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K.C., Shiva Raj. "Pathology of Inflammatory Bowel Disease." Journal of Pathology of Nepal 5, no. 9 (March 27, 2015): 756–65. http://dx.doi.org/10.3126/jpn.v5i9.13787.
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Inflammatory bowel disease is a group of inflammatory disorders of unknown etiology. Various genetic factors, mucosal immune response, inappropriate activation of immune system driven by the presence of various luminal flora and epithelial defects have been postulated. Crohn disease and Ulcerative colitis are the two most common inflammatory bowel diseases. Since, specific clinical laboratory features are lacking which may help in establishing a diagnosis histopathological diagnosis remains the gold standard. This review highlights the known hypothesis regarding the etiopathogenesis of these two diseases and also describes pertinent histological features.Journal of Pathology of Nepal (2015) Vol. 5, 756-765
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Bernshtein, Biana, Caterina Curato, Marianna Ioannou, Christoph A. Thaiss, Mor Gross-Vered, Masha Kolesnikov, Qian Wang, et al. "IL-23–producing IL-10Rα–deficient gut macrophages elicit an IL-22–driven proinflammatory epithelial cell response." Science Immunology 4, no. 36 (June 14, 2019): eaau6571. http://dx.doi.org/10.1126/sciimmunol.aau6571.
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Cytokines maintain intestinal health, but precise intercellular communication networks remain poorly understood. Macrophages are immune sentinels of the intestinal tissue and are critical for gut homeostasis. Here, we show that in a murine inflammatory bowel disease (IBD) model based on macrophage-restricted interleukin-10 (IL-10) receptor deficiency (Cx3cr1Cre:Il10rafl/fl mice), proinflammatory mutant gut macrophages cause severe spontaneous colitis resembling the condition observed in children carrying IL-10R mutations. We establish macrophage-derived IL-23 as the driving factor of this pathology. Specifically, we report that Cx3cr1Cre:Il10rafl/fl:Il23afl/fl mice harboring macrophages deficient for both IL-10R and IL-23 are protected from colitis. By analyzing the epithelial response to proinflammatory macrophages, we provide evidence that T cells of colitic animals produce IL-22, which induces epithelial chemokine expression and detrimental neutrophil recruitment. Collectively, we define macrophage-specific contributions to the induction and pathogenesis of colitis, as manifested in mice harboring IL-10R deficiencies and human IBDs.
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Durbin, Sienna, Meghan Mooradian, Leyre Zubiri, Ian Matthew Allen, Florian Fintelmann, Avinash Kambadakone, Nisanard Pisuchpen, Kerry Lynn Reynolds, and Michael Lawrence Dougan. "Diagnostic evaluation of immune checkpoint inhibitor (CPI) colitis: The role of CT scan." Journal of Clinical Oncology 38, no. 4_suppl (February 1, 2020): 821. http://dx.doi.org/10.1200/jco.2020.38.4_suppl.821.
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821 Background: CPI therapy has expanded rapidly in recent years and represents a major advancement in the treatment of many cancers, including hepatocellular carcinoma, gastric cancer, and colon cancer. However, these therapies are associated with significant toxicities. CPI colitis is one of the most common toxicities and can be fatal, especially when not diagnosed and treated promptly. The current gold standard for diagnosis is endoscopy with biopsy, an invasive procedure that is resource- and time-intensive. CT has emerged as a possible alternative. The primary objective of this study is to identify the diagnostic performance of CT in the evaluation of CPI colitis. Methods: With IRB approval, we conducted a retrospective cohort study of patients who received CPI therapy between 2009-2019 across a single healthcare system. Patients were included if they underwent both abdominal CT and upper/lower endoscopy with biopsy within 72 hours of each other. We reviewed the electronic medical record to identify possible cases of colitis based on either CT or pathology. All cases were labeled as either true positive or false positive based on pathology. We examined clinical characteristics, including CTCAE grade and treatment received. We calculated the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of CT for diagnosing CPI colitis when compared to the gold standard of tissue diagnosis. Results: Of the 4,474 patients screened, 141 met inclusion criteria. Average age was 63 years (23 – 91); 43% were male. Most common tumor types were melanoma (36%) and NSCLC (20%). Seventy-four percent of patients were treated with anti-PD-1/PD-L1 monotherapy. Forty percent had signs of colitis on CT scan and 59% had biopsy-proven CPI colitis. Sensitivity and specificity of CT were 51% and 74%, respectively. PPV of CT was 74% and NPV was 51%. Of those with confirmed CPI colitis, 78% had symptoms that were classified as grade 3 or above. Seventy-three percent received IV steroids and 38% received infliximab. Conclusions: CT demonstrates moderate specificity and PPV and remains an important diagnostic test but does not replace endoscopy/biopsy in the evaluation of CPI colitis.
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Cineus, R., D. Boesel, S. Hainbuch, C. Jukes, Y. H. Hsieh, J. Reich, Z. Borek, A. Kuehl, and A. N. Hegazy. "P107 The expression and regulation of Oncostatin M and its receptor in intestinal inflammation." Journal of Crohn's and Colitis 14, Supplement_1 (January 2020): S189. http://dx.doi.org/10.1093/ecco-jcc/jjz203.236.
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Abstract Background Intestinal homeostasis depends on the interplay between the gut microbiota, epithelium and immune cells. A novel role of Oncostatin M (OSM), a pro-inflammatory cytokine has recently been identified in mouse and human intestinal inflammation. Previous studies have shown OSM as a key driver of chronic inflammation in anti-TNF-α-refractory colitis. A single-nucleotide polymorphism in the human OSM genetic locus is strongly associated with risk of developing inflammatory bowel disease (IBD), thus, biological therapies targeting OSM could have therapeutic potential. Our project aims to explore the impact of OSM on intestinal barrier function in health and disease. Methods To evaluate the role of OSM in intestinal inflammation, we utilized a combination of in vitro and in vivo techniques. This included the generation of 3D intestinal organoids from mice and patients. Organoids were stimulated with a repertoire of different cytokines to determine the responsiveness of OSM receptor (OSMR) to different cytokine signals using a quantitative-PCR-based approach. For in vivo modelling of disease, the Helicobacter hepaticus colitis model was used, as it combines both immune and dysbiosis-driven aspects of disease. This allowed us to measure OSM and OSMR expression in response to inflammation and within specific organs and cell subsets. Furthermore, RNAscope in situ hybridisation was used to determine the localisation of OSM- and OSMR-expressing cells in inflamed mucosal tissue from colitic mice and IBD patients. Results RNAscope in situ hybridisation as well as gene expression analysis have shown that the OSM and OSMR were highly expressed in C57BL/6 mice upon induction of colitis in the H. hepaticus model of disease and in mucosal tissues of IBD patients. In addition, a plethora of pro-inflammatory cytokines were upregulated during colitis, with colitic mice showing increased tissue pathology. Furthermore, FACS analysis shows excessive immune cell infiltration in the spleen, colon and mesenteric lymph nodes of colitic mice. Conclusion Our preliminary results have shown that different gut-resident hematopoietic and non-hematopoietic cell types express OSM and OSMR and this expression was modulated by pro-inflammatory cytokines. We therefore hypothesis that OSM might drive distinct transcriptional responses in various gut-resident cell populations. Thus, differential targeting of the OSM receptor might be a potential therapeutic approach in IBD.
