vasoactive-intestinal-peptide and Autoimmune-Diseases

The neuroendocrine and immune systems are coordinated to maintain the homeostasis of the organism, generating bidirectional communication through shared mediators and receptors. Vasoactive intestinal peptide (VIP) is the paradigm of an endogenous neuropeptide produced by neurons and endocrine and immune cells, involved in the control of both innate and adaptive immune responses. Exogenous administration of VIP exerts therapeutic effects in models of autoimmune/inflammatory diseases mediated by G-protein-coupled receptors (VPAC1 and VPAC2). Currently, there are no curative therapies for inflammatory and autoimmune diseases, and patients present complex diagnostic, therapeutic, and prognostic problems in daily clinical practice due to their heterogeneous nature. This review focuses on the biology of VIP and VIP receptor signaling, as well as its protective effects as an immunomodulatory factor. Recent progress in improving the stability, selectivity, and effectiveness of VIP/receptors analogues and new routes of administration are highlighted, as well as important advances in their use as biomarkers, contributing to their potential application in precision medicine. On the 50th anniversary of VIP's discovery, this review presents a spectrum of potential clinical benefits applied to inflammatory and autoimmune diseases.

Topics: Animals; Autoimmune Diseases; Diabetes Mellitus, Type 1; Humans; Inflammation; Inflammatory Bowel Diseases; Receptors, Vasoactive Intestinal Peptide, Type II; Receptors, Vasoactive Intestinal Polypeptide, Type I; Rheumatic Diseases; Sjogren's Syndrome; Vasoactive Intestinal Peptide

Neuropeptides represent an important category of endogenous contributors to the establishment and maintenance of immune deviation in the immune-privileged organs such as the CNS and in the control of acute inflammation in the peripheral immune organs. Vasoactive intestinal peptide (VIP) is a major immunoregulatory neuropeptide widely distributed in the central and peripheral nervous system. In addition to neurones, VIP is synthesized by immune cells which also express VIP receptors. Here, we review the current information on VIP production and VIP-receptor-mediated effects in the immune system, the role of endogenous and exogenous VIP in inflammatory and autoimmune disorders and the present and future VIP therapeutic approaches.

Topics: Animals; Autoimmune Diseases; Humans; Inflammation; Neuropeptides; Receptors, Vasoactive Intestinal Peptide; T-Lymphocytes; Vasoactive Intestinal Peptide

Because there are no particular molecular signatures of self, autoimmunity is the inevitable evolutionary price of being able to make effective responses against a wide variety of pathogens by the immune system. Without the various phenomena referred to as immune tolerance, the organism would surely self-destruct. Considerable evidence suggests that various endogenous neuropeptides play a major role in the education of our immune system to be self-tolerant. The fact that neuropeptides regulate various layers involved in maintenance of tolerance, including regulation of the balance between pro-inflammatory and anti-inflammatory responses and between self-reactive Th1/Th17 cells and regulatory T cells, makes them attractive candidates for the development of new therapies for the treatment of autoimmune disorders. Here we use the vasoactive intestinal peptide of a prototype of immunomodulatory neuropeptide to review the most relevant data found for other neuropeptides with similar characteristics, including melanocyte-stimulating hormone, urocortin, adrenomedullin, neuropeptide Y, cortistatin and ghrelin. We also evaluate the challenges that must be overcome before achieving their clinical application and offer our opinion on how a physiologically functional neuropeptide system contributes to general health.

Topics: Animals; Autoimmune Diseases; Autoimmunity; Humans; Immune Tolerance; Immunologic Factors; Models, Biological; Neuroimmunomodulation; Neuropeptides; Vasoactive Intestinal Peptide

Identification of the factors that regulate the immune tolerance and control the appearance of exacerbated inflammatory conditions is crucial for the development of new therapies of autoimmune diseases. Some neuropeptides and hormones have emerged as endogenous agents that participate in the regulation of the processes that ensure self-tolerance. Among them, the vasoactive intestinal peptide (VIP), a well-characterised endogenous anti-inflammatory neuropeptide, has shown therapeutic potential for a variety of immune disorders. Here we examine the latest research findings, which indicate that VIP participates in maintaining immune tolerance in two distinct ways: by regulating the balance between pro-inflammatory and anti-inflammatory factors, and by inducing the emergence of regulatory T cells with suppressive activity against autoreactive T cell effectors.

Topics: Anti-Inflammatory Agents; Autoimmune Diseases; Autoimmunity; Humans; Immune Tolerance; Immunity, Cellular; Immunity, Innate; Immunosuppressive Agents; Models, Immunological; T-Lymphocytes, Regulatory; Th1 Cells; Vasoactive Intestinal Peptide

An imbalance of pro-inflammatory and anti-inflammatory cytokines, autoreactive and inflammatory T helper 1 (Th1) cells, and regulatory T (Treg) cells results in the loss of immune tolerance and the subsequent appearance of inflammatory autoimmune diseases. On the other hand, hormones and neuropeptides are endogenous factors controlling the immune homeostasis that have been proposed as therapeutic agents in different autoimmune disorders. Among them, the vasoactive intestinal peptide (VIP) has been shown to downregulate the inflammatory response and to alter the Th1/Th2 balance in favor of anti-inflammatory Th2 immune responses. Recent studies have revealed a greater diversification of the T cell effector repertoire with the identification of Th17 cells. This subpopulation has been shown to be pathogenic in several autoimmune diseases previously attributed to the Th1 lineage. Arising new data and a critical revision of already published studies indicate that VIP is an immunomodulatory therapeutic agent targeting the Th17/Treg pathway.

