight loss and higher food intake verses the control animals. This data suggests that IL-1 antagonists such as soluble receptors for IL-1 may be used to attenuate the inflammation associated with acute allograft rejection. Future studies will evaluate the ability of rAAV2-sIL-1r to attenuate inflammation associated with acute graft rejection.

Ocular immune privilege: the eye takes a dim but practical view of immunity and inflammation.

The delicate visual axis that makes precise vision possible is highly vulnerable to the destructive potential of immunogenic inflammation. Immune privilege of the eye is the experimental expression of the way in which evolution has coped with the countermanding threats to vision of ocular infections and ocular immunity and inflammation. Ocular immune privilege has five primary features that account for its existence: blood:ocular barriers, absent lymphatic drainage pathways, soluble immunomodulatory factors in aqueous humor, immunomodulatory ligands on the surface of ocular parenchymal cells, and indigenous, tolerance-promoting antigen-presenting cells (APCs). Three manifestations of ocular immune privilege that have received the most extensive study are the intraocular microenvironment, which is selectively anti-inflammatory and immunosuppressive; the prolonged acceptance of solid tissue and tumor allografts in the anterior chamber; and the induction of systemic tolerance to eye-derived antigens. Anterior chamber-associated immune deviation is known to arise when indigenous, ocular APCs capture eye-derived antigens and deliver them to the spleen where multicellular clusters of these cells, natural killer T cells, marginal zone B cells, and gammadelta T cells create an antigen-presentation environment that leads to CD4(+) and CD8(+) alpha/beta T cells, which as regulators, suppress induction and expression of T helper cell type 1 (Th1) and Th2 immune expression systems. The ways the eye influences local and systemic immune responses to ocular antigens and pathogens carry risks to and benefits for mammalian organisms. As loss of sight is a powerful, negative-selecting force, the benefits of ocular immune privilege outweigh the risks.

Sinus headache or migraine? Considerations in making a differential diagnosis.

Neurology. 2002 May 14;58(9 Suppl 6):S10‐S14Sinus headache is commonly diagnosed, and patients with headache often cite sinus pain and pressure as a cause of their headaches. A high frequency of diagnosis of sinus headache, which specialists consider to be relatively rare, among patients meeting International Headache Society (IHS) diagnostic criteria for migraine raises the possibility that migraine and perhaps other headache types are sometimes mistaken for sinus headache. This article considers clinical, epidemiologic, and pathophysiologic relationships between sinus headache and migraine and discusses the implications for clinical management of headache. Both historic and new data show that nasal symptoms frequently accompany migraine, although these symptoms are not part of the IHS diagnostic criteria for migraine. Parasympathetic activation, as well as the hypothesized mechanism of neurogenic or immunogenic switching (i.e., crossover interactions of neurogenic and immunogenic inflammation), may account for both the frequent occurrence of nasal symptoms in migraine and the possibility that sinus inflammation can sometimes act as a migraine trigger. Considered in aggregate, the data show that the occurrence of nasal symptoms associated with a headache should neither trigger a diagnosis of sinus disease nor exclude a diagnosis of migraine. It should, in fact, prompt diagnostic consideration of both conditions.Comment: This article summarizes a small pilot study performed in the United States, in which patients with self‐diagnosed “sinus headache” were evaluated as to International Headache Society (IHS) diagnosis. Ninety‐six percent met IHS criteria for migraine or migrainous headache, suggesting that this entity, at least in the United States, is most frequently migraine with accompanying cranial parasympathetic activation. The article is worth tracking down and reading in its entirety, as the section of the article on pathophysiology is quite original and thought provoking. SJT

Sinus headache or migraine? Considerations in making a differential diagnosis.