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Yeung, Cecilia C. S., David M. Hockenbery, Maria Westerhoff, Steven Coutre, Ruth H. Sedlak, Ronald L. Dubowy, A. Mario Marcondes, Veerendra Munugalavadla, Kerry Taylor, and Francesc Bosch. "Pathology Results of Tissue Biopsy during Idelalisib-Associated Diarrhea/Colitis." Blood 128, no. 22 (December 2, 2016): 4391. http://dx.doi.org/10.1182/blood.v128.22.4391.4391.
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Abstract Introduction: Idelalisib (IDELA) is a targeted PI3Kd inhibitor approved for the treatment of patients (pts) with relapsed CLL/FL. The established toxicity profile of IDELA includes diarrhea/colitis with a grade ≥3 incidence of ~15%. Here, we present the histopathological-as well as immune profiling and viral testing-results of gastrointestinal tissue specimens from pts who received diagnostic biopsies for abdominal pain or diarrhea during treatment with IDELA. Methods: Intestinal biopsy specimens obtained from 31 pts during treatment with IDELA across 10 trials (monotherapy n = 3 or in combination with: rituximab n = 9; ofatumumab n = 14; and bendamustine/rituximab n = 5) were reviewed separately by 2 independent pathologists with expertise in the area of gastrointestinal and transplant pathology. If more than 1 biopsy time point per pt was available (n = 3), all time points would be evaluated and, if discordant, would be reported separately. Evaluation included hematoxylin and eosin stain; and immunohistochemistry (IHC) for CD3, CD8, FOXP3, CD79a, CMV, and adenovirus (as adequate tissue allowed). Additionally, droplet digital PCR (ddPCR) was performed for cytomegalovirus (CMV), adenovirus, and human herpesvirus 6 (HHV-6). Colon/small bowel tissues from 18 normal individuals who underwent biopsy during routine screening colonoscopy and had normal pathology results were included as controls. Results: Baseline characteristics of pts included CLL n = 24 (77.4%) and iNHL n = 7 (22.6%), age range 50 to 82 years with median 65.6 years, male n = 19 (61.3%). IDELA median dose = 150 mg BID. Diarrhea/colitis (Grade 1-3) was reported in 24 cases (75%) including 1 case of hemorrhagic colitis. One patient each had concurrent laboratory-confirmed Mycobacterium avium-intracellulare and norovirus and 2 patients were excluded from histomorphological analysis, 1 due to celiac disease and 1 due to total loss of glands secondary to CMV. Four distinct morphological patterns were identified: 1) predominantly normal, 2) apoptotic, 3) inflammatory/ischemic, and 4) mixed apoptotic/inflammatory/ischemic. CMV IHC was performed in all 31 cases; 2 showed strong/moderate positivity, and 2 were weakly positive. Adenovirus IHC was performed on 29 specimens, and 1 was weakly positive. ddPCR performed on 27 formalin-fixed paraffin-embedded tissues identified 6 positive CMV cases (including all 4 IHC+ cases), 0 adenovirus cases, and 1 HHV-6-positive case. Among the CMV cases, the most common pattern was mixed, seen in 4 of 6 cases, whereas the most common morphologic feature was apoptosis, seen in 5 of 6 cases. A summary of findings is shown in Table 1. Conclusion: In this subset of pts who underwent intestinal biopsy during IDELA clinical trials, most biopsies (87%) were performed in the context of ongoing diarrhea/colitis and the majority of tissue samples (90%) revealed some component of inflammation. Immune profiling by IHC showed increased Tregs in patterns associated with glandular destruction. Immunohistochemistry and ddPCR for virus in conjunction with microbiology studies revealed that in 28% of these cases, a pathogen was identified. This dataset suggests that in a significant number of cases, idelalisib-associated diarrhea/colitis may be due to an infectious etiology secondary to immune dysfunction that results in either an inflammatory/ischemic or a mixed histologic pattern; however, the majority of these cases have no identifiable infectious etiology. Based on these findings, we recommend that a workup of pts with idelalisib-associated diarrhea/colitis should include a complete evaluation for infectious causes including intestinal biopsy when a pathogen is elusive with standard testing. Disclosures Yeung: Gilead Sciences: Research Funding. Hockenbery:Gilead Sciences: Research Funding. Coutre:Gilead Sciences: Consultancy, Research Funding. Dubowy:Gilead Sciences: Employment, Equity Ownership. Marcondes:Gilead Sciences: Employment, Equity Ownership. Munugalavadla:Gilead Sciences: Employment, Equity Ownership. Bosch:Gilead Sciences: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Research Funding.
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Ma, Weijie, Anusha Thomas, and Yinghong Wang. "Is chronic refractory colitis from immune checkpoint inhibitor associated with good cancer outcome?" Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e15102-e15102. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e15102.
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e15102 Background: Immune checkpoint inhibitors (ICIs) are efficacious in treating many advanced malignancies. However, drug induced colitis limits their use significantly. We present cases with chronic refractory ICI colitis requiring long term immunosuppressive therapy and favorable cancer outcomes. Methods: We identified 3 cases who developed ICI colitis and persisted for longer than 6 months requiring long term immunosuppressant therapy. The patients’ clinical data was collected. Results: All patients were male, with median age of 55. Two had melanoma, one urothelial cancer. All patients received PD-1(L)-1 agents with colitis onset about 3-6 months after ICI treatment. All patients were taken off ICI permanently due to colitis over a duration of 19-30 months (peak grade of 3). Endoscopy of all three were grossly unremarkable, with lymphocytic colitis on pathology in all three. Patient A’s colitis achieved clinical and histological remission after 5 doses of vedolizumab, however recurred after 9 months with biopsy proven recurrence. Current management is anti-diarrheal medication given mild symptom. Patient B had more aggressive disease, with first recurrence after 2 doses of infliximab and steroid, achieved initial histological remission after 3 doses of vedolizumab and 2 additional infliximab, then had 2nd recurrence after 3 months. Fecal microbiota transplantation as compassionate treatment was not effective. Thereafter, patient was resumed on vedolizumab ever since with clinical remission. Last histology evaluation showed persistent lymphocytic colitis 30 months after initial diagnosis. The third case had initial histological remission after 3 doses of vedolizumab, followed by recurrence after 4 months, which triggered another 3 doses of vedolizumab, with persistent grade 3 diarrhea despite resolution of histological inflammation after total 6 doses of vedolizumab. Patient was subsequently treated with steroid and ustekinumab with clinical remission. At the end of follow up, all three patients have sustained cancer remission over 19-31 months. Conclusions: IMC is a common adverse event from ICI, and could progress to a chronic inflammatory condition that require long term treatment. Histological remission does not preclude future recurrence of colitis. Persistent toxicity could be a surrogate marker for enduring ICI effect which may be associated with favorable cancer outcome. Long term immunosuppression can be essential for refractory ICI colitis cases for clinical remission.
