IBD immunopathogenesis: A comprehensive review of inflammatory molecules.
TL;DR: The roles of numerous inflammatory molecules including but not limited to cytokines, chemokines, inflammasomes, microRNAs and neuropeptides and their expression status in ulcerative colitis and Crohn's disease are discussed in relation to their effects on the overall intestinal inflammatory process.
About: This article is published in Autoimmunity Reviews.The article was published on 2017-04-01. It has received 207 citations till now. The article focuses on the topics: Inflammatory bowel disease & Ulcerative colitis.
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TL;DR: In this paper, the authors explore the current knowledge about distinct signalling cascades resulting from self TLR activation and highlight the involvement of endogenous TLR activators in disease and highlight how specifically targeting DAMPs may yield therapies that do not globally suppress the immune system.
Abstract: Damage-associated molecular patterns (DAMPs) include endogenous intracellular molecules released by activated or necrotic cells and extracellular matrix (ECM) molecules that are upregulated upon injury or degraded following tissue damage. DAMPs are vital danger signals that alert our immune system to tissue damage upon both infectious and sterile insult. DAMP activation of Toll-like receptors (TLRs) induces inflammatory gene expression to mediate tissue repair. However, DAMPs have also been implicated in diseases where excessive inflammation plays a key role in pathogenesis, including rheumatoid arthritis (RA), cancer, and atherosclerosis. TLR activation by DAMPs may initiate positive feedback loops where increasing tissue damage perpetuates pro-inflammatory responses leading to chronic inflammation. Here we explore the current knowledge about distinct signalling cascades resulting from self TLR activation. We also discuss the involvement of endogenous TLR activators in disease and highlight how specifically targeting DAMPs may yield therapies that do not globally suppress the immune system.
724 citations
TL;DR: This study determined how TSLP contributes to allergic disease pathogenesis by performing studies in mice and human studies with the use of basophils from patients with eosinophilic esophagitis or from healthy controls.
Abstract: MC Siracusa, SA Saenz, DA Hill. Nature. 2011;477(7363):229–233
Allergic diseases involve epithelial surfaces, and the epithelial cytokine thymic stromal lymphopoietin (TSLP) has been described as the “master switch” for allergic inflammation. The purpose of this study was to determine how TSLP contributes to allergic disease pathogenesis.
Most studies were performed in mice. Human studies were performed with the use of basophils from patients with eosinophilic esophagitis or from healthy controls.
TSLP-treated mice were evaluated for changes in circulating immune cells and cytokine secretion. The effect of tissue-specific TSLP production …
204 citations
TL;DR: This extensive review of JAK inhibitors presents evidence- or hypothesis-based perspectives for these drugs in various rheumatologic conditions, such as r heumatoid arthritis, systemic lupus erythematosus, giant cell arteritis, and autoinflammatory diseases.
171 citations
TL;DR: Clinical evidence regarding the safety, barriers to engagement, and impact of physical activity on autoimmune diseases is reviewed, showing physical activity has been shown to be safe in most of autoimmune diseases.
167 citations
Cites background from "IBD immunopathogenesis: A comprehen..."
...[216] found no association between physical activity and the risk of developing UC [217]....
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...IBD patients are predisposed to the development of colon cancer development and therefore follow up is advised [215,216]....
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TL;DR: The evidence presented in this review supports HS as an auto-inflammatory skin disorder associated with alterations in the innate immune system and further research is warranted to ultimately improve the management and treatment of patients with HS and related syndromic conditions.