Topics: Animals; Autoimmune Diseases; Humans; Inflammation; Interleukin-23; T-Lymphocytes; T-Lymphocytes, Helper-Inducer; T-Lymphocytes, Regulatory; Th1 Cells; Th2 Cells; Vasoactive Intestinal Peptide

Dendritic cells (DCs) are the most potent antigen-presenting cells (APCs) involved in the defense of the body and in the maintenance of the immune tolerance. The regulation of their maturation, migration, and expression of stimulatory and costimulatory molecules has major consequences on the immune response. The endogenous factors that regulate DC function are poorly known. Vasoactive intestinal peptide (VIP) is a neuropeptide with potent anti-inflammatory actions. This anti-inflammatory profile is maintained partially through effects on DC differentiation/function. Thus, VIP has differential effects on DCs, depending on the differentiation and stimulatory states. Immature DCs treated with VIP exhibit increased CD86 expression and induce CD4(+) T cell proliferation. In addition, the CD4(+) T cells activated in vitro or in vivo by VIP-treated iDCs exhibit a Th2 phenotype. In contrast, VIP reduces both CD86 and CD80 expression on lipopolysaccharide (LPS)-stimulated DCs, and inhibits the capacity of DCs to induce in vitro or in vivo T cell proliferation. However, addition of VIP in the early states of DC differentiation results in the generation of DCs that cannot mature following inflammatory stimuli that exhibit a tolerogenic phenotype, characterized by low expression of costimulatory molecules (CD40, CD80, and CD86), low production of proinflammatory cytokines, increased production of IL-10, and capacity to induce regulatory T cells with suppressive actions. The effect of VIP on the DC-Treg axis represents an additional mechanism for their general anti-inflammatory role, particularly relevant in autoimmunity and transplantation.

Topics: Animals; Autoimmune Diseases; Cell Differentiation; Dendritic Cells; Graft Rejection; Humans; Transplantation Immunology; Vasoactive Intestinal Peptide

Topics: Adaptation, Physiological; Autoimmune Diseases; Humans; Neuroimmunomodulation; Psychophysiologic Disorders; Somatoform Disorders; Stress, Physiological; Vasoactive Intestinal Peptide

Catalytic autoantibodies (abzymes) are autoantibodies that are potentially ready to realize certain effects in the organism, first of all antibody-mediated catalysis and cytotoxicity. Natural abzymes with protolytic (protabzymes) and DNA-hydrolyzing DNA-abzymes) activity are of the greatest interest. The most impressive example of the catalytic activity of protabzymes is hydrolysis of specific proteins, revealed in patients with autoimmune diseases, such as bronchial asthma (vasoactive intestinal neuropeptide), autoimmune thyroiditis (thyroglobulin), multiple sclerosis (myelin basic protein), and autoimmune myocarditis (cardiomyosin). The pathogenic role of DNA-abzymes is not quite clear yet. However, it has been proven that they present a powerful regulator of apoptosis and other cytotoxicity mechanisms in systemic autoimmune diseases and tumors. The most promising is use of abzymes as illness activity markers, and as therapeutic agents capable of catalyzing specific proteins or activating antitumoral chemotherapeutic preparations.

Topics: Animals; Antibodies, Catalytic; Apoptosis; Asthma; Autoantibodies; Autoimmune Diseases; Biomarkers; Cytotoxicity, Immunologic; DNA; Humans; Hydrolysis; Mice; Multiple Sclerosis; Myelin Basic Protein; Prodrugs; Thyroglobulin; Thyroiditis, Autoimmune; Vasoactive Intestinal Peptide

Vasoactive intestinal peptide (VIP), a peptide produced by immune cells, exerts a wide spectrum of immunological functions that control the homeostasis of the immune system. In the last decade, VIP has been clearly identified as a potent anti-inflammatory factor, both in innate and adaptive immunity. In innate immunity, this peptide inhibits the production of inflammatory cytokines and chemokines from macrophages, microglia and dendritic cells. In addition, VIP reduces the expression of co-stimulatory molecules on antigen-presenting cells, and therefore reduces stimulation of antigen-specific CD4 T-cells. In terms of adaptive immunity, VIP promotes T-helper (Th)2-type responses, and reduces inflammatory Th1-type responses. Several of the molecular mechanisms involved in the inhibition of cytokine and chemokine expression, and in the preferential development and/or survival of Th2 effectors are known. Therefore, VIP and its analogs have been proposed as promising alternative candidates to existing therapies for the treatment of acute and chronic inflammatory and autoimmune diseases. The aim of this review is to update knowledge of the cellular and molecular events that are relevant to VIP function in the immune system. The central functions that VIP plays in cellular processes is being recognized and attention is being focused on this important peptide with regard to exciting new candidates for therapeutic intervention and drug development.

Topics: Animals; Anti-Inflammatory Agents; Autoimmune Diseases; Autoimmunity; CD4-Positive T-Lymphocytes; Dendritic Cells; Drug Design; Homeostasis; Humans; Immunity, Innate; Inflammation; Lymphoid Tissue; Macrophages; Microglia; Neurodegenerative Diseases; Receptors, Vasoactive Intestinal Peptide; Shock, Septic; T-Lymphocyte Subsets; Th2 Cells; Vasoactive Intestinal Peptide

The immune system and the brain continuously signal to each other, often along the same pathways, which might explain the connection between immunity, the brain and disease. Neuropeptides and their receptors represent part of this communication network, and recent work has examined their relevance to health, proving a potentially crucial clinical significance. The structurally related neuropeptides, vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP), are emerging as a means of fine tuning in the maintenance a balanced steady state in the immune system. Murine knockout and transgenic models for a VIP receptor suggest that VIP is an endogenous anti-inflammatory mediator with characteristics resembling those of a T-helper-2 cytokine. Thus, through molecular mechanisms that are being discovered, VIP might extend the range of therapeutic treatments available for various disorders, including acute and chronic inflammatory diseases, septic shock and autoimmune diseases.

Topics: Adjuvants, Immunologic; Animals; Autoimmune Diseases; Mice; Neuropeptides; Pituitary Adenylate Cyclase-Activating Polypeptide; Receptors, G-Protein-Coupled; Vasoactive Intestinal Peptide

Vasoactive intestinal peptide (VIP), a neuropeptide that is produced by lymphoid as well as neural cells, exerts a wide spectrum of immunological functions, controlling the homeostasis of the immune system through different receptors expressed in various immunocompetent cells. In the last decade, VIP has been clearly identified as a potent anti-inflammatory factor, which acts by regulating the production of both anti- and pro-inflammatory mediators. In this sense, VIP has been described to prevent death by septic shock, an acute inflammatory disease with a high mortality. In addition, VIP regulates the expression of co-stimulatory molecules, this being an action that may be related to modulating the shift toward Th1 and Th2 differentiation. We have recently reported that VIP prevents the deleterious effects of an experimental model of rheumatoid arthritis, by downregulating both inflammatory and autoimmune components of the disease. Therefore, VIP has been proposed as a promising candidate alternative treatment for acute and chronic inflammatory and autoimmune diseases such as septic shock, arthritis, multiple sclerosis, Crohn disease, or autoimmune diabetes.