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Comunoglu, N., S. Kara, and N. Kepil. "Inflammatory bowel disease-like colitis pathology in a patient with common variable immune deficiency." Case Reports 2015, feb25 1 (February 25, 2015): bcr2014207177. http://dx.doi.org/10.1136/bcr-2014-207177.
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Forsberg, L., C. H. Florén, E. Hederström, and H. Prytz. "Ultrasound Examination in Diffuse Liver Disease." Acta Radiologica 28, no. 3 (May 1987): 281–84. http://dx.doi.org/10.1177/028418518702800310.
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Seventy-three patients with pathologic liver function tests were examined using ultrasound one day prior to liver biopsy. The ultrasound findings were compared with the histologic findings. In 23 patients enlarged lymph nodes were found in the hepato-duodenal ligament and 21 of these had active immune-mediated liver disease. Of the remaining 2 patients one had ulcerative colitis (and fatty liver) and one chronic cholecystitis (and ***haemosiderosis). Of the 33 patients with biopsy-proven active ***immune-mediated liver disease 21 had pathologic lymph nodes in the hepato-duodenal ligament at ultrasound. It was not possible to identify the ligament in 8 patients and in the remaining 4 no pathologic lymph nodes could be found. Twenty-one of these patients had normal liver echoes on ultrasound, 5 exhibited increased echogenicity and 5 had heterogeneous echogenicity. In a further 2 patients both increased echogenicity and heterogeneous parenchyma were found. Ultrasound examination of the liver parenchyma alone would thus lead to 21 of the 33 patients being classified as normal and a further 5 being classified as having fatty changes of the liver. Only 7 would be regarded as having significant liver pathology. However, if demonstration at ultrasound of pathologic lymph nodes in the hepato-duodenal ligament is regarded as being consistent with significant hepatic pathology a further 15 patients could be added to these 7 patients, giving a total of 22 out of 33 patients (67%) identified as having significant liver pathology using ultrasound alone. The reliability of ultrasound in the diagnosis of immune-mediated liver disease can thus be improved considerably by actively searching for lymph nodes in the hepato-duodenal ligament.
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Chidlow, John H., Deepti Shukla, Matthew B. Grisham, and Christopher G. Kevil. "Pathogenic angiogenesis in IBD and experimental colitis: new ideas and therapeutic avenues." American Journal of Physiology-Gastrointestinal and Liver Physiology 293, no. 1 (July 2007): G5—G18. http://dx.doi.org/10.1152/ajpgi.00107.2007.
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Angiogenesis is now understood to play a major role in the pathology of chronic inflammatory diseases and is indicated to exacerbate disease pathology. Recent evidence shows that angiogenesis is crucial during inflammatory bowel disease (IBD) and in experimental models of colitis. Examination of the relationship between angiogenesis and inflammation in experimental colitis shows that initiating factors for these responses simultaneously increase as disease progresses and correlate in magnitude. Recent studies show that inhibition of the inflammatory response attenuates angiogenesis to a similar degree and, importantly, that inhibition of angiogenesis does the same to inflammation. Recent data provide evidence that differential regulation of the angiogenic mediators involved in IBD-associated chronic inflammation is the root of this pathological angiogenesis. Many factors are involved in this phenomenon, including growth factors/cytokines, chemokines, adhesion molecules, integrins, matrix-associated molecules, and signaling targets. These factors are produced by various vascular, inflammatory, and immune cell types that are involved in IBD pathology. Moreover, recent studies provide evidence that antiangiogenic therapy is a novel and effective approach for IBD treatment. Here we review the role of pathological angiogenesis during IBD and experimental colitis and discuss the therapeutic avenues this recent knowledge has revealed.
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Egorova, О. N., and В. S. Belov. "Erythema nodosum in rheumatic diseases." Medical Council, no. 6 (April 28, 2019): 95–99. http://dx.doi.org/10.21518/2079-701x-2019-6-95-99.
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The review is devoted to erythema nodosum (UE), which is a typical variant of septal panniculitis without vasculitis and is a nonspecific immune inflammatory syndrome. Often, UE acts as one of the symptoms of systemic pathology, including rheumatic diseases (RH), sarcoidosis, Crohn’s disease, ulcerative colitis, cancer, etc., which can cause late diagnosis and, accordingly, the appointment of adequate therapy.
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Chetty, R., S. Hafezi, and E. Montgomery. "An incidental enterocolic lymphocytic phlebitis pattern is seen commonly in the rectal stump of patients with diversion colitis superimposed on inflammatory bowel disease." Journal of Clinical Pathology 62, no. 5 (January 15, 2009): 464–67. http://dx.doi.org/10.1136/jcp.2008.063917.
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Aims:Enterocolic lymphocytic phlebitis (ELP) is an uncommon cause of bowel pathology and most frequently results in ischaemia. It is characterised by an artery-sparing, venulocentric lymphoid infiltrate that causes a phlebitis and vascular compromise. Rare cases of ELP have been encountered with lymphocytic colitis in the absence of ischaemic bowel change. The present study examined the occurrence of ELP in the setting of diversion colitis and inflammatory bowel disease, as well as in random colectomy specimens.Methods:The study cohort comprised the following: 26 completion proctectomy specimens for ulcerative colitis with superimposed diversion colitis in the rectal stump; 3 colectomy specimens for Crohn disease with diversion colitis; 6 colectomy specimens for adenocarcinoma and/or diverticular disease with diversion colitis; 34 resection specimens with ulcerative colitis only; 19 with Crohn disease only; and 100 random colon resection specimens for adenocarcinoma, adenoma, diverticular disease and ischaemia.Results:ELP was present in 18 of the 26 ulcerative colitis cases with diversion colitis, 3/3 Crohn disease cases with diversion colitis, 1/6 cases of diverticular disease with diversion colitis, 6/34 cases of ulcerative colitis without diversion, 2/19 Crohn disease cases without diversion colitis, and only 1 of 100 colectomy cases without inflammatory bowel disease or diversion colitis.Conclusion:ELP occurs most frequently in cases that have been diverted for inflammatory bowel disease. Fewer cases of ELP were noted in cases of inflammatory bowel disease in the absence of diversion colitis. It is postulated that altered bowel flora and immune dysregulation may be pivotal in the causation of this association.
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Rubio, Carlos A. "Lysozyme expression in microscopic colitis." Journal of Clinical Pathology 64, no. 6 (April 2, 2011): 510–15. http://dx.doi.org/10.1136/jcp.2010.086850.