Abstract: Background: The pathogenesis of hidradenitis suppurativa (HS) is not fully understood. This systematic review examined the latest evidence for molecular inflammatory pathways involved in HS as a chronic inflammatory skin disease. Methods: A systematic literature search was performed in PubMed/Medline and EMBASE from January 2013 through September 2017, according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA). Findings on HS pathogenesis were also compared with those of other immune-mediated inflammatory diseases (IMIDs) in a non-systematic review. In addition, current therapeutic options for HS are briefly discussed on the basis of the findings for the inflammatory pathways involved in HS. Results: A total of 32 eligible publications were identified by the systematic search; these were supplemented with three additional publications. The extracted data indicated that four key themes underlie the pathogenesis of HS and related syndromic conditions. First, nicastrin (NCSTN) and PSTPIP1 mutations are directly associated with auto-inflammatory disease. Secondly, the up-regulation of several cytokines including tumor necrosis factor-α and T helper-17/interleukin-23 are connected to auto-inflammatory mechanisms in the pathogenesis of HS. Thirdly, the microbiome of lesional skin differs significantly vs. normal-appearing skin. Fourthly, HS risk is enhanced through physiological and environmental factors such as smoking, obesity, and mechanical friction. There is significant overlap between the pathogenesis of HS, its syndromic forms and other IMIDs, particularly with respect to aberrations in the innate immune response. Conclusions: The evidence presented in this review supports HS as an auto-inflammatory skin disorder associated with alterations in the innate immune system. Based on these most recent data, an integrative viewpoint is presented on the pathogenesis of HS. Current management strategies on HS consist of anti-inflammatory therapies, surgical removal of chronic lesions, and lifestyle changes such as smoking cessation and weight loss. As large gaps remain in the understanding of the pathogenesis of HS, further research is warranted to ultimately improve the management and treatment of patients with HS and related syndromic conditions.
131 citations
References
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TL;DR: Transcript expression in perigonadal adipose tissue from groups of mice in which adiposity varied due to sex, diet, and the obesity-related mutations agouti (Ay) and obese (Lepob) found that the expression of 1,304 transcripts correlated significantly with body mass.
Abstract: Obesity alters adipose tissue metabolic and endocrine function and leads to an increased release of fatty acids, hormones, and proinflammatory molecules that contribute to obesity associated complications. To further characterize the changes that occur in adipose tissue with increasing adiposity, we profiled transcript expression in perigonadal adipose tissue from groups of mice in which adiposity varied due to sex, diet, and the obesity-related mutations agouti (Ay) and obese (Lepob). We found that the expression of 1,304 transcripts correlated significantly with body mass. Of the 100 most significantly correlated genes, 30% encoded proteins that are characteristic of macrophages and are positively correlated with body mass. Immunohistochemical analysis of perigonadal, perirenal, mesenteric, and subcutaneous adipose tissue revealed that the percentage of cells expressing the macrophage marker F4/80 (F4/80+) was significantly and positively correlated with both adipocyte size and body mass. Similar relationships were found in human subcutaneous adipose tissue stained for the macrophage antigen CD68. Bone marrow transplant studies and quantitation of macrophage number in adipose tissue from macrophage-deficient (Csf1op/op) mice suggest that these F4/80+ cells are CSF-1 dependent, bone marrow-derived adipose tissue macrophages. Expression analysis of macrophage and nonmacrophage cell populations isolated from adipose tissue demonstrates that adipose tissue macrophages are responsible for almost all adipose tissue TNF-alpha expression and significant amounts of iNOS and IL-6 expression. Adipose tissue macrophage numbers increase in obesity and participate in inflammatory pathways that are activated in adipose tissues of obese individuals.
8,902 citations
"IBD immunopathogenesis: A comprehen..." refers background in this paper
...shown to produce higher levels of soluble mediators such as adiponectin, leptin, resitin, and macrophage colony-stimulating factor (M-CSF) and aggravate IBD via increased obesityrelated chronic inflammation [62-64]....
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TL;DR: Patient stratification by GI microbiota provides further evidence that CD represents a spectrum of disease states and suggests that treatment of some forms of IBD may be facilitated by redress of the detected microbiological imbalances.
Abstract: The two primary human inflammatory bowel diseases, Crohn's disease (CD) and ulcerative colitis (UC), are idiopathic relapsing disorders characterized by chronic inflammation of the intestinal tract. Although several lines of reasoning suggest that gastrointestinal (GI) microbes influence inflammatory bowel disease (IBD) pathogenesis, the types of microbes involved have not been adequately described. Here we report the results of a culture-independent rRNA sequence analysis of GI tissue samples obtained from CD and UC patients, as well as non-IBD controls. Specimens were obtained through surgery from a variety of intestinal sites and included both pathologically normal and abnormal states. Our results provide comprehensive molecular-based analysis of the microbiota of the human small intestine. Comparison of clone libraries reveals statistically significant differences between the microbiotas of CD and UC patients and those of non-IBD controls. Significantly, our results indicate that a subset of CD and UC samples contained abnormal GI microbiotas, characterized by depletion of commensal bacteria, notably members of the phyla Firmicutes and Bacteroidetes. Patient stratification by GI microbiota provides further evidence that CD represents a spectrum of disease states and suggests that treatment of some forms of IBD may be facilitated by redress of the detected microbiological imbalances.
