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BMJ (Clinical Research Ed.) Jan 2018The role of the gut microbiome in models of inflammatory and autoimmune disease is now well characterized. Renewed interest in the human microbiome and its metabolites,... (Review)
Review
The role of the gut microbiome in models of inflammatory and autoimmune disease is now well characterized. Renewed interest in the human microbiome and its metabolites, as well as notable advances in host mucosal immunology, has opened multiple avenues of research to potentially modulate inflammatory responses. The complexity and interdependence of these diet-microbe-metabolite-host interactions are rapidly being unraveled. Importantly, most of the progress in the field comes from new knowledge about the functional properties of these microorganisms in physiology and their effect in mucosal immunity and distal inflammation. This review summarizes the preclinical and clinical evidence on how dietary, probiotic, prebiotic, and microbiome based therapeutics affect our understanding of wellness and disease, particularly in autoimmunity.
Topics: Autoimmune Diseases; Fecal Microbiota Transplantation; Feeding Behavior; Gastrointestinal Microbiome; Humans; Inflammation; Inflammatory Bowel Diseases; Microbiota; Mucous Membrane; Prebiotics; Probiotics
PubMed: 29311119
DOI: 10.1136/bmj.j5145 -
Seminars in Cancer Biology Apr 2020Mucosal melanoma is a rare and aggressive subtype of melanoma that has a less favorable prognosis due to the lack of understanding and identification of oncogenic... (Review)
Review
Mucosal melanoma is a rare and aggressive subtype of melanoma that has a less favorable prognosis due to the lack of understanding and identification of oncogenic drivers. Recently, whole genome and whole exome sequencing have unveiled the molecular landscape and potential oncogenic drivers of mucosal melanoma, which remains distinct from cutaneous melanoma. In this review, we provide an overview of the genomic landscape of mucosal melanoma, with a focus on molecular studies identifying potential oncogenic drivers allowing for a better mechanistic understanding of the biology of mucosal melanoma. We summarized the published genomics and clinical data supporting the observations that mucosal melanoma harbors distinct genetic alterations and oncogenic drivers from cutaneous melanoma, and thus should be treated accordingly. The common drivers (BRAF and NRAS) found in cutaneous melanoma have lower mutation rate in mucosal melanoma. In contrast, SF3B1 and KIT have higher mutation rate in mucosal melanoma as compared to cutaneous melanoma. From the meta-analysis, we also observed that the mutational profiles are slightly different between the "upper" and "lower" regions of mucosal melanoma, providing new insights and therapeutic options for the mucosal melanoma patients. Mutations identified in mucosal melanoma should be incorporated into routine clinical testing, as there are targeted therapies already developed for treating patients with these mutations in the precision medicine era.
Topics: Alternative Splicing; Biomarkers, Tumor; Combined Modality Therapy; Gene Expression Regulation, Neoplastic; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Melanocytes; Melanoma; Molecular Targeted Therapy; Mucous Membrane; Mutation; Oncogenes; Precision Medicine; Prognosis; Signal Transduction
PubMed: 31655118
DOI: 10.1016/j.semcancer.2019.09.013 -
Nature Reviews. Cancer Oct 2017Metaplasia is the replacement of one differentiated somatic cell type with another differentiated somatic cell type in the same tissue. Typically, metaplasia is... (Review)
Review
Metaplasia is the replacement of one differentiated somatic cell type with another differentiated somatic cell type in the same tissue. Typically, metaplasia is triggered by environmental stimuli, which may act in concert with the deleterious effects of microorganisms and inflammation. The cell of origin for intestinal metaplasia in the oesophagus and stomach and for pancreatic acinar-ductal metaplasia has been posited through genetic mouse models and lineage tracing but has not been identified in other types of metaplasia, such as squamous metaplasia. A hallmark of metaplasia is a change in cellular identity, and this process can be regulated by transcription factors that initiate and/or maintain cellular identity, perhaps in concert with epigenetic reprogramming. Universally, metaplasia is a precursor to low-grade dysplasia, which can culminate in high-grade dysplasia and carcinoma. Improved clinical screening for and surveillance of metaplasia might lead to better prevention or early detection of dysplasia and cancer.
Topics: Adaptation, Biological; Animals; Barrett Esophagus; Epigenesis, Genetic; Epithelium; Gastric Mucosa; Humans; Intestinal Mucosa; Metaplasia; Mucous Membrane; Respiratory Mucosa; Transcription Factors
PubMed: 28860646
DOI: 10.1038/nrc.2017.68 -
Cold Spring Harbor Perspectives in... Jan 2018Mucosal surfaces are lined by epithelial cells. In the intestine, the epithelium establishes a selectively permeable barrier that supports nutrient absorption and waste... (Review)
Review
Mucosal surfaces are lined by epithelial cells. In the intestine, the epithelium establishes a selectively permeable barrier that supports nutrient absorption and waste secretion while preventing intrusion by luminal materials. Intestinal epithelia therefore play a central role in regulating interactions between the mucosal immune system and luminal contents, which include dietary antigens, a diverse intestinal microbiome, and pathogens. The paracellular space is sealed by the tight junction, which is maintained by a complex network of protein interactions. Tight junction dysfunction has been linked to a variety of local and systemic diseases. Two molecularly and biophysically distinct pathways across the intestinal tight junction are selectively and differentially regulated by inflammatory stimuli. This review discusses the mechanisms underlying these events, their impact on disease, and the potential of using these as paradigms for development of tight junction-targeted therapeutic interventions.
Topics: Animals; Humans; Immunity, Mucosal; Interleukin-13; Intestinal Mucosa; Mucous Membrane; Myosin-Light-Chain Kinase; Permeability; Tight Junctions; Zonula Occludens-1 Protein
PubMed: 28507021
DOI: 10.1101/cshperspect.a029314 -
Immunity Jul 2015Type-2-cell-mediated immunity, rich in eosinophils, basophils, mast cells, CD4(+) T helper 2 (Th2) cells, and type 2 innate lymphoid cells (ILC2s), protects the host... (Review)
Review
Type-2-cell-mediated immunity, rich in eosinophils, basophils, mast cells, CD4(+) T helper 2 (Th2) cells, and type 2 innate lymphoid cells (ILC2s), protects the host from helminth infection but also drives chronic allergic diseases like asthma and atopic dermatitis. Barrier epithelial cells (ECs) represent the very first line of defense and express pattern recognition receptors to recognize type-2-cell-mediated immune insults like proteolytic allergens or helminths. These ECs mount a prototypical response made up of chemokines, innate cytokines such as interleukin-1 (IL-1), IL-25, IL-33, and thymic stromal lymphopoietin (TSLP), as well as the alarmins uric acid, ATP, HMGB1, and S100 proteins. These signals program dendritic cells (DCs) to mount Th2-cell-mediated immunity and in so doing boost ILC2, basophil, and mast cell function. Here we review the general mechanisms of how different stimuli trigger type-2-cell-mediated immunity at mucosal barriers and how this leads to protection or disease.
Topics: Animals; Chemokines; Cytokines; Dendritic Cells; Epithelial Cells; Helminthiasis; Humans; Hypersensitivity; Immunity, Cellular; Mucous Membrane; Th2 Cells; Tight Junctions
PubMed: 26200011
DOI: 10.1016/j.immuni.2015.07.007 -
Immunological Reviews Jul 2014The gastrointestinal tract is covered by mucus that has different properties in the stomach, small intestine, and colon. The large highly glycosylated gel-forming mucins... (Review)
Review
The gastrointestinal tract is covered by mucus that has different properties in the stomach, small intestine, and colon. The large highly glycosylated gel-forming mucins MUC2 and MUC5AC are the major components of the mucus in the intestine and stomach, respectively. In the small intestine, mucus limits the number of bacteria that can reach the epithelium and the Peyer's patches. In the large intestine, the inner mucus layer separates the commensal bacteria from the host epithelium. The outer colonic mucus layer is the natural habitat for the commensal bacteria. The intestinal goblet cells secrete not only the MUC2 mucin but also a number of typical mucus components: CLCA1, FCGBP, AGR2, ZG16, and TFF3. The goblet cells have recently been shown to have a novel gate-keeping role for the presentation of oral antigens to the immune system. Goblet cells deliver small intestinal luminal material to the lamina propria dendritic cells of the tolerogenic CD103(+) type. In addition to the gel-forming mucins, the transmembrane mucins MUC3, MUC12, and MUC17 form the enterocyte glycocalyx that can reach about a micrometer out from the brush border. The MUC17 mucin can shuttle from a surface to an intracellular vesicle localization, suggesting that enterocytes might control and report epithelial microbial challenge. There is communication not only from the epithelial cells to the immune system but also in the opposite direction. One example of this is IL10 that can affect and improve the properties of the inner colonic mucus layer. The mucus and epithelial cells of the gastrointestinal tract are the primary gate keepers and controllers of bacterial interactions with the host immune system, but our understanding of this relationship is still in its infancy.
Topics: Animals; Enterocytes; Gastrointestinal Tract; Goblet Cells; Humans; Immune System; Mucins; Mucous Membrane; Mucus; Peyer's Patches
PubMed: 24942678
DOI: 10.1111/imr.12182 -
Cell Jan 2016Proper adaptation to environmental perturbations is essential for tissue homeostasis. In the intestine, diverse environmental cues can be sensed by immune cells, which...
Proper adaptation to environmental perturbations is essential for tissue homeostasis. In the intestine, diverse environmental cues can be sensed by immune cells, which must balance resistance to microorganisms with tolerance, avoiding excess tissue damage. By applying imaging and transcriptional profiling tools, we interrogated how distinct microenvironments in the gut regulate resident macrophages. We discovered that macrophages exhibit a high degree of gene-expression specialization dependent on their proximity to the gut lumen. Lamina propria macrophages (LpMs) preferentially expressed a pro-inflammatory phenotype when compared to muscularis macrophages (MMs), which displayed a tissue-protective phenotype. Upon luminal bacterial infection, MMs further enhanced tissue-protective programs, and this was attributed to swift activation of extrinsic sympathetic neurons innervating the gut muscularis and norepinephrine signaling to β2 adrenergic receptors on MMs. Our results reveal unique intra-tissue macrophage specialization and identify neuro-immune communication between enteric neurons and macrophages that induces rapid tissue-protective responses to distal perturbations.
Topics: Animals; Cell Line; Intestinal Mucosa; Intestine, Small; Macrophages; Mice; Mucous Membrane; Neuroimmunomodulation; Neurons; Receptors, Adrenergic, beta-2; Salmonella Infections; Salmonella typhimurium; Specific Pathogen-Free Organisms
PubMed: 26777404
DOI: 10.1016/j.cell.2015.12.023 -
Biomolecules Oct 2022Anti-laminin (LM) 332-type mucous membrane pemphigoid (MMP) is a rare autoimmune bullous disease and was originally discovered as anti-epiligrin cicatricial pemphigoid.... (Review)
Review
Anti-laminin (LM) 332-type mucous membrane pemphigoid (MMP) is a rare autoimmune bullous disease and was originally discovered as anti-epiligrin cicatricial pemphigoid. Anti-LM332-type MMP has clinical manifestations similar to those of other types of MMP and can only be distinguished through the detection of circulating autoantibodies against LM332. Our group and others have established a number of immunological methods with varying sensitivity and specificity for detection of anti-LM332 autoantibodies; however, none of the established methods has been widely used for clinical diagnosis. There is currently no unified standard treatment, and it is very difficult to completely cure anti-LM332-type MMP. In addition, an increasing body of evidence suggests that there may be a strong correlation between anti-LM332-type MMP and tumors. In this article, we review the current progression of diagnosis and treatment of anti-LM332-type MMP, as well as the possible correlation between anti-LM332-type MMP and tumors.
Topics: Humans; Autoantibodies; Autoimmune Diseases; Mucous Membrane; Neoplasms; Pemphigoid, Benign Mucous Membrane; Pemphigoid, Bullous; Laminin
PubMed: 36291670
DOI: 10.3390/biom12101461 -
Journal of Innate Immunity 2020
Topics: Chymases; Humans; Immunity, Innate; Immunity, Mucosal; Inflammatory Bowel Diseases; Macrophages; Mast Cells; Membrane Glycoproteins; Mucosal-Associated Invariant T Cells; Mucous Membrane; Receptors, Interleukin-1
PubMed: 32818941
DOI: 10.1159/000510316 -
Journal of Interferon & Cytokine... Feb 2017Several chemokines have important functions in mucosal immunity. While there are many chemokines, 4 of them (CCL25, CCL28, CXCL14, and CXCL17) are especially important... (Review)
Review
Several chemokines have important functions in mucosal immunity. While there are many chemokines, 4 of them (CCL25, CCL28, CXCL14, and CXCL17) are especially important in mucosal immunity because they are homeostatically expressed in mucosal tissues. Of these, only CCL25 and CCL28 have been widely recognized as mucosal chemokines. In this study, we review the physiology of these chemokines with specific emphasis on their function in mucosal immunity. CCL25 recruits certain important subsets of T cells that express CCR9 to the small intestine. These CCR9 T cells also express the integrin α4β7 and have been shown to play important roles in the control of intestinal inflammation. CCL28 recruits CCR10 IgA plasmablasts to the lactating mammary gland. The role of CXCL14 in mucosal immunity is less well defined, but a Cxcl14 mouse exhibits significant metabolic abnormalities. Finally, CXCL17 was the last chemokine to be described and signals through a new chemokine receptor (GPR35/CXCR8), which is expressed in a subset of macrophages that are recruited to mucosal tissues by this chemokine. We conclude that these 4 chemokines play very important roles in mucosal immunity and their continued functional characterization will likely identify novel therapeutic targets.
Topics: Adaptive Immunity; Animals; Biomarkers; Chemokines; Disease Susceptibility; Gene Expression Regulation; Humans; Immunity, Innate; Immunity, Mucosal; Mucous Membrane; Signal Transduction
PubMed: 28207301
DOI: 10.1089/jir.2016.0076