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AimsTo audit the cellular expression of the innate antibacterial enzyme lysozyme in colonic biopsies from a cohort of patients having microscopic colitis (MC—collagenous colitis (CC) or lymphocytic colitis (LC)). Results were compared with those recorded in patients with inflammatory bowel disease (IBD) of the colon (ulcerative colitis (UC) or Crohn's colitis).MethodsFifty-five consecutive cases having biopsies from the left colon were investigated: 27 MC (14 CC and 13 LC) and 28 IBD (14 UC and 14 Crohn's colitis). Sections were stained with antilysozyme antibody. Twelve cases (3 CC, 3 LC, 3 UC and 3 Crohn's colitis) were challenged with the macrophage marker CD68 (clone PG-M1).ResultsIn MC, marked lysozyme expression in the colonic crypts was recorded in CC (p<0.05). The number of cases with metaplastic Paneth cells was higher in CC than in LC (p<0.05). In IBD, only active Crohn's colitis displayed marked lysozyme expression in the colonic crypts. Marked lysozyme immune-reactivity in subepithelial lamina propria mucosa (lpm) macrophages was found in LC (LC vs CC p<0.05).ConclusionsThe increased production of the antibacterial enzyme lysozyme in CC and LC supports a bacterial aetiology for these two diseases. Lysozyme upregulation in different cell types (epithelial vs macrophages) supports the notion that CC and LC might be two different maladies.
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Choi, Kati, Hamzah Abu-Sbeih, Rashmi Samdani, Graciela Nogueras Gonzalez, Gottumukkala Subba Raju, David M. Richards, Jianjun Gao, Sumit Subudhi, John Stroehlein, and Yinghong Wang. "Can Immune Checkpoint Inhibitors Induce Microscopic Colitis or a Brand New Entity?" Inflammatory Bowel Diseases 25, no. 2 (August 29, 2018): 385–93. http://dx.doi.org/10.1093/ibd/izy240.
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Abstract Background Microscopic colitis (MC) has been described as 1 pattern of injury in immune checkpoint inhibitor (ICPI)–induced colitis. The main objective of this study was to characterize ICPI-induced MC by exploring the differences in risk factors, colitis treatments, endoscopic features, and clinical outcomes between cancer and noncancer patients with MC with and without exposure to ICPIs. Methods A retrospective chart review was conducted among patients diagnosed with MC from our institutional pathology database from January 2012 to January 2018. Patients were categorized into MC in cancer patients with or without ICPI exposure and in noncancer patients. Risk factors (use of tobacco and certain medications), colitis treatments (antidiarrheals and immunosuppressants), endoscopic features (with or without mucosal abnormality), and clinical outcomes (diarrhea recurrence, hospitalization, mortality) were collected and compared among the 3 groups. Results Of the 65 eligible patients with MC, 15 cancer patients had exposure to ICPI, 39 cancer patients had no exposure to ICPI, and 11 had no cancer diagnosis. Among the risk factors, proton pump inhibitor was more frequently used in the ICPI-induced MC cohort (P = 0.040). Furthermore, in this population, mucosal abnormality was the most common endoscopic feature compared with normal findings in the non-ICPI-induced MC groups (P = 0.106). Patients with ICPI-induced MC required more treatments with oral and intravenous steroids and nonsteroidal immunosuppressive agents (all P < 0.001) and had a higher rate of hospitalization (P < 0.001). Conclusion This study suggests that despite some similarities between MC with and without exposure to ICPIs, ICPI-induced MC has a more aggressive disease course that requires more potent immunosuppressive treatment regimens and greater need for hospitalization.
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Poggio, Juan, and Robert Kucejko. "Considerations and Changes in the Evaluation, Management, and Outcomes in the Management of Diverticular Disease: The Diagnosis, Pathology, and Treatment of Diverticular Colitis." Clinics in Colon and Rectal Surgery 31, no. 04 (June 22, 2018): 221–25. http://dx.doi.org/10.1055/s-0037-1607467.
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AbstractDiverticular colitis, also known as segmental colitis associated with diverticulosis, is a colonic inflammatory disorder on the spectrum of inflammatory bowel disease (IBD). The disease consists of macroscopic and microscopic inflammation affecting inter-diverticular mucosa, sparing peri-diverticular mucosa, with inflammation confined to the descending and sigmoid colon. The disease likely arises from the altered immune response of an individual, genetically susceptible to the IBD spectrum of diseases. Patients with segmental colitis associated with diverticulosis (SCAD) are typically older, and likely represent a subgroup of IBD—susceptible patients who lacked an environmental trigger until that point in their life. Most patients remain in remission with initial treatments of mesalamine or topical steroids, and maintenance mesalamine afterwards. Only the most severe form of the disease necessitates immunomodulatory therapy and the consideration of surgery.
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Messmer, Marcus, Sunita Upreti, Yaman Tarabishy, Nikhilesh Mazumder, Reezwana Chowdhury, Mark Yarchoan, and Matthias Holdhoff. "Ipilimumab-Induced Enteritis without Colitis: A New Challenge." Case Reports in Oncology 9, no. 3 (November 8, 2016): 705–13. http://dx.doi.org/10.1159/000452403.
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Introduction: Ipilimumab is an immune checkpoint inhibitor targeting cytotoxic T-lymphocyte associated antigen 4 (CTLA4), approved to treat metastatic melanoma. It was the first therapy shown to prolong survival in a large, randomized clinical trial. However, immune-related adverse events are common and can be severe. Enterocolitis is a common adverse event with ipilimumab, but enteritis without colitis has not been previously described. Case Report: An 83-year-old man presented to our hospital with grade 3 diarrhea for 5 days. One month prior, he had started treatment with ipilimumab for metastatic melanoma. On presentation, he was found to have severe electrolyte disturbances, including hyponatremia, hypokalemia, and acute kidney injury. Causes of infectious diarrhea were excluded, and he was treated with corticosteroids for presumed ipilimumab-associated enterocolitis. However, colonoscopy revealed normal mucosa, both grossly and on pathology of random biopsies. Steroids were weaned but his symptoms recurred. He then underwent upper endoscopy with enteroscopy. Biopsy of the duodenum was notable for acute inflammation, villous blunting, and other changes consistent with ipilimumab-associated injury. He was restarted on high-dose steroids and his symptoms resolved. Discussion: Ipilimumab-induced enteritis is a serious and potentially life-threatening immune related adverse event that warrants prompt recognition and aggressive management. As in cases of ipilimumab-associated enterocolitis, steroids are an effective therapy. Enteritis without colitis should be suspected in patients on ipilimumab who present with severe diarrhea but have a normal colonoscopy.
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Karamchandani, Dipti M., and Runjan Chetty. "Immune checkpoint inhibitor-induced gastrointestinal and hepatic injury: pathologists’ perspective." Journal of Clinical Pathology 71, no. 8 (April 27, 2018): 665–71. http://dx.doi.org/10.1136/jclinpath-2018-205143.
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Immune checkpoint inhibitors (CPIs) are a relatively new class of ‘miracle’ dugs that have revolutionised the treatment and prognosis of some advanced-stage malignancies, and have increased the survival rates significantly. This class of drugs includes cytotoxic T lymphocyte antigen-4 inhibitors such as ipilimumab; programmed cell death protein-1 inhibitors such as nivolumab, pembrolizumab and avelumab; and programmed cell death protein ligand-1 inhibitors such as atezolizumab. These drugs stimulate the immune system by blocking the coinhibitory receptors on the T cells and lead to antitumoural response. However, a flip side of these novel drugs is immune-related adverse events (irAEs), secondary to immune-mediated process due to disrupted self-tolerance. The irAEs in the gastrointestinal (GI) tract/liver may result in diarrhoea, colitis or hepatitis. An accurate diagnosis of CPI-induced colitis and/or hepatitis is essential for optimal patient management. As we anticipate greater use of these drugs in the future given the significant clinical response, pathologists need to be aware of the spectrum of histological findings that may be encountered in GI and/or liver biopsies received from these patients, as well as differentiate them from its histopathological mimics. This present review discusses the clinical features, detailed histopathological features, management and the differential diagnosis of the luminal GI and hepatic irAEs that may be encountered secondary to CPI therapy.
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Pagliari, Danilo, Giovanni Gambassi, Ciriaco A. Piccirillo, and Rossella Cianci. "The Intricate Link among Gut “Immunological Niche,” Microbiota, and Xenobiotics in Intestinal Pathology." Mediators of Inflammation 2017 (2017): 1–12. http://dx.doi.org/10.1155/2017/8390595.
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Inflammatory bowel diseases (IBDs) are diseases characterized by various degrees of inflammation involving the gastrointestinal tract. Ulcerative colitis and Crohn’s disease are characterized by a dysregulated immune response leading to structural gut alterations in genetically predisposed individuals. Diverticular disease is characterized by abnormal immune response to normal gut microbiota. IBDs are linked to a lack of physiological tolerance of the mucosal immune system to resident gut microbiota and pathogens. The disruption of immune tolerance involves inflammatory pathways characterized by an unbalance between the anti-inflammatory regulatory T cells and the proinflammatory Th1/Th17 cells. The interaction among T cell subpopulations and their related cytokines, mediators of inflammation, gut microbiota, and the intestinal mucosa constitute the gut “immunological niche.” Several evidences have shown that xenobiotics, such as rifaximin, can positively modulate the inflammatory pathways at the site of gut immunological niche, acting as anti-inflammatory agents. Xenobiotics may interfere with components of the immunological niche, leading to activation of anti-inflammatory pathways and inhibition of several mediators of inflammation. In summary, xenobiotics may reduce disease-related gut mucosal alterations and clinical symptoms. Studying the complex interplay between gut immunological niche and xenobiotics will certainly open new horizons in the knowledge and therapy of intestinal pathologies.
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Vallance, Bruce A., Wanyin Deng, Leigh A. Knodler, and B. Brett Finlay. "Mice Lacking T and B Lymphocytes Develop Transient Colitis and Crypt Hyperplasia yet Suffer Impaired Bacterial Clearance during Citrobacter rodentium Infection." Infection and Immunity 70, no. 4 (April 2002): 2070–81. http://dx.doi.org/10.1128/iai.70.4.2070-2081.2002.
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ABSTRACT The bacterial pathogen Citrobacter rodentium belongs to a family of gastrointestinal pathogens that includes enteropathogenic and enterohemorrhagic Escherichia coli and is the causative agent of transmissible colonic hyperplasia in mice. The molecular mechanisms used by these pathogens to colonize host epithelial surfaces and form attaching and effacing (A/E) lesions have undergone intense study. In contrast, little is known about the host's immune response to these infections and its importance in tissue pathology and bacterial clearance. To address these issues, wild-type mice and mice lacking T and B lymphocytes (RAG1 knockout [KO]) were infected with C. rodentium. By day 10 postinfection (p.i.), both wild-type and RAG1 KO mice developed colitis and crypt hyperplasia, and these responses became more exaggerated in wild-type mice over the next 2 weeks, as they cleared the infection. By day 24 p.i., bacterial clearance was complete, and the colitis had subsided; however, crypt heights remained increased. In contrast, inflammatory and crypt hyperplastic responses in the RAG1 KO mice were transient, subsiding after 2 weeks. By day 24 p.i., RAG1 KO mice showed no signs of bacterial clearance and infection was often fatal. Surprisingly, despite remaining heavily infected, tissues from RAG1 KO mice surviving the acute colitis showed few signs of disease. These results thus emphasize the important contribution of the host immune response during infection by A/E bacterial pathogens. While T and/or B lymphocytes are essential for host defense against C. rodentium, they also mediate much of the tissue pathology and disease symptoms that occur during infection.
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Bailey, J. R., V. Vince, N. A. Williams, and T. A. Cogan. "Streptococcus thermophilus NCIMB 41856 ameliorates signs of colitis in an animal model of inflammatory bowel disease." Beneficial Microbes 8, no. 4 (August 24, 2017): 605–14. http://dx.doi.org/10.3920/bm2016.0110.
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Treatment of inflammatory bowel disease (IBD) is mainly based on suppression of symptoms, often with numerous side effects. Trials of probiotics in IBD have frequently produced disappointing results. The majority of probiotics are unusual, since they do not require iron for growth, unlike many bacteria resident in the intestine. The IBD intestine is iron-rich due to bleeding and use of oral iron supplements; conventional probiotics would be rapidly outcompeted. We have evaluated an iron-responsive Streptococcus thermophilus strain for its potential to reduce signs of colitis. Efficacy of S. thermophilus was evaluated in the dextran sodium sulphate mouse model of colitis. Treated animals were given 1×108 cfu S. thermophilus per day and clinical observations were taken daily. At termination, gross and histopathological signs of disease, cellular infiltration, location of bacteria, and cytokine expression in the intestine were determined. S. thermophilus delayed onset of colitis and reduced clinical signs of disease, including bodyweight loss and gastrointestinal bleeding. It reduced bacterial translocation into the colonic tissue. Increased numbers of CD8+ intraepithelial lymphocytes were seen in control animals treated with S. thermophilus. S. thermophilus had no effect on gross pathology, histopathology or cytokine production in either colitic or control animals. We propose that S. thermophilus promotes maintenance of mucosal barrier function which reduces bacterial translocation, thereby reducing immune stimulation and associated inflammation. This allows mucosal healing, reducing gastrointestinal bleeding and weight loss. This could be studied as a locally-acting adjunct or alternative to current IBD treatments.
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Hapfelmeier, Siegfried, Andreas J. Müller, Bärbel Stecher, Patrick Kaiser, Manja Barthel, Kathrin Endt, Matthias Eberhard, et al. "Microbe sampling by mucosal dendritic cells is a discrete, MyD88-independent stepin ΔinvG S. Typhimurium colitis." Journal of Experimental Medicine 205, no. 2 (February 11, 2008): 437–50. http://dx.doi.org/10.1084/jem.20070633.
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Intestinal dendritic cells (DCs) are believed to sample and present commensal bacteria to the gut-associated immune system to maintain immune homeostasis. How antigen sampling pathways handle intestinal pathogens remains elusive. We present a murine colitogenic Salmonella infection model that is highly dependent on DCs. Conditional DC depletion experiments revealed that intestinal virulence of S. Typhimurium SL1344 ΔinvG mutant lacking a functional type 3 secretion system-1 (ΔinvG)critically required DCs for invasion across the epithelium. The DC-dependency was limited to the early phase of infection when bacteria colocalized with CD11c+CX3CR1+ mucosal DCs. At later stages, the bacteria became associated with other (CD11c−CX3CR1−) lamina propria cells, DC depletion no longer attenuated the pathology, and a MyD88-dependent mucosal inflammation was initiated. Using bone marrow chimeric mice, we showed that the MyD88 signaling within hematopoietic cells, which are distinct from DCs, was required and sufficient for induction of the colitis. Moreover, MyD88-deficient DCs supported transepithelial uptake of the bacteria and the induction of MyD88-dependent colitis. These results establish that pathogen sampling by DCs is a discrete, and MyD88-independent, step during the initiation of a mucosal innate immune response to bacterial infection in vivo.
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Bisht, Nalini, Vishal Khatri, Nikhil Chauhan, and Ramaswamy Kalyanasundaram. "Cystatin from Filarial Parasites Suppress the Clinical Symptoms and Pathology of Experimentally Induced Colitis in Mice by Inducing T-Regulatory Cells, B1-Cells, and Alternatively Activated Macrophages." Biomedicines 7, no. 4 (October 31, 2019): 85. http://dx.doi.org/10.3390/biomedicines7040085.
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Potential alternative therapeutic strategies for immune-mediated disorders are being increasingly recognized and are studied extensively. We previously reported the therapeutic potential of Brugia malayi derived recombinant cystatin (rBmaCys) in attenuating clinical symptoms of experimental colitis. The aim of this study was to elucidate the mechanisms involved in the rBmaCys-induced suppression of inflammation in the colon. Our results show that, the frequency of CD4+CD25+FoxP3+ regulatory T-cells was elevated in the colon and mesenteric lymph nodes. Similarly, the peritoneal macrophages recovered from the rBmaCys-treated colitis mice were alternatively activated and displayed reduced expression of TNF-α and IL-6. Another finding was significant increases in IgM+B1a-cells in the peritoneal cavity of mice following rBmaCys-treatment. These findings suggested that the regulatory cell network promoted by the rBmaCys in the colon and associated lymphoid tissues is important for its anti-inflammatory activity in the dextran sulfate sodium (DSS)-induced colitis mice.
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Frosali, Simona, Danilo Pagliari, Giovanni Gambassi, Raffaele Landolfi, Franco Pandolfi, and Rossella Cianci. "How the Intricate Interaction among Toll-Like Receptors, Microbiota, and Intestinal Immunity Can Influence Gastrointestinal Pathology." Journal of Immunology Research 2015 (2015): 1–12. http://dx.doi.org/10.1155/2015/489821.
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The gut is able to maintain tolerance to microbial and food antigens. The intestine minimizes the number of harmful bacteria by shaping the microbiota through a symbiotic relationship. In healthy human intestine, a constant homeostasis is maintained by the perfect regulation of microbial load and the immune response generated against it. Failure of this balance may result in various pathological conditions. Innate immune sensors, such as Toll-like receptors (TLRs), may be considered an interface among intestinal epithelial barrier, microbiota, and immune system. TLRs pathway, activated by pathogens, is involved in the pathogenesis of several infectious and inflammatory diseases. The alteration of the homeostasis between physiologic and pathogenic bacteria of intestinal flora causes a condition called dysbiosis. The breakdown of homeostasis by dysbiosis may increase susceptibility to inflammatory bowel diseases. It is evident that environment, genetics, and host immunity form a highly interactive regulatory triad that controls TLR function. Imbalanced relationships within this triad may promote aberrant TLR signaling, critically contributing to acute and chronic intestinal inflammatory processes, such as in IBD, colitis, and colorectal cancer. The study of interactions between different components of the immune systems and intestinal microbiota will open new horizons in the knowledge of gut inflammation.
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Ayyadurai, Saravanan, Moiz A. Charania, Bo Xiao, Emilie Viennois, and Didier Merlin. "PepT1 expressed in immune cells has an important role in promoting the immune response during experimentally induced colitis." Laboratory Investigation 93, no. 8 (June 24, 2013): 888–99. http://dx.doi.org/10.1038/labinvest.2013.77.
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Byrnes, Kathleen, Armen Khararjian, Abul A. S. R. Mannan, Michael Arnold, and Lysandra Voltaggio. "Young-Onset Ischemic Colitis: A Condition of Elusive Etiology Frequently Associated With Immune Dysregulation." International Journal of Surgical Pathology 28, no. 4 (December 23, 2019): 361–66. http://dx.doi.org/10.1177/1066896919894671.
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Ischemic colitis (IC) associates with older age, hypertension, and heart disease, among others. Young-onset IC is rare. We aimed to delineate clinical characteristics of young patients (<40 years) with IC. Cases from 1984 to 2017 were re-reviewed. Of the 60 cases available, 52% (n = 31) had histologic features of IC. Fifty-five percent were female with a mean age of 32 (range = 14-40) years. Fifty-eight percent (n = 18) were resections. The most common presentations were diarrhea and abdominal pain. Three teenagers had IC associated with prior surgery, volvulus, and constipation. In the 21- to 40-year group, 43% (n = 12) lacked clinical associations. A second subset (n = 6, 21%) had histories of immune dysregulation (lupus, dermatomyositis, vasculitis) and poorly controlled HIV/AIDS (n = 5, 18%). Smoking and cocaine were endorsed by 1 and 2 patients, respectively. One patient had premature atherosclerosis while another had HMG Co-A lyase deficiency. Vasculitis was identified in 22% of the resections and in none of the biopsies. Nineteen percent of patients died (n = 6) from complications of IC, all treated surgically, including 1 patient previously misdiagnosed as ulcerative colitis; 2 patients died of unrelated causes. While rare before 20 years of age, IC in teenagers relates to mechanical issues and is rare in children. Associations in young adults include immune dysregulation, cocaine and cigarette use, and premature atherosclerosis. Our retrospective cohort had a surgical mortality rate within the range reported by others, highlighting the importance of accurate diagnosis in young individuals.
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Hoving, Jennifer Claire, Roanne Keeton, Maxine A. Höft, Mumin Ozturk, Patricia Otieno-Odhiambo, and Frank Brombacher. "IL-4 Receptor-Alpha Signalling of Intestinal Epithelial Cells, Smooth Muscle Cells, and Macrophages Plays a Redundant Role in Oxazolone Colitis." Mediators of Inflammation 2020 (January 17, 2020): 1–11. http://dx.doi.org/10.1155/2020/4361043.
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A hallmark of ulcerative colitis is the chronic colonic inflammation, which is the result of a dysregulated intestinal mucosal immune response. Epithelial barrier disruption which allows the entry of microorganisms eventually leads to more aggressive inflammation and potentially the removal of the colon. We have previously shown that the T helper- (Th-) type 2 cytokines, Interleukin- (IL-) 4 and IL-13, mediate CD4+ T cell- or B cell-driven inflammation in the oxazolone-induced mouse model of ulcerative colitis. In contrast, mice deficient in the shared receptor of IL-4 and IL-13, IL-4 receptor-alpha (IL-4Rα), on all cells develop an exacerbated disease phenotype. This suggests that a regulatory role of IL-4Rα is required to protect against severe colitis. However, the cell populations responsible for regulating the severity of disease onset through IL-4Rα in colitis are yet to be identified. By deleting IL-4Rα on specific cell subsets shown to play a role in mediating colitis, we determined their role in a loss of function approach. Our data demonstrated that the loss of IL-4Rα signalling on intestinal epithelial cells, smooth muscle cells, and macrophages/neutrophils had no effect on alleviating the pathology associated with colitis. These results suggest that IL-4/IL-13 signalling through IL-4Rα on nonhematopoietic intestinal epithelial or smooth muscle cells and hematopoietic macrophage/neutrophils has a redundant role in driving acute oxazolone colitis.
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Turpin, Brian K., Kris Steinbrecher, Maureen Shaw, Kathryn E. McElhinney, Richard Baylis, Matthew J. Flick, Whitney M. Miller, and Joseph S. Palumbo. "PAR-1 Is a Context Dependent Determinant of Colitis and Colitis-Associated Cancer." Blood 120, no. 21 (November 16, 2012): 2221. http://dx.doi.org/10.1182/blood.v120.21.2221.2221.
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Abstract Abstract 2221 Increased thrombin generation and hypercoagulability are prominent features of inflammatory colitis and previous studies from our laboratory have suggested that thrombin-mediated proteolysis is a driver of both colitis and colitis-associated colon cancer (CAC). However, the downstream thrombin targets important in these disease processes have not been fully defined. Based on studies showing that the protease activated receptor-1 (PAR-1) can contribute to both inflammatory pathologies and cancer progression in other settings, we hypothesized that PAR-1 is a significant determinant of colitis and CAC. To test this hypothesis, we induced colitis in PAR-1−/− and control mice using intrarectal administration of 2,4,6-trinitrobenzenesulfonic acid (TNBS). Consistent with the concept that PAR-1 is a modifier of colitis pathobiology, PAR-1−/− mice lost significantly less weight than WT mice challenged in parallel. Furthermore, multiple inflammatory cytokines known to drive colitis pathology, including IL-6, TNFa, and MIP-1α, were significantly diminished in PAR-1−/− mice. However, histological analyses of colonic tissue revealed similar degrees of inflammatory cell infiltration, crypt abscesses, and mucosal hyperplasia in both genotypes. In order to explore the role of PAR-1 in the more complex process of inflammation-driven colon cancer pathogenesis, we induced CAC in PAR-1−/− and WT mice using a two step protocol consisting of azoxymethane (AOM) and dextran sodium sulfate (DSS) exposure. In contrast to findings in the setting of TNBS challenge, PAR-1−/− mice challenged with DSS developed, not less, but more severe clinical signs of colitis, including wasting and severe diarrhea. More detailed comparative studies of DSS-challenged PAR-1−/− and control mice established that PAR-1-deficient animals developed significantly greater immunological and histopathological evidence of colitis, including elevated IL-6 and MIP-1α levels in colonic tissue and increased edema, ulceration, crypt loss, and inflammatory cell infiltration. Consistent with the more severe antecedent colitis, PAR-1−/− mice challenged with AOM/DSS developed significantly larger adenomas than WT mice challenged and evaluated in parallel. Thus, the impact of PAR-1 on colitis appears to be context-dependent and the distinct outcomes in TNBS- and DSS-challenged mice are likely to stem from the different mechanisms by which these agents induce colitis. TNBS is thought to haptenate colonic mucosal proteins inducing a T cell-mediated colitis akin to human Crohn's disease. In contrast, DSS directly intoxicates colonic crypt epithelia, resulting in loss of barrier function and translocation of colonic microflora, leading to a primarily innate immune-driven colitis sharing many features with ulcerative colitis. A major challenge in dissecting the precise mechanisms coupling PAR-1 to colitis is the fact that PAR-1 is expressed on multiple cell types that can influence colitis and CAC in distinct ways, including immune cells, endothelial cells and colonic mucosa. Therefore, we recently generated mice carrying a conditional “floxed” PAR-1 allele. We interbred these animals with mice expressing Cre recombinase in either colonic epithelia or the hematopoietic/endothelial compartment. Preliminary studies revealed that loss of PAR-1 expression in the hematopoietic/endothelial compartments, but not the colonic epithelia, recapitulates the more severe DSS-induced weight loss and mucosal damage observed in constitutionally PAR-1-deficient mice. These results suggest that PAR-1 activation in either immune cells and/or endothelial cells limits colitis severity in this experimental context. Taken together, these data show that PAR-1 contributes to the pathogenesis of inflammatory colitis and CAC, but the precise contribution is dependent on the underlying insult and disease pathway. Analyses in mice carrying a conditional PAR-1 allele should prove invaluable for dissecting the precise mechanisms coupling PAR-1 to inflammatory bowel disease. Disclosures: Palumbo: Novo Nordisk Corporation: Consultancy.
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Renga, Giorgia, Marina M. Bellet, Marilena Pariano, Marco Gargaro, Claudia Stincardini, Fiorella D’Onofrio, Paolo Mosci, et al. "Thymosin α1 protects from CTLA-4 intestinal immunopathology." Life Science Alliance 3, no. 10 (August 14, 2020): e202000662. http://dx.doi.org/10.26508/lsa.202000662.
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The advent of immune checkpoint inhibitors has represented a major boost in cancer therapy, but safety concerns are increasingly being recognized. Indeed, although beneficial at the tumor site, unlocking a safeguard mechanism of the immune response may trigger autoimmune-like effects at the periphery, thus making the safety of immune checkpoint inhibitors a research priority. Herein, we demonstrate that thymosin α1 (Tα1), an endogenous peptide with immunomodulatory activities, can protect mice from intestinal toxicity in a murine model of immune checkpoint inhibitor–induced colitis. Specifically, Tα1 efficiently prevented immune adverse pathology in the gut by promoting the indoleamine 2,3-dioxygenase (IDO) 1–dependent tolerogenic immune pathway. Notably, Tα1 did not induce IDO1 in the tumor microenvironment, but rather modulated the infiltration of T-cell subsets by inverting the ratio between CD8+ and Treg cells, an effect that may depend on Tα1 ability to regulate the differentiation and chemokine expression profile of DCs. Thus, through distinct mechanisms that are contingent upon the context, Tα1 represents a plausible candidate to improve the safety/efficacy profile of immune checkpoint inhibitors.
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Cox, Jennifer H., Noelyn M. Kljavin, Nandhini Ramamoorthi, Lauri Diehl, Marcel Batten, and Nico Ghilardi. "IL-27 promotes T cell–dependent colitis through multiple mechanisms." Journal of Experimental Medicine 208, no. 1 (December 20, 2010): 115–23. http://dx.doi.org/10.1084/jem.20100410.
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Interleukin-27 (IL-27) is a cytokine known to have both proinflammatory and immunoregulatory functions. The latter appear to dominate in vivo, where IL-27 suppresses TH17 responses and promotes the differentiation of Tr1 cells expressing interferon-γ and IL-10 and lacking forkhead box P3 (Foxp3). Accordingly, IL-27 receptor α (Il27ra)–deficient mice suffer from exacerbated immune pathology when infected with various parasites or challenged with autoantigens. Because the role of IL-27 in human and experimental mouse colitis is controversial, we studied the consequences of Il27ra deletion in the mouse T cell transfer model of colitis and unexpectedly discovered a proinflammatory role of IL-27. Absence of Il27ra on transferred T cells resulted in diminished weight loss and reduced colonic inflammation. A greater fraction of transferred T cells assumed a Foxp3+ phenotype in the absence of Il27ra, suggesting that IL-27 functions to restrain regulatory T cell (Treg) development. Indeed, IL-27 suppressed Foxp3 induction in vitro and in an ovalbumin-dependent tolerization model in vivo. Furthermore, effector cell proliferation and IFN-γ production were reduced in the absence of Il27ra. Collectively, we describe a proinflammatory role of IL-27 in T cell–dependent intestinal inflammation and provide a rationale for targeting this cytokine in pathological situations that result from a breakdown in peripheral immune tolerance.
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Krizaj, Igor. "Roles of Secreted Phospholipases A2 in the Mammalian Immune System." Protein & Peptide Letters 21, no. 12 (November 5, 2014): 1201–8. http://dx.doi.org/10.2174/0929866521666140819122624.
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Secreted phospholipase A2 (sPLA2) molecules constitute a family of proteins that are involved functionally in many biological processes. In particular, they participate in diverse pathophysiological settings as enzymes that release free fatty acids and lysophospholipids from phospholipids in biological membranes, or as ligands for various cellular receptors. In this review the confirmed or expected functions of sPLA2s in the mammalian immune system are surveyed. Some of the twelve mammalian sPLA2 molecules constitute part of the so-called innate immune system by virtue of their antibacterial, antiviral and antifungal activities. They are also involved in acute inflammation, a protective reaction of the body to infection or injury. The acute inflammation sometimes escapes regulation, becomes chronic and can evolve into a severe pathology. One or more types of sPLA2 are involved in asthma, rheumatoid arthritis, sepsis, atherosclerosis, myocardial infarction, Crohn’s disease, ulcerative colitis and cancer. sPLA2s are thus important therapeutic targets as well as biotherapeutic molecules. Improving the selectivity of inhibitors of sPLA2s to be able to target a particular sPLA2 could therefore be one of the most important tasks for future research.
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Kleinwort, Annabel, Paula Döring, Christine Hackbarth, Claus-Dieter Heidecke, and Tobias Schulze. "Deviation of the Fecal Stream in Colonic Bowel Segments Results in Increased Numbers of Isolated Lymphoid Follicles in the Submucosal Compartment in a Novel Murine Model of Diversion Colitis." BioMed Research International 2017 (2017): 1–10. http://dx.doi.org/10.1155/2017/5265969.
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Introduction.Diversion colitis is a significant health problem due to its high incidence in patients with diverting enterostomy. This mucosal inflammation presents characteristic histopathological features allowing for the differentiation of this entity from other inflammatory bowel diseases. The pathophysiology of this disease remains ill-defined, in part due to the lack of appropriate animal models. The present study was performed in order to develop and characterize a murine model of diversion colitis.Methods.A diverting loop colostomy was performed in C57BL/6 mice either in the ascending colon or in the transverse colon. Animals were assessed for clinical and histopathological parameters during short-term and long-term survival.Results.Animals with a colostomy in the transverse colon showed a good long-term survival and developed a mild colitis in the bypassed bowel closely resembling the human pathology on a histopathological level.Conclusion.This model is a promising tool to further elucidate the pathomechanism leading to impaired mucosal homeostasis in bypassed colonic segments. Moreover, the establishment of the model in the C57BL/6 background allows the combination of this colitis model with various transgenic mouse strains to investigate the effect of locally deregulated mucosal immunity on systemic immune homeostasis and to develop specific therapeutic strategies.
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Nair, Divek V. T., Devendra Paudel, Margherita Cantorna, and Vishal Singh. "DIETARY FIBER GUAR GUM EXACERBATES COLONIC INFLAMMATION IN MULTIPLE EXPERIMENTAL MODELS OF INFLAMMATORY BOWEL DISEASE." Inflammatory Bowel Diseases 27, Supplement_1 (January 1, 2021): S2—S3. http://dx.doi.org/10.1093/ibd/izaa347.004.
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Abstract The role of fermentable dietary fibers in patients with inflammatory bowel disease (IBD) is not understood. Herein, we elucidated the effect of dietary fiber guar gum, commonly added to a wide range of processed foods, on colonic inflammation. The use of three different IBD models allowed us to examine the effect of guar gum on various aspects of human IBD, such as immune hyperactivity [IL-10 receptor (IL-10R) neutralization], epithelial injury [dextran sulfate sodium (DSS)], and infection [Citrobacter rodentium (CR)]-mediated inflammation. Wild-type (WT, C57BL/6) mice fed either control cellulose (insoluble fiber, aka non-fermentable fiber) or guar gum (soluble fiber, aka fermentable fiber, 7.5% w/w) were administered four weekly injections of IL-10R neutralizing antibody (α-IL-10R) to induce immune-hyperactivation mediated chronic colitis. Guar gum treated mice developed robust α-IL-10R mediated colitis. Guar gum fed mice had splenomegaly, colomegaly, elevated systemic proinflammatory markers [serum amyloid A (SAA), lipocalin 2 (Lcn2) and keratinocyte-derived chemokine (KC)] and elevated colonic Lcn2 and interleukin (IL)-1β, and histopathology scores compared to control, cellulose-fