The lymphatic vasculature has been regarded as a passive conduit for interstitial fluid and responsible for the absorption of macromolecules such as proteins or lipids and transport of nutrients from food. However, emerging data show that the lymphatic vasculature system plays an important role in immune modulation. One of its major roles is to coordinate antigen transport and immune-cell trafficking from peripheral tissues to secondary lymphoid organs, lymph nodes. This perspective was recently updated with the notion that the interaction between lymphatic endothelial cells and leukocytes controls the immune-cell migration and immune responses by regulating lymphatic flow and various secreted molecules such as chemokines and cytokines. In this review, we introduce the lymphatic vasculature networks and genetic transgenic models for research on the lymphatic vasculature system. Next, we discuss the contribution of lymphatic endothelial cells to the control of immune-cell trafficking and to maintenance of peripheral tolerance. Finally, the physiological roles and features of the lymphatic vasculature system are further discussed regarding inflammation-induced lymphangiogenesis in a pathological condition, especially in mucosal tissues such as the gastrointestinal tract and respiratory tract.
Absorption ; Chemokines ; Cytokines ; Endothelial Cells ; Endothelium ; Extracellular Fluid ; Gastrointestinal Tract ; Leukocytes ; Lymph Nodes ; Lymphangiogenesis ; Mucous Membrane ; Peripheral Tolerance ; Respiratory System

Chronic rhinosinusitis (CRS) is one of the most common presentations of upper airway illness and severely affects patient quality of life. Its frequency is not surprising given levels of environmental exposure to microbes, pollutants, and allergens. Inflammatory cells, inflammatory cytokine and chemokine production, and airway remodeling have been detected in the sinonasal mucosae of CRS patients, although the precise pathophysiological mechanisms causing such persistent inflammation remain unclear. Given its high prevalence and considerable associated morbidity, continued research into CRS is necessary to increase our understanding of factors likely to contribute to its pathogenesis, and facilitate the development of novel therapeutic strategies to improve treatment. The purpose of this review is to summarize the current state of knowledge regarding immune cell responses and epithelial alterations in CRS.
Airway Remodeling ; Allergens ; Cytokines ; Environmental Exposure ; Eosinophils ; Epithelial-Mesenchymal Transition ; Humans ; Inflammation ; Mucous Membrane ; Nasal Mucosa ; Nasal Polyps ; Prevalence ; Quality of Life

Complex communities of microorganisms, termed commensal microbiota, inhabit mucosal surfaces and profoundly influence host physiology as well as occurrence of allergic diseases. Perturbing factors such as the mode of delivery, dietary fibers and antibiotics can influence allergic diseases by altering commensal microbiota in affected tissues as well as in intestine. Here, we review current findings on the relationship between commensal microbiota and allergic diseases, and discuss the underlying mechanisms that contribute to the regulation of allergic responses by commensal microbiota.
Anti-Bacterial Agents ; Asthma ; Dermatitis, Atopic ; Dietary Fiber ; Food Hypersensitivity ; Hygiene* ; Intestines ; Microbiota* ; Physiology

Eosinophils are potent effector cells implicated in allergic responses and helminth infections. Responding to stimuli, they release their granule-derived cytotoxic proteins and are involved in inflammatory processes. However, under homeostatic conditions, eosinophils are abundantly present in the intestine and are constantly in contact with the gut microbiota and maintain the balance of immune responses without inflammation. This situation indicates that intestinal eosinophils have an anti-inflammatory function unlike allergic eosinophils. In support of this notion, some papers have shown that eosinophils have different phenotypes depending on the site of residence and are a heterogeneous cell population. Recently, it was reported that eosinophils in the small intestine and adipose tissue, respectively, contribute to homeostasis of intestinal immune responses and metabolism. Accordingly, in this review, we summarize new functions of eosinophils demonstrated in recent studies and discuss their homeostatic functions.
Adipose Tissue ; Eosinophils* ; Gastrointestinal Microbiome ; Helminths ; Homeostasis ; Immunoglobulin A ; Inflammation* ; Interleukin-4 ; Intestine, Small ; Intestines ; Metabolism ; Phenotype ; Th17 Cells