Sinus headache is commonly diagnosed, and patients with headache often cite sinus pain and pressure as a cause of their headaches. A high frequency of diagnosis of sinus headache, which specialists consider to be relatively rare, among patients meeting International Headache Society (IHS) diagnostic criteria for migraine raises the possibility that migraine and perhaps other headache types are sometimes mistaken for sinus headache. This article considers clinical, epidemiologic, and pathophysiologic relationships between sinus headache and migraine and discusses the implications for clinical management of headache. Both historic and new data show that nasal symptoms frequently accompany migraine, although these symptoms are not part of the IHS diagnostic criteria for migraine. Parasympathetic activation, as well as the hypothesized mechanism of neurogenic or immunogenic switching (i.e., crossover interactions of neurogenic and immunogenic inflammation), may account for both the frequent occurrence of nasal symptoms in migraine and the possibility that sinus inflammation can sometimes act as a migraine trigger. Considered in aggregate, the data show that the occurrence of nasal symptoms associated with a headache should neither trigger a diagnosis of sinus disease nor exclude a diagnosis of migraine. It should, in fact, prompt diagnostic consideration of both conditions.

The eye’s view of antigen presentation

A form of systemic tolerance is created when antigenic material is placed in the anterior chamber of the eye, an immune privileged site. Termed anterior chamber associated immune deviation (ACAID), this form of tolerance insures that the systemic immune response to eye-derived antigens is devoid of T cells that mediate delayed hypersensitivity and antibodies that fix complement. As a consequence, the eye is spared the disruptive blinding influence of immunogenic inflammation. ACAID arises when antigen is captured by intraocular antigen presenting cells, then carried to the marginal zone of the spleen where, in the presence of natural killer T cells and marginal zone B cells, a microenvironment is created that activates antigen-specific T cells to differentiate into regulatory cells that interfere with the induction of delayed hypersensitivity as well as its expression. Transforming growth factor beta-2 (TGFβ-2), constitutively present in the aqueous humor of the eye, imposes distinctive properties on antigen presenting cells. Thrombospondin is an early activated gene following TGFβ-2 treatment and as a consequence the eye-derived antigen presenting cells fail to secrete IL-12 or express CD40. The lack of these potent stimulators of Th1 cell differentiation is central to the induction of ACAID.

Ocular immune privilege and the impact of intraocular inflammation.

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.

Expression of thrombospondin in TGFbeta-treated APCs and its relevance to their immune deviation-promoting properties.

APCs deployed within iris/ciliary body are responsible for promoting anterior chamber-associated immune deviation following injection of Ag into the eye. TGFbeta-2, a constituent of the ocular microenvironment, converts conventional APCs that are pulsed with Ag into cells that induce immune deviation when injected into naive mice. TGFbeta-2-treated APCs under-express IL-12 and CD40, and over-express active TGFbeta. We have examined transcriptional changes within macrophage hybridoma no. 59, which promotes Th1 cell differentiation, and TGFbeta-2-treated no. 59 as well as macrophage hybridoma no. 63, both of which induce immune deviation similar to anterior chamber-associated immune deviation. Immune deviation-inducing hybridomas up-regulated expression of thrombospondin, TGFbeta, IFN-alpha and beta, murine macrophage elastase, and macrophage-inflammatory protein-2 genes, while down-regulating expression of the genes for NF-kappaB and CD40. Based on the known properties of these gene products, a model is proposed in which these gene products, alone and through interacting signaling pathways, confer upon conventional APCs the capacity to create and surround themselves with an immunomodulatory microenvironment. The model proposes that the pleiotropic effects of thrombospondin are primarily responsible for creating this microenvironment that is stabile, rich in active TGFbeta and IFN-alpha and beta, deficient in IL-12, and chemoattractant via macrophage-inflammatory protein-2 for NK T cells. It is further proposed that presentation of Ag to T cells in this microenvironment leads to their differentiation into regulatory cells that suppress Th1 cell-dependent immunogenic inflammation.

Analysis of immunomodulatory activities of aqueous humor from eyes of mice with experimental autoimmune uveitis.

Aqueous humor (AqH) contains immunosuppressive factors, especially TGF-beta2, that contribute to the immune privileged status of the anterior chamber. However, this may not be true when the blood-ocular barrier is compromised by ocular inflammation. To determine the immunosuppressive status of AqH from murine eyes afflicted with experimental autoimmune uveitis, B10.A mice were immunized with interphotoreceptor retinoid-binding protein. AqH was collected from eyes of affected mice periodically after immunization and then evaluated for content of TGF-beta, proinflammatory cytokines, and the capacity to suppress anti-CD3-driven T cell proliferation. mRNA expression of selected cytokines in iris and ciliary body from inflamed eyes was analyzed by ribonuclease protection assay. We found that TGF-beta levels were significantly increased in AqH from EAU eyes on days 11, 17, and 28. AqH collected on day 11 (onset of disease) failed to suppress T cell proliferation and contained large amounts of locally produced IL-6 that antagonized TGF-beta. In contrast, AqH collected at 17 days (when ocular inflammation was progressively severe) re-expressed the ability to suppress T cell proliferation, in this case due to high levels of blood-derived TGF-beta1 and eye-derived TGF-beta2 in the absence of IL-6. Thus, during the onset of experimental autoimmune uveitis, the ocular microenvironment loses its immunosuppressive properties due to local production of IL-6. But as inflammation mounts, AqH IL-6 content falls, and the fluid reacquires sufficient TGF-beta eventually to suppress immunogenic inflammation. The paradoxical roles of IL-6 in antagonizing TGF-beta, while promoting TGF-beta accumulation during ocular inflammation, is discussed.

Neural control of ocular immune privilege.

Ocular immune privilege arises from interactions between the immune apparatus and the eye itself, thereby providing immune protection for the eye that is devoid of sight-threatening inflammation. On the one hand, antigens injected intraocularly elicit deviant systemic immune responses that are devoid of immunogenic inflammation (Anterior Chamber-Associated Immune Deviation, ACAID). On the other hand, the ocular microenvironment (aqueous humor, secreted by cells that surround this chamber) suppresses intraocular expression of immunogenic inflammation. Several lines of evidence indicate that ocular immune privilege is under neural control. First, aqueous humor contains neuropeptides (alpha-MSH, VIP, CGRP) that inhibit and alter the functional properties of T lymphocytes and macrophages. Second, when corneal nerves are severed, the tissues surrounding the anterior chamber cease secreting immunosuppressive factors and ACAID fails--until the nerves regrow. Third, light deprivation abolishes the capacity of the anterior chamber to support ACAID induction, a process that is sensitive to neuropeptides and melatonin. The photoreceptor(s) responsible for ACAID are connected to the nervous system and may reside in the anterior segment and/or the retina. Thus, neural elements from the central nervous system and within the eye help to shape both the induction and the expression of ocular immunity, thereby promoting immune privilege.

Immunoregulatory mechanisms of the eye.

Immunity to protect the eye from invading pathogens is an absolute requirement for the preservation of vision. However, immune responses carry their own threat of tissue damage, due chiefly to the participation of non-specific inflammation. Because of its delicate microanatomy, the visual axis is vulnerable to distortion (and resulting blindness) from relatively trivial amounts of intraocular inflammation. Therefore, regulation of expression of immunity in the eye is critical to preservation of vision. Regulation of ocular immunity is one expression of the general phenomenon of regional immunity in which local tissue factors mold immune responses to local purposes. Ocular immune privilege is an extreme example of regional immunity. Immune privilege is an active, rather than a passive, process in which regulatory molecules and cells of the eye modulate both the induction and the expression of immunity to eye-derived antigens. Immune privilege is achieved primarily through unique features of the eye, ranging from special microanatomic factors (blood:eye barrier, absence of lymphatic draining), to soluble factors secreted by ocular cells into the ocular microenvironment, to regulatory molecules constitutively expressed on the surfaces of ocular cells. In general, the most important consequence of regulation of ocular immune responses is the virtual elimination of immunogenic inflammation from the eye. While this enables the eye to receive immune protection without the threat of blinding inflammation, it also renders the eye vulnerable to those pathogens whose elimination requires the participation of inflammatory molecules and cells.

The role of microglia and astrocytes in CNS immune surveillance and immunopathology.

Efficient immune surveillance and tissue repair within the central nervous system (CNS) are achieved through a complex and highly regulated network of interactions between resident brain cells and the immune system. Due to its unique structure and environment, the CNS exerts a strict control on the development of inflammatory and immune reactions that can be extremely injurious (Cserr and Knopf, 1992). Major features that contribute to the immune privilege of the CNS include: the presence of structural barriers such as the tight endothelial junctions of the brain vasculature restricting the passage of circulating immune cells and molecules; the lack of a lymphatic drainage; the absence of potent antigen presenting cells (APC) such as dendritic cells that capture potential antigens in the tissues and transport them to regional lymph nodes to initiate immune responses. Several other local mechanisms have been recently proposed which may actively limit immunogenic inflammation and tissue damage within the CNS. These include: the presence of mediators, such as transforming growth factor-β (TGF-β) (Cserr and Knopf, 1992) or brain lipids (Irani et al., 1997) with an immunosuppressive role; a strict downregulatory control exerted by neurons on major histocompatibility complex (MHC) antigen expression within the CNS parenchyma, thereby limiting the potential for local antigen presentation (Neumann et al., 1996); apoptotic elimination of T cells as a mean to terminate cell-mediated immune responses once they have been initiated within the CNS (Bauer et al., 1995).

On the mystique of the immunological self.

Since the time of Paul Ehrlich 100 years ago, we have known that the immunological apparatus somehow inhibits most damaging autoimmune responses while permitting a response to exogenous immunogens. With the discovery of tolerance, the concept of immunological surveillance, and especially with the discovery of HLA restriction of T-cell recognition, the term "the immunological self" and the phrase "self-nonself discrimination" have gained wide currency. Immunology has been called "The Science of Self", and self-nonself discrimination has been assigned as the driving force for its complex evolution. The concept of self has thus been given such mystical trappings since the time of Macfarlane Burnet that recent workers have felt free to pronounce it the central paradigm of modern immunology, and to claim to overthrow it! In this article, we challenge some of the more egregious claims about the immunological self by recalling important historical findings, by reviewing the mechanisms of Darwinian evolution, and by remembering that the general pathology of immunogenic inflammation shows that the immune response cannot discriminate between the benign and the noxious.

TOPICAL INTERLEUKIN 1 RECEPTOR ANTAGONIST PROMOTES CORNEAL TRANSPLANT SURVIVAL1

Interleukin (IL)-1 is a potent proinflammatory cytokine that plays a critical role in initiating and maintaining immunogenic inflammation. We performed a series of experiments to determine whether the topical application of IL-1 receptor antagonist (IL-1ra) can prolong corneal transplant survival in the murine model of orthotopic allotransplantation. For all experiments, C57BL/6 corneas were transplanted into BALB/c (major histocompatibility and minor histocompatibility-disparate) eyes. "High-risk" transplants were transplants that had been sutured into BALB/c recipient beds with corneal neovascularization induced by placement of three interrupted sutures in the host cornea 2 weeks earlier. Both risk groups were divided in a masked fashion into treatment subgroups that received either 20 mg/ml of IL-1ra mixed in 0.2% sodium hyaluronate vehicle (n=28) or placebo alone (n=25). All transplants were evaluated for 8 weeks after surgery for signs of rejection. At the end of follow-up, corneal specimens were processed for enumeration of Langerhans cells and histopathological evaluation. Survival rates of both normal-risk and high-risk transplants increased significantly among the IL-1ra-treated animals compared with untreated controls by both stratified Mantel-Haenszel (P=0.02) and Kaplan-Meier survival (P=0.03) analyses. Furthermore, both normal- and high-risk IL-1ra-treated grafts had significantly less inflammation and Langerhans cells infiltration compared with untreated controls. Topical treatment with IL-1ra has a significantly positive effect in promoting corneal allograft survival.

Regulation of ocular immune responses.

The existence of immune privilege in numerous tissues and organs, including the eye, has been re-emphasised during the past few years, and experimental studies have begun to unravel the multiple mechanisms, both passive and active, that make privilege possible. In this review, recent evidence bearing on the factors responsible for immune privilege in the anterior chamber of the eye is described. One dimension of ocular immune privilege depends upon local factors that limit and modify the expression of immunity. As a consequence, the local expression of immunogenic inflammation is largely curtailed within the eye. Another dimension of ocular immune privilege concerns the modification of induction of systemic immunity to antigens placed within, or arising from, the eye. Systemic responses to ocular antigens are devoid of delayed hypersensitivity T cells and complement-fixing antibodies, and the stage for these stereotypic responses is set by factors within the ocular microenvironment acting on indigenous antigen presenting cells. Overall, regulation of immune responses directed at ocular antigens appears to be designed to prevent inflammation from disrupting the visual axis and thereby causing blindness.