3,967 citations
"IBD immunopathogenesis: A comprehen..." refers background in this paper
...Sequence analysis of 16s rDNA revealed reduction in Firmicutes and Bacteroidetes and increase in Actinobacteria and Proteobacteria in UC [145, 146]....
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TL;DR: The authors showed that colonisation of mice with a segmented filamentous bacterium (SFB) is sufficient to induce the appearance of CD4+ T helper cells that produce IL-17 and IL-22 (Th17 cells) in the lamina propria.
3,860 citations
"IBD immunopathogenesis: A comprehen..." refers background in this paper
...cell-associated cytokines such as IL-17A and IL-17F in response to upregulated levels of IL6 and IL-23 upon stimulation by microbiota [89-92]....
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TL;DR: The results suggest that counterbalancing dysbiosis using F. prausnitzii as a probiotic is a promising strategy in CD treatment and exhibits anti-inflammatory effects on cellular and TNBS colitis models, partly due to secreted metabolites able to block NF-κB activation and IL-8 production.
Abstract: A decrease in the abundance and biodiversity of intestinal bacteria within the dominant phylum Firmicutes has been observed repeatedly in Crohn disease (CD) patients. In this study, we determined the composition of the mucosa-associated microbiota of CD patients at the time of surgical resection and 6 months later using FISH analysis. We found that a reduction of a major member of Firmicutes, Faecalibacterium prausnitzii, is associated with a higher risk of postoperative recurrence of ileal CD. A lower proportion of F. prausnitzii on resected ileal Crohn mucosa also was associated with endoscopic recurrence at 6 months. To evaluate the immunomodulatory properties of F. prausnitzii we analyzed the anti-inflammatory effects of F. prausnitzii in both in vitro (cellular models) and in vivo [2,4,6-trinitrobenzenesulphonic acid (TNBS)-induced] colitis in mice. In Caco-2 cells transfected with a reporter gene for NF-kappaB activity, F. prausnitzii had no effect on IL-1beta-induced NF-kappaB activity, whereas the supernatant abolished it. In vitro peripheral blood mononuclear cell stimulation by F. prausnitzii led to significantly lower IL-12 and IFN-gamma production levels and higher secretion of IL-10. Oral administration of either live F. prausnitzii or its supernatant markedly reduced the severity of TNBS colitis and tended to correct the dysbiosis associated with TNBS colitis, as demonstrated by real-time quantitative PCR (qPCR) analysis. F. prausnitzii exhibits anti-inflammatory effects on cellular and TNBS colitis models, partly due to secreted metabolites able to block NF-kappaB activation and IL-8 production. These results suggest that counterbalancing dysbiosis using F. prausnitzii as a probiotic is a promising strategy in CD treatment.
3,653 citations
"IBD immunopathogenesis: A comprehen..." refers background in this paper
...prausnitzii was found to correlate with the severity of inflammation in TNBS-induced colitis mice model [144]....
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...prausnitzzi was also found in active UC [144]....
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TL;DR: T-bet initiates Th1 lineage development from naive Thp cells both by activating Th1 genetic programs and by repressing the opposing Th2 programs, as evidenced by the simultaneous induction of IFNgamma and repression of IL-4 and IL-5.
3,479 citations
"IBD immunopathogenesis: A comprehen..." refers background in this paper
...Subsequent studies have also found that the NKp46+ ILC1 subset is dependent on signaling by T-bet, which is a crucial transcriptional regulator of Th1 cells and Th1 cytokines such as TNF and IFN- [114, 118]....
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...based on defining transcription factors and releasing cytokines [114]....
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...cells and Th1 cytokines such as TNF and IFN- [114, 118]....
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