Inflammatory bowel disease (IBD) is a chronic intestinal inflammatory disorder with an unknown etiology. IBD is composed of two different disease entities: Crohn's disease (CD) and ulcerative colitis (UC). IBD has been thought to be idiopathic but has two main attributable causes that include genetic and environmental factors. The gastrointestinal tract in which this disease occurs is central to the immune system, and the innate and the adaptive immune systems are balanced in complex interactions with intestinal microbes under homeostatic conditions. However, in IBD, this homeostasis is disrupted and uncontrolled intestinal inflammation is perpetuated. Recently, the pathogenesis of IBD has become better understood owing to advances in genetic and immunologic technology. Moreover, new therapeutic strategies are now being implemented that accurately target the pathogenesis of IBD. Beyond conventional immunesuppressive therapy, the development of biological agents that target specific disease mechanisms has resulted in more frequent and deeper remission in IBD patients, with mucosal healing as a treatment goal of therapy. Future novel biologics should overcome the limitations of current therapies and ensure that individual patients can be treated with optimal drugs that are safe and precisely target IBD.
Biological Factors ; Biological Products ; Biological Therapy* ; Colitis ; Colitis, Ulcerative ; Crohn Disease ; Gastrointestinal Tract ; Homeostasis ; Humans ; Immune System ; Inflammation ; Inflammatory Bowel Diseases*

A symbiotic relationship between humans and the microbiota is critical for the maintenance of our health, including development of the immune system, enhancement of the epithelial barrier, and acquisition of nutrients. Recent research has shown that the microbiota impacts immune cell development and differentiation. These findings suggest that the microbiota may also influence adjuvant and vaccine efficacy. Indeed, several factors such as malnutrition and poor sanitation, which affect gut microbiota composition, impair the efficacy of vaccines. Although there is little evidence that microbiota alters vaccine efficacy, further understanding of human immune system-microbiota interactions may lead to the effective development of adjuvants and vaccines for the treatment of diseases.
Gastrointestinal Microbiome ; Humans ; Immune System ; Malnutrition ; Microbiota* ; Sanitation ; Vaccines

Vitamins are micronutrients which are essential for the maintenance of biological responses including immune system. Hence, vitamin deficiency increases a risk of infectious, allergic, and inflammatory diseases. Accumulating evidence has recently revealed the molecular and cellular mechanisms of vitamin-mediated regulation in the active and quiescent immune responses. In this review, we focus on the immunologic roles of vitamins in the regulation of homeostasis and surveillance in the gut.
Avitaminosis ; Energy Metabolism ; Homeostasis* ; Immune System ; Immunoglobulin A ; Inflammation ; Micronutrients ; Monitoring, Immunologic* ; Vitamins*

A vast community of commensal microorganisms, commonly referred to as the gut microbiota, colonizes the gastrointestinal tract (GI). The involvement of the gut microbiota in the maintenance of the gut ecosystem is two-fold: it educates host immune cells and protects the host from pathogens. However, when healthy microbial composition and function are disrupted (dysbiosis), the dysbiotic gut microbiota can trigger the initiation and development of various GI diseases, including inflammatory bowel disease (IBD). IBD, primarily includes ulcerative colitis (UC) and Crohn's disease (CD), is a major global public health problem affecting over 1 million patients in the United States alone. Accumulating evidence suggests that various environmental and genetic factors contribute to the pathogenesis of IBD. In particular, the gut microbiota is a key factor associated with the triggering and presentation of disease. Gut dysbiosis in patients with IBD is defined as a reduction of beneficial commensal bacteria and an enrichment of potentially harmful commensal bacteria (pathobionts). However, as of now it is largely unknown whether gut dysbiosis is a cause or a consequence of IBD. Recent technological advances have made it possible to address this question and investigate the functional impact of dysbiotic microbiota on IBD. In this review, we will discuss the recent advances in the field, focusing on host-microbial cross-talk in IBD.
Bacteria ; Colitis, Ulcerative ; Colon ; Crohn Disease ; Dysbiosis ; Ecosystem ; Gastrointestinal Microbiome ; Gastrointestinal Tract ; Humans ; Inflammatory Bowel Diseases* ; Microbiota ; Public Health ; United States

BACKGROUND: Stromal cell-derived factor (SDF)-1 is a potent chemoattractant for activated T cells into the inflamed Rheumatoid arthritis (RA) synovium. To determine the effect of macrophage migration inhibitory factor (MIF) on the production of SDF-1 in the inflamed RA synovium. METHODS: The expression of SDF-1 and MIF in RA and Osteoarthritis (OA) synovium was examined by immunohistochemical staining. The SDF-1 was quantified by RT-PCR and ELISA after RA fibroblast like synoviocyte (FLS) were treated with MIF in the presence and absence of inhibitors of intracellular signal molecules. The synovial fluid (SF) and serum levels of MIF and SDF-1 in RA, OA and healthy control were measured by ELISA. RESULTS: Expression of SDF-1 and MIF in synovium was higher in RA patients than in OA patients. The production of SDF-1 was enhanced in RA FLS by MIF stimulation. Such effect of MIF was blocked by the inhibitors of NF-kappaB. Concentrations of SDF-1 in the serum and SF were higher in RA patients than in OA patients and healthy control. SDF-1 and MIF was overexpressed in RA FLS, and MIF could up-regulate the production of SDF-1 in RA FLS via NF-kappaB- mediated pathways. CONCLUSION: These results suggest that an inhibition of interaction between MIF from T cells and SDF-1 of FLS may provide a new therapeutic approach in the treatment of RA.
Arthritis, Rheumatoid* ; Chemokine CXCL12* ; Enzyme-Linked Immunosorbent Assay ; Fibroblasts* ; Humans ; Macrophages* ; NF-kappa B ; Osteoarthritis ; Synovial Fluid ; Synovial Membrane ; T-Lymphocytes

BACKGROUND: Mizoribine (MZR) is an imidazole nucleoside isolated from Eupenicillium brefeldianum. MZR is currently in clinical use for patients who have undergone renal transplantation. Therapeutic efficacy of MZR has also been demonstrated in rheumatoid arthritis and lupus nephritis. MZR has been shown to inhibit the proliferation of lymphocytes by interfering with inosine monophosphate dehydrogenase. Since the exact mechanism by which MZR benefits rheumatoid arthritis (RA) is not clear, we investigated the ability of MZR to direct its immunosuppressive influences on other antigen presenting cells, such as macrophages. METHODS: Mouse macrophage RAW264.7 cells were stimulated with lipopolysaccharide in the presence of MZR. To elucidate the mechanism of the therapeutic efficacy in chronic inflammatory diseases, we examined the effects of MZR on the production of pro-inflammatory cytokines, nitric oxide (NO) and prostaglandin E2 (PGE2) in macrophages. RESULTS: MZR dose-dependently decreased the production of nitric oxide and pro- inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha), interleukins 1beta (IL-beta) and IL-6 PGE2. Examination of gene expression levels showed that the anti-inflammatory effect correlated with the down-regulation of inducible nitiric oxide synthase expression, cycloxygenase-2 expression and TNF-alpha gene expression. CONCLUSION: In this work, we resulted whether MZR (1.25~10 microgram/ml) inhibited macrophage activation by inhibiting secretion of pro-inflammatory cytokines, NO and PGE2. These findings provide an explanation for the therapeutic efficacy of MZR in chronic inflammation- associated diseases.
Animals ; Antigen-Presenting Cells ; Arthritis, Rheumatoid ; Cytokines* ; Dinoprostone* ; Down-Regulation ; Eupenicillium ; Gene Expression ; Humans ; Inosine Monophosphate ; Interleukin-6 ; Interleukins ; Kidney Transplantation ; Lupus Nephritis ; Lymphocytes ; Macrophage Activation ; Macrophages* ; Mice ; Nitric Oxide ; Oxidoreductases ; Tumor Necrosis Factor-alpha