Aqueous humor induces transforming growth factor-ß (TGF-ß)-producing regulatory T-cells

PURPOSE. The intraocular microenvironment is an immune-privileged site where immunogenic inflammation is suppressed. Suppression of immunogenic inflammation has been associated with immunosuppressive factors found in aqueous humor produced by ocular tissues. To further understand the mechanisms suppressing immunogenic inflammation in the eye, we have examined the production of lymphokines by primed T-cells activated in the presence of aqueous humor. METHODS. Enriched in vivo primed T-cells were T-cell receptor-stimulated in the presence of fresh aqueous humor. The culture supernatant was assayed for IFN-? and IL-4 by sandwich ELISA. TGF-ß production by T-cells stimulated in the presence of aqueous humor was assayed by a TGF-ß bioassay of the culture supernatant and by quantitative RT-PCR for TGF-ß1 mRNA expression. Aqueous humor-treated T-cells were assayed for their capacity to suppress IFN-? production by stimulated, primed T-cells. RESULTS. Aqueous humor-enhanced proliferation but irreversibly suppressed production of both IFN-? and IL-4 by in vitro -activated, in vivo -primed T-cells. Aqueous humor induced in vivo primed T-cells to produce TGF-ß in vitro, and these TGF-ß-producing T-cells suppressed IFN-? production by other T-cells activated in co-cultures. CONCLUSIONS. Aqueous humor alters the functional program of TCR-ligand-activated, primed T-cells, converting the cells to TGF-ß-producing regulatory cells.

Neuroimmunomodulation in immune privilege: role of neuropeptides in ocular immunosuppression.

The microenvironments of the eye and brain are physiologically adapted to protect their delicate structures and functions from damaging immunogenic inflammation (delayed-type hypersensitivity). This adaptation is immune privilege. Aqueous humor, the fluid filling the ocular anterior chamber, suppresses antigen-stimulated primed T cells from mediating inflammation by inhibiting the production of the proinflammatory lymphokine interferon gamma. This suppression is mediated by immunosuppressive cytokines and neuropeptides constitutively produced in the eye and released into aqueous humor. Cerebrospinal fluid has similar immunosuppressive activities, cytokines, and neuropeptides as aqueous humor, indicating that similar mechanisms may mediate immune privilege in the eye and brain. The importance of neuropeptides in mediating immunosuppression indicates that immunosuppressive neuroimmunomodulation has a role in preventing induction of immunogenic inflammation within immune-privileged tissues.

Neurogenic switching: a hypothesis for a mechanism for shifting the site of inflammation in allergy and chemical sensitivity.

Neurogenic switching is proposed as a hypothesis for a mechanism by which a stimulus at one site can lead to inflammation at a distant site. Neurogenic inflammation occurs when substance P and other neuropeptides released from sensory neurons produce an inflammatory response, whereas immunogenic inflammation results from the binding of antigen to antibody or leukocyte receptors. There is a crossover mechanism between these two forms of inflammation. Neurogenic switching is proposed to result when a sensory impulse from a site of activation is rerouted via the central nervous system to a distant location to produce neurogenic inflammation at the second location. Neurogenic switching is a possible explanation for systemic anaphylaxis, in which inoculation of the skin or gut with antigen produces systemic symptoms involving the respiratory and circulatory systems, and an experimental model of anaphylaxis is consistent with this hypothesis. Food-allergy-iducing asthma, urticaria, arthritis, and fibromyalgia are other possible examples of neurogenic switching. Neurogenic switching provides a mechanism to explain how allergens, infectious agents, irritants, and possibly emotional stress can exacerbate conditions such as migraine, asthma, and arthritis. Because neurogenic inflammation is known to be triggered by chemical exposures, it may play a role in the sick building syndrome and the multiple chemical sensitivity syndrome. Thus neurogenic switching would explain how the respiratory irritants lead to symptoms at other sites in these disorders.