Topics: Animals; Anti-Inflammatory Agents; Autoimmune Diseases; Humans; Inflammation; Mice; Receptors, Vasoactive Intestinal Peptide; Vasoactive Intestinal Peptide

Sjögren's disease (SjD) is a chronic autoimmune disease characterized by the loss of the secretory function of the exocrine glands. At present, drugs that can both correct the immune imbalance and improve exocrine gland function are needed. Meanwhile, vasoactive intestinal peptide (VIP) has been reported as a candidate with anti-inflammatory and immunoregulatory properties for treating autoimmune diseases.. Nonobese diabetic (NOD) mice and the primary splenic lymphocyte cells (SPLCs) were used to construct the SS model. The therapeutic effects of VIP for SjD by evaluating water consumption, histopathology, T cell subsets, and related cytokines. RT-qPCR and Western blot analysis were used to identify the expression of the PTEN/PI3K/AKT pathway.. We found that VIP therapy in NOD mice could increase the expression of PTEN and VIP/VPAC1 receptor, as well as decrease the PI3K/AKT pathway. In vitro, the results showed that the PTEN knockdown decreased the Treg/Th17 ratio and enhanced the phosphorylated PI3K/AKT pathway, which were reversed with VIP treatment.. VIP exerts potential therapeutic action in SjD by upregulating PTEN through the PI3K/AKT pathway and Treg/Th17 cell balance.

Topics: Animals; Autoimmune Diseases; Mice; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Sjogren's Syndrome; Vasoactive Intestinal Peptide

The K/BxN mouse model of rheumatoid arthritis (RA) closely resembles the human disease. In this model, arthritis results from activation of autoreactive KRN T cells recognizing the glycolytic enzyme glucose-6-phosphate isomerase (GPI) autoantigen, which provides help to GPI-specific B cells, resulting in the production of pathogenic anti-GPI antibodies that ultimately leads to arthritis symptoms from 4 weeks of age. Vasoactive intestinal peptide (VIP) is a neuropeptide broadly distributed in the central and peripheral nervous system that is also expressed in lymphocytes and other immune cell types. VIP is a modulator of innate and adaptive immunity, showing anti-inflammatory and immunoregulatory properties. Basically, this neuropeptide promotes a shift in the Th1/Th2 balance and enhances dedifferentiation of T regulatory cells (Treg). It has demonstrated its therapeutic effects on the collagen-induced arthritis (CIA) mouse model of RA. In the present hypothesis and theory article, we propose that the immunoregulatory properties of VIP may be due likely to the inhibition of T cell plasticity toward non-classic Th1 cells and an enhanced follicular regulatory T cells (Tfr) activity. The consequences of these regulatory properties are the reduction of systemic pathogenic antibody titers.

Topics: Animals; Arthritis, Experimental; Arthritis, Rheumatoid; Autoantibodies; Autoantigens; Autoimmune Diseases; Disease Models, Animal; Glucose-6-Phosphate Isomerase; Humans; Mice; Mice, Inbred C57BL; T-Lymphocytes, Regulatory; Th1 Cells; Th2 Cells; Vasoactive Intestinal Peptide

Topics: Angiotensin-Converting Enzyme 2; Arthritis, Rheumatoid; Autoimmune Diseases; Drug Combinations; Gastrointestinal Neoplasms; Humans; Inflammation; Inflammatory Bowel Diseases; Neurodegenerative Diseases; Phentolamine; Receptors, G-Protein-Coupled; Vasoactive Intestinal Peptide

Vasoactive intestinal peptide (VIP) is a neuropeptide that exerts various vascular and cardioprotective functions and regulates immune function and inflammatory response at multiple levels. However, its role in inflammatory cardiovascular disorders is largely unknown. Myocarditis and atherosclerosis are two inflammatory and autoimmune cardiovascular diseases that cause important adverse circulatory events. In this study, we investigate the therapeutic effects of VIP in various well-established preclinical models of experimental autoimmune myocarditis and atherosclerosis. Intraperitoneal injection of VIP during the effector phase of experimental autoimmune myocarditis in susceptible BALB/c mice significantly reduced its prevalence, ameliorated signs of heart hypertrophy and injury, attenuated myocardial inflammatory infiltration, and avoided subsequent profibrotic cardiac remodeling. This effect was accompanied by a reduction of Th17-driven cardiomyogenic responses in peripheral lymphoid organs and in the levels of myocardial autoantibodies. In contrast, acute and chronic atherosclerosis was induced in apolipoprotein E-deficient mice fed a hyperlipidemic diet and subjected to partial carotid ligation. Systemic VIP treatment reduced the number and size of atherosclerotic plaques in carotid, aorta, and sinus in hypercholesterolemic mice. VIP reduced Th1-driven inflammatory responses and increased regulatory T cells in atherosclerotic arteries and their draining lymph nodes. VIP also regulated cholesterol efflux in macrophages and reduced the formation of foam cells and their presence in atherosclerotic plaques. Finally, VIP inhibited proliferation and migration of smooth muscle cells and neointima formation in a mouse model of complete carotid ligation. These findings encourage further studies aimed to assess whether VIP can be used as a pharmaceutical agent to treat heart inflammation and atherosclerosis.

Topics: Animals; Apolipoproteins E; Atherosclerosis; Autoantibodies; Autoimmune Diseases; Autoimmunity; Disease Models, Animal; Female; Inflammation; Lymph Nodes; Macrophages; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Muscle, Smooth; Myocarditis; Myocardium; Neuropeptides; T-Lymphocytes, Regulatory; Th17 Cells; Vasoactive Intestinal Peptide

Sjögren's syndrome (SS) is a chronic autoimmune disease characterized by a progressive oral and ocular dryness that correlates poorly with the autoimmune damage of the glands. It has been proposed that a loss of homeostatic equilibrium in the glands is partly responsible for salivary dysfunction with acinar cells involved actively in the pathogenesis of SS. The non-obese diabetic (NOD) mouse model of Sjögren's syndrome develops secretory dysfunction and early loss of glandular homeostatic mechanisms, with mild infiltration of the glands. Based on the vasodilator, prosecretory and trophic effects of the vasoactive intestinal peptide (VIP) on acini as well as its anti-inflammatory properties we hypothesized that the local expression of VIP/vasoactive intestinal peptide receptor (VPAC) system in salivary glands could have a role in acinar cell apoptosis and macrophage function thus influencing gland homeostasis. Here we show a progressive decline of VIP expression in submandibular glands of NOD mice with no changes in VPAC receptor expression compared with normal mice. The deep loss of endogenous VIP was associated with a loss of acinar cells through apoptotic mechanisms that could be induced further by tumour necrosis factor (TNF)-α and reversed by VIP through a cyclic adenosine-5'-monophosphate (cAMP)/protein kinase A (PKA)-mediated pathway. The clearance of apoptotic acinar cells by macrophages was impaired for NOD macrophages but a shift from inflammatory to regulatory phenotype was induced in macrophages during phagocytosis of apoptotic acinar cells. These results support that the decline in endogenous VIP/VPAC local levels might influence the survival/apoptosis intracellular set point in NOD acinar cells and their clearance, thus contributing to gland homeostasis loss.

Topics: Acinar Cells; Animals; Apoptosis; Autoimmune Diseases; Cell Survival; Cells, Cultured; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Disease Models, Animal; Macrophages; Mice; Mice, Inbred BALB C; Mice, Inbred NOD; NF-kappa B; Phagocytosis; Receptors, Vasoactive Intestinal Peptide; Sjogren's Syndrome; Submandibular Gland; Tumor Necrosis Factor-alpha; Vasoactive Intestinal Peptide

The neuropeptide vasoactive intestinal peptide (VIP) has been shown to inhibit macrophage proinflammatory actions, promote a positive Th2/Th1 balance, and stimulate regulatory T-cell production. The fact that this peptide is highly efficacious in animal models of inflammatory diseases such as collagen-induced arthritis and experimental autoimmune encephalomyelitis (EAE) suggests that the endogenous peptide might normally provide protection against such pathologies. We thus studied the response of VIP-deficient (i.e., VIP KO) mice to myelin oligodendrocyte protein-induced EAE. Surprisingly, VIP KO mice were almost completely resistant to EAE, with delayed onset and mild or absent clinical profile. Despite this, flow cytometric analyses and antigen-rechallenge experiments indicated that myelin oligodendrocyte protein-treated VIP KO mice exhibited robust Th1/Th17 cell inductions and antigen-specific proliferation and cytokine responses. Moreover, adoptive transfer of lymphocytes from immunized VIP KO mice to WT recipients resulted in full-blown EAE, supporting their encephalitogenic potential. In contrast, transfer of encephalitogenic WT cells to VIP KO hosts did not produce EAE, suggesting that loss of VIP specifically affected the effector phase of the disease. Histological analyses indicated that CD4 T cells entered the meningeal and perivascular areas of VIP-deficient mice, but that parenchymal infiltration was strongly impaired. Finally, VIP pretreatment of VIP KO mice before immunization was able to restore their sensitivity to EAE. These results indicate that VIP plays an unanticipated permissive and/or proinflammatory role in the propagation of the inflammatory response in the CNS, a finding with potential therapeutic relevance in autoimmune neuroinflammatory diseases such as multiple sclerosis.

Topics: Animals; Autoimmune Diseases; Cell Movement; Central Nervous System; Cytokines; Encephalomyelitis, Autoimmune, Experimental; Inflammation; Lymphocyte Activation; Mice; Mice, Knockout; Myelin-Associated Glycoprotein; T-Lymphocytes; Th1 Cells; Th17 Cells; Vasoactive Intestinal Peptide

Pituitary adenylyl cyclase-activating polypeptide (PACAP) is a widely expressed neuropeptide originally discovered in the hypothalamus. It closely resembles vasoactive intestinal peptide (VIP), a neuropeptide well known to inhibit macrophage activity, promote Th2-type responses, and enhance regulatory T cell (Treg) production. Recent studies have shown that administration of PACAP, like VIP, can attenuate dramatically the clinical and pathological features of murine models of autoimmune diseases such as experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis. However, specific roles (if any) of endogenous VIP and PACAP in the protection against autoimmune diseases have not been explored. Here, we subjected PACAP-deficient mice to myelin oligodendrocyte glycoprotein (MOG(35-55))-induced EAE. MOG immunization of PACAP-deficient mice triggered heightened clinical and pathological manifestations of EAE compared to wild-type mice. The increased sensitivity was accompanied by enhanced mRNA expression of proinflammatory cytokines (TNFalpha, IL-6, IFN-gamma, IL-12p35, IL-23p19, and IL-17), chemokines (MCP-1/CCL2, MIP-1alpha/CCL3, and RANTES/CCL5), and chemotactic factor receptors (CCR1, CCR2, and CCR5), but downregulation of the anti-inflammatory cytokines (IL-4, IL-10, and TGF-beta) in the spinal cord. Moreover, the abundance of CD4(+)CD25(+)FoxP3(+) Tregs in lymph nodes and levels of FoxP3 mRNA in the spinal cord were also diminished. The reduction in Tregs was associated with increased proliferation and decreased TGF-beta secretion in lymph node cultures stimulated with MOG. These results demonstrate that endogenous PACAP provides protection in EAE and identify PACAP as an intrinsic regulator of Treg abundance after inflammation.

Topics: Animals; Autoimmune Diseases; Cytokines; Encephalomyelitis, Autoimmune, Experimental; Gene Expression Regulation; Lymph Nodes; Lymphocyte Count; Mice; Mice, Knockout; Myelin Proteins; Myelin-Associated Glycoprotein; Myelin-Oligodendrocyte Glycoprotein; Pituitary Adenylate Cyclase-Activating Polypeptide; Receptors, CCR; Spinal Cord; T-Lymphocytes, Regulatory; Vasoactive Intestinal Peptide

The aim of this study was to investigate the effect of a single intravitreal (i.v.t.) injection of vasoactive intestinal peptide (VIP) loaded in rhodamine-conjugated liposomes (VIP-Rh-Lip) on experimental autoimmune uveoretinitis (EAU).. An i.v.t. injection of VIP-Rh-Lip, saline, VIP, or empty-(E)-Rh-Lip was performed simultaneously, either 6 or 12 days after footpad immunization with retinal S-antigen in Lewis rats. Clinical and histologic scores were determined. Immunohistochemistry and cytokine quantification by multiplex enzyme-linked immunosorbent assay were performed in ocular tissues. Systemic immune response was determined at day 20 postimmunization by measuring proliferation and cytokine secretion of cells from inguinal lymph nodes (ILNs) draining the immunization site, specific delayed-type hypersensitivity (DTH), and the serum concentration of cytokines. Ocular and systemic biodistribution of VIP-Rh-Lip was studied in normal and EAU rats by immunofluorescence.. The i.v.t. injection of VIP-Rh-Lip performed during the afferent, but not the efferent, phase of the disease reduced clinical EAU and protected against retinal damage. No effect was observed after saline, E-Rh-Lip, or VIP injection. VIP-Rh-Lip and VIP were detected in intraocular macrophages and in lymphoid organs. In VIP-Rh-Lip-treated eyes, macrophages expressed transforming growth factor-beta2, low levels of major histocompatibility complex class II, and nitric oxide synthase-2. T-cells showed activated caspase-3 with the preservation of photoreceptors. Intraocular levels of interleukin (IL)-2, interferon-gamma (IFN-gamma), IL-17, IL-4, GRO/KC, and CCL5 were reduced with increased IL-13. At the systemic level, treatment reduced retinal soluble autoantigen lymphocyte proliferation, decreased IL-2, and increased IL-10 in ILN cells, and diminished specific DTH and serum concentration of IL-12 and IFN-gamma.. An i.v.t. injection of VIP-Rh-Lip, performed during the afferent stage of immune response, reduced EAU pathology through the immunomodulation of intraocular macrophages and deviant stimulation of T-cells in ILN. Thus, the encapsulation of VIP within liposomes appears as an effective strategy to deliver VIP into the eye and is an efficient means of the prevention of EAU severity.

Topics: Animals; Arrestin; Autoimmune Diseases; Cell Proliferation; Cytokines; Disease Models, Animal; Injections; Liposomes; Lymph Nodes; Macrophages; Male; Rats; Rats, Inbred Lew; Retinitis; Rhodamines; T-Lymphocytes; Uveitis; Vasoactive Intestinal Peptide; Vitreous Body

A wealth of evidence supports the concept that achalasia represents an autoimmune disorder in which a triggering factor (probably a virus) is the starter of an uncontrolled myenteric ganglionitis leading to neurodegeneration. The reasons whereby this process occurs only in some individuals and at the oesophageal level are unknown, but it is reasonable to assume that some genetic influence may affect the achalasia phenotype, making some individuals more or less susceptible to the disease. Association studies between achalasia and polymorphisms of genes involved in the regulation of immune responses may help to explain the complexity of achalasia pathogenesis and progression.

Topics: Aging; Autoimmune Diseases; Esophageal Achalasia; Humans; Neurons; Nitric Oxide; Polymorphism, Genetic; Receptors, Vasoactive Intestinal Polypeptide, Type I; Vasoactive Intestinal Peptide

CD4+,CD25+ T regulatory cells (Treg) control the immune response to a variety of antigens, including self antigens, and may offer opportunities to intervene in the course of autoimmune diseases. Several models support the idea of the peripheral generation of CD4+,CD25+ Treg from CD4+,CD25- T cells, but little is known about the endogenous factors and mechanisms controlling the peripheral expansion of CD4+,CD25+ Treg. We undertook this study to investigate the capacity of the vasoactive intestinal peptide (VIP), an immunosuppressive antiarthritic neuropeptide, to induce functional Treg in vivo during the development of collagen-induced arthritis (CIA).. We measured the number of CD4+,CD25+ Treg following VIP administration to CIA mice, and we characterized their phenotype and their ability to suppress activation of autoreactive T cells. We determined the capacity of VIP to induce Treg in vitro as well as the use of Treg in the treatment of CIA, measuring the clinical evolution and the inflammatory and autoimmune components of the disease.. The administration of VIP to arthritic mice resulted in the expansion of CD4+,CD25+,Foxp3+ Treg in the periphery and joints, which inhibited autoreactive T cell activation/expansion. VIP induced more efficient suppressors on a per-cell basis. The VIP-generated CD4+,CD25+ Treg transfer suppressed and significantly ameliorated the progression of the disease.. These results demonstrate the involvement of the generation of Treg in the therapeutic effect of VIP on CIA. The generation of highly efficient Treg by VIP ex vivo could be used as an attractive therapeutic tool in the future, avoiding the administration of the peptide to patients with rheumatoid arthritis.

Topics: Animals; Arthritis, Experimental; Arthritis, Rheumatoid; Autoimmune Diseases; CD4-Positive T-Lymphocytes; Collagen; Disease Progression; Immunosuppressive Agents; Male; Mice; Mice, Inbred DBA; Receptors, Interleukin-2; T-Lymphocytes, Regulatory; Vasoactive Intestinal Peptide

Autoimmune dysfunction of certain vasoactive neuropeptides may be implicated in a range of disorders associated with fatigue like states (chronic fatigue syndrome, Gulf War syndrome) and even sudden infant death syndrome. These substances have neurotrophic, neuroregulatory, and neurotransmission functions, as well as that of immune modulators and hormones. They exert significant control over carbohydrate and lipid metabolism. The hypothesis is that because these substances have vital and indispensable roles in cellular processes, loss or compromise of these roles would lead to predictable and severe cellular and systemic effects. The important roles of certain VNs make them a vulnerable target for autoimmune dysfunction. They are known to be associated with heat shock proteins for intracellular functioning with which they may form immunostimulating complexes. While peptide-HSP complexes are a relatively new area for research, this paper asserts that attention could be focused on these substances and complexes in an effort to elucidate a number of perplexing fatigue-associated disorders.

Topics: Autoimmune Diseases; Autoimmunity; Fatigue; Fatigue Syndrome, Chronic; Heat-Shock Proteins; Humans; Infant, Newborn; Models, Immunological; Neuroimmunomodulation; Neuropeptides; Persian Gulf Syndrome; Sudden Infant Death; Vasoactive Intestinal Peptide

Vasoactive intestinal peptide (VIP) exhibits immunomodulatory activities both in vivo and in vitro, including efficient inhibition of murine experimental arthritis. In this study, we investigated the effects of VIP treatment on the induction of experimental autoimmune uveoretinitis (EAU).. EAU was induced in B10.RIII mice by immunization with interphotoreceptor retinoid-binding protein (IRBP) using routine methods, but without treatment with pertussis toxin (PTX). VIP was injected i.p. at different doses into mice on alternate days. Mice were tested by conventional methods for ocular inflammation, antibody levels, lymphocyte proliferation, and cytokine release by cultured lymphocytes.. Treatment with VIP, at different doses, had essentially no effect on the development of EAU or antibody production in the B10.RIII mice. The treatment did have variable effects on the low interferon-gamma production by lymphocytes of these mice.. Unlike its inhibitory effect in the experimental arthritis system, VIP did not modulate the development of EAU in B10.RIII mice.

Topics: Animals; Antibody Formation; Autoimmune Diseases; B-Lymphocytes; Cytokines; Eye Proteins; Female; Immunoglobulin G; Injections, Intraperitoneal; Lymphocyte Activation; Mice; Neuroprotective Agents; Retinitis; Retinol-Binding Proteins; T-Lymphocytes; Uveitis; Vasoactive Intestinal Peptide

Toll-like receptor 2 (TLR2) and -4 mediate signals from a great variety of bacterial gut products, giving the host a panel of microbe-recognizing receptors. Under homeostatic conditions, TLRs act as protective receptors of the intestinal epithelium. When homeostasis is disrupted in diseases such as inflammatory bowel disease, TLR2 and -4 are deregulated. Our study demonstrates, by using a trinitrobenzene sulfonic acid-induced colitis model of Crohn's disease, the constitutive expression and the up-regulation of TLR2 and -4 at messenger and protein levels in colon extracts, as well as in macrophages, dendritic cells, and lymphocytes from mesenteric lymphoid nodes. Vasoactive intestinal peptide (VIP) treatment induced a decrease of TLR2 and -4 expressions approaching ethanol control levels. Our results suggest that VIP modulation of TLR2 and -4 could be explained by two possible mechanisms. The first one would be the secondary reduction of TLR2 and -4 caused by the VIP-mediated decrease of inflammatory mediators such as interleukin-1beta and interferon-gamma, which synergize with bacterial products, contributing to the amplification of TLR presence in the intestine. The other possible mechanism would involve a VIP-mediated decrease of nuclear factor-kappaB, which would cause a direct down-regulation of TLR expression. In summary, the resultant physiological effect is the decrease of TLR2 and -4 expressions to homeostatic levels. Our study describes for the first time the role of a peptide present in the gut microenvironment as an effective modulator of the initial steps of acute inflammation, acting at local and systemic levels and leading to the restoration of the homeostasis lost after an established inflammatory/autoimmune disease.

Topics: Animals; Autoimmune Diseases; Gene Expression Regulation; Homeostasis; Inflammation; Inflammatory Bowel Diseases; Injections, Intraperitoneal; Interferon-gamma; Interleukin-1; Intestinal Mucosa; Intestines; Male; Membrane Glycoproteins; Mice; Mice, Inbred BALB C; Neuroprotective Agents; Receptors, Cell Surface; Recovery of Function; Toll-Like Receptor 2; Toll-Like Receptors; Trinitrobenzenesulfonic Acid; Vasoactive Intestinal Peptide

Vasoactive neuropeptides such as pituitary adenylate cyclase activating polypeptide (PACAP), calcitonin gene related peptide (CGRP) and vasoactive intestinal peptide (VIP) have been implicated in a number of fatigue-related conditions. Associations of these vasoactive neuropeptides with heat shock proteins (hsps) and cytosine-guanosine dinucleotide (CpG) DNA fragments in autoimmune phenomena have been postulated to interfere with receptor signal activation for adenylate cyclase and other vital cellular processes. However, a specific mechanism for receptor dysfunction has not been explored to date. G protein-coupled receptors (GPCRs) constitute a high proportion of biological receptor mechanisms and serve a wide range of substances including nucleosides, nucleotides, catecholamines, calcium, histamine, serotonin and prostaglandins. They are complex transmembrane hepta-helical serpentine structures with specific binding capabilities resulting in conformational changes that activate cognate cyclic GMP (G proteins). GPCRs adapt to certain stimuli through desensitisation and changes in phosphorylation and are subject to distortions of signalling processes. Hence, these vital signalling structures are susceptible to impairment of function through a range of mechanisms. One of their vital functions is signalling through adenylate cyclase, a vital step in cyclic AMP metabolism. This step involves ATP metabolism and therefore is a crucial mediator of cellular energy pathways. Some GPCRs act to inhibit adenylate cyclase (Gi proteins). Also vasoactive neuropeptides, such as PACAP display a number of receptor isotypes including null variants. Overexpression of Gi proteins and null variant receptors may account for major disruptions of signal transduction and ATP/cAMP metabolism. This paper examines the possible role of GPCR dysfunction in contributing to fatigue-related vasoactive neuropeptide autoimmune disorders which may include chronic fatigue syndrome (CFS), Gulf War syndrome (GWS) and even sudden infant death syndrome (SIDS).

Topics: Adenosine Triphosphate; Adenylyl Cyclases; Autoimmune Diseases; Calcitonin Gene-Related Peptide; Cyclic AMP; Fatigue Syndrome, Chronic; Genetic Variation; Humans; Infant; Models, Biological; Nerve Growth Factors; Neuropeptides; Neurotransmitter Agents; Oligopeptides; Persian Gulf Syndrome; Pituitary Adenylate Cyclase-Activating Polypeptide; Protein Conformation; Protein Structure, Secondary; Receptors, G-Protein-Coupled; Sudden Infant Death; Vasoactive Intestinal Peptide

Sudden infant death syndrome (SIDS) remains a perplexing diagnosis with conflicting laboratory investigation and lack of a biologically plausible aetiology. Investigations into the endogenous vasoactive neuropeptides, including pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) are revealing the critical role these substances have in homeostasis including thermo- and cardiovascular regulation. For example, studies in PACAP receptor-deficient mice have revealed sudden neonatal death attributed to respiratory control defects, possibly due to mutations in genes encoding components of PACAP signalling pathways. PACAP and VIP belong to the secretin/glucagon superfamily of hormones and function as vasoactive neuropeptides. They act as hormones, neurotransmitters, immune modulators and neurotrophes. They are readily catalysed to small peptide fragments. They and their binding sites are immunogenic and are known to be associated with a range of autoimmune conditions. Vasoactive neuropeptides have a known role in thermoregulation and deficiency states are associated with higher neonatal death rates in rats. PACAP plays a significant role in carbohydrate and lipid metabolism and impairment of functioning has potentially serious consequences. It is postulated PACAP and VIP receptors in brain may become compromised through autoimmune phenomena resulting in cardio-respiratory dysfunction and death. This paper discusses the potential role of certain vasoactive neuropeptides in causing autoimmune responses in susceptible infants predisposing them to SIDS.

Topics: Autoimmune Diseases; Autoimmunity; Humans; Immunity, Innate; Infant; Infant, Newborn; Models, Immunological; Neuroimmunomodulation; Neuropeptides; Nitric Oxide; Pituitary Adenylate Cyclase-Activating Polypeptide; Sudden Infant Death; Vasoactive Intestinal Peptide; Vasoconstrictor Agents; Vasodilator Agents

Gulf War Syndrome (GWS) remains a contentious diagnosis with conflicting laboratory investigation and lack of a biologically plausible aetiology. This paper discusses the potential role of maxadilan, a potent sandfly vasoactive peptide, in causing autoimmune responses in susceptible individuals through possible molecular mimicry with pituitary adenylate cyclase activating polypeptide (PACAP) and the PAC1R receptor. Gulf War Syndrome may share some causative pathology with Chronic Fatigue Syndrome (CFS), a disorder characterised by prolonged fatigue and debility mostly associated with post-infection sequelae although ongoing infection is unproven. Immunological aberration associated with an expanding group of vasoactive neuropeptides in the context of molecular mimicry and inappropriate immunological memory has been recently raised as possible cause of CFS. Vasoactive neuropeptides act as hormones, neurotransmitters, immune modulators and neurotrophes. They are readily catalysed to small peptide fragments. They and their binding sites are immunogenic and are known to be associated with a range of autoimmune conditions. Maxadilan, while not sharing substantial sequence homology with PACAP is a known agonist of the PACAP specific receptor (PAC1R) and therefore emulates these functions. Moreover a specific amino acid sequence peptide deletion within maxadilan converts it to a PACAP receptor antagonist raising the possibility of this substance provoking a CFS like response in humans exposed to it. This paper describes a biologically plausible mechanism for the development of a GWS-like chronic fatigue state based on loss of immunological tolerance to the vasoactive neuropeptide PACAP or its receptor following bites of the sandfly Phlebotomus papatasi and injection of the vasodilator peptide maxadilan. Exacerbation of this autoimmune response as a consequence of recent or simultaneous multiple vaccination exposures deserves further investigation. While the possible association between the relatively recently discovered vasoactive neuropeptides and chronic fatigue conditions has only recently been reported in the literature, this paper explores links for further research into GWS and CFS.

Topics: Autoimmune Diseases; Autoimmunity; Humans; Immunity, Innate; Insect Proteins; Models, Immunological; Molecular Mimicry; Neuroimmunomodulation; Neuropeptides; Persian Gulf Syndrome; Pituitary Adenylate Cyclase-Activating Polypeptide; Vasoactive Intestinal Peptide; Vasoconstrictor Agents; Vasodilator Agents

Fibromyalgia (FM) is a disorder characterised by soft tissue pain, disturbance of function an often prolonged course and variable fatigue and debility. A clearly defined aetiology has not been described. This paper proposes that immunological aberration is likely and this may prove to be associated with an expanding group of novel vasoactive neuropeptides. Vasoactive neuropeptides act as hormones, neurotransmitters, immune modulators and neurotrophes. They are readily catalysed to small peptide fragments. They and their binding sites are immunogenic and are known to be associated with a range of autoimmune conditions. They have a vital role in maintaining vascular flow in organs, and in thermoregulation, memory and concentration. They are co-transmitters for acetylcholine, are potent immune regulators with primarily anti-inflammatory activity, and have a significant role in protection of the nervous system to toxic assault and the maintenance of homeostasis. Failure of these substances has adverse consequences for homeostasis. This paper describes a biologically plausible mechanism for the development of FM based on loss of immunological tolerance to the vasoactive neuropeptides. The proposed mechanism of action is that inflammatory cytokines are provoked by tissue injury from unaccustomed exercise or physical injury. This may trigger a response by certain vasoactive neuropeptides which then undergo autoimmune dysfunction as well as affecting their receptor binding sites. The condition may potentially arise de novo perhaps in genetically susceptible individuals. FM is postulated to be an autoimmune disorder and may include dysfunction of purine nucleotide metabolism and nociception.

Topics: Autoimmune Diseases; Autoimmunity; Fibromyalgia; Humans; Immunity, Innate; Models, Immunological; Neuroimmunomodulation; Neuropeptides; Pituitary Adenylate Cyclase-Activating Polypeptide; Vasoactive Intestinal Peptide; Vasoconstrictor Agents; Vasodilator Agents

Vasoactive intestinal peptide (VIP), a neuropeptide that is known to be present in lymphoid tissue microenvironments, shows prominent anti-inflammatory actions.. To examine the potential effect of VIP on the development of experimental autoimmune uveoretinitis (EAU).. We immunized C57BL/6 mice with human interphotoreceptor retinoid-binding protein peptide 1-20 (h-IRBP peptide). Vasoactive intestinal peptide was administered intraperitoneally on alternate days until day 21 after immunization (entire group). In some cases, VIP was injected at different time points after the induction of immunity with h-IRBP peptide (efferent group). In each experiment, a control group of mice was injected with phosphate-buffered saline instead of VIP. Development of EAU was evaluated by means of histological examination on day 21 after immunization. Furthermore, we determined whether intravenous injection of peritoneal exudate cells cultured with VIP overnight in vitro abrogated EAU. We analyzed delayed hypersensitivity for h-IRBP peptide and the occurrence and severity of EAU using evaluation of histopathological sections for inflammatory ocular disease.. Treatment with VIP suppressed the expression of delayed hypersensitivity responses to h-IRBP peptide significantly (positive control vs entire group, P =.02; positive control vs efferent group, P<.001). Mice treated with VIP (n = 10) showed a lower occurrence (40%) and decreased severity of EAU (entire group mean score, 0.3; median score, 0) compared with untreated mice (occurrence, 80%; mean score, 0.85; median score, 0.75), as assessed by histopathological analyses (P =.049). Suppressive effects of VIP on EAU were also observed, even when VIP was administered on days 8 through 20 after immunization (efferent group [n = 9] occurrence, 11%; mean score, 0.1; median score, 0) (P =.003). Moreover, expression of EAU was significantly suppressed when the animals were pretreated with peritoneal exudate cells pulsed with h-IRBP in the presence of VIP (control mean score, 1.2; median score, 1.0; occurrence, 80% [n = 10]) compared with the VIP-treatment group (mean score, 0.3; median score, 0; occurrence, 30% [n = 10]) (P =.004). In addition, VIP-treated peritoneal exudate cells generated regulator T cells in the spleens of recipient mice that were able to interfere with the development of EAU (control group mean score, 0.5; median score, 0.5; occurrence, 63% [n = 8]) compared with the VIP-treatment group (mean score, 0.08; median score, 0; occurrence, 17% [n = 6]) (P =.08).. Treatment with VIP is a highly effective therapy to suppress EAU.. As a result of its efficacy in preventing EAU, VIP might be considered as a novel therapeutic modality for human uveitis.

Topics: Animals; Autoimmune Diseases; Eye Proteins; Female; Hypersensitivity, Delayed; Injections, Intraperitoneal; Mice; Mice, Inbred C57BL; Peptides; Peritoneal Cavity; Retinitis; Retinol-Binding Proteins; Specific Pathogen-Free Organisms; Spleen; T-Lymphocytes; Uveitis; Vasoactive Intestinal Peptide

Topics: Autoimmune Diseases; Autoimmunity; Humans; Immunity, Innate; Insect Proteins; Models, Immunological; Molecular Mimicry; Nerve Growth Factors; Neuroimmunomodulation; Neuropeptides; Neurotransmitter Agents; Persian Gulf Syndrome; Pituitary Adenylate Cyclase-Activating Polypeptide; Vasoactive Intestinal Peptide; Vasoconstrictor Agents; Vasodilator Agents

The immunoregulatory neuropeptide vasoactive intestinal peptide (VIP) was cleaved by purified IgG from Fas-defective C3H/gld mice, lupus patients, and autoimmune thyroiditis patients. No VIPase activity was detected in IgG from control mice and humans. Kinetic analyses of VIPase IgG preparations suggested low-affinity recognition of VIP. Yet the VIPase activity was VIP selective, judged by lack of correlation with other protease activities expressed by the IgG and by noninterference of unrelated peptides in the activity. Recombinant Fv constructs selected from a human lupus phage show library displayed VIPase activity, confirming that the active site is located in the V domains. Inhibition of the VIPase activity by di-isopropylfluorophosphate suggested a serine protease-like mechanism of catalysis. Irreversible binding of a biotinyated phosphonate diester by the IgG and Fv preparations was observed, consistent with the presence of activated nucleophiles similar to those in enzymes capable of covalent catalysis. These observations show that VIP is a target for specific catalytic autoantibodies in autoimmune disease.

Topics: Animals; Autoantibodies; Autoimmune Diseases; Catalysis; Cloning, Molecular; fas Receptor; Humans; Hydrolysis; Immunoglobulin Fragments; Immunoglobulin G; Lupus Erythematosus, Systemic; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Molecular Sequence Data; Mutation; Oligopeptides; Thyroglobulin; Thyroiditis, Autoimmune; Vasoactive Intestinal Peptide

The salivary glands of non-obese diabetic (NOD) mice and BALB/c controls were evaluated for the stimulatory effects of the following neuropeptides; substance P (SP), vasoactive intestinal polypeptide (VIP), and neuropeptide Y (NPY). Injection of either of the three neuropeptides in combination with the muscarinic-cholinergic agonist pilocarpine increased saliva flow rates in BALB/c mice while there was no observable augmentation to flow rates in pre-diabetic or diabetic NOD mice. Small increases in protein content of the stimulated saliva were observed in the BALB/c group of animals with the injection of any of the above neuropeptides in combination with pilocarpine. In pre-diabetic NOD animals, only VIP and NPY increased the protein content-ratio above pilocarpine alone. Radioimmunoassay determination of neuropeptide concentrations in the submandibular and parotid glands revealed reduced levels of SP with diabetes onset as compared with pre-diabetic NOD or BALB/c mice. The levels of NPY were similar between BALB/c and NOD animals except in the pre-diabetic parotid gland where NPY concentrations were 1.3-fold greater. On the other hand, VIP concentrations were substantially reduced in the submandibular gland of NOD mice, while in the parotid gland neuropeptide levels were evaluated 3.8-fold relative to BALB/c controls. Immunohistochemical staining of the parotid and submandibular glands for SP revealed primarily ductal cell staining which was reduced with diabetes onset in NOD animals. These findings further define the sialoadenitis observed in NOD mice to be due, in part, to a general loss of neurotransmitter responsiveness on the part of salivary gland cells.

Topics: Animals; Autoimmune Diseases; Disease Models, Animal; Mice; Mice, Inbred BALB C; Mice, Inbred NOD; Neuropeptide Y; Neuropeptides; Salivary Glands; Sialadenitis; Substance P; Vasoactive Intestinal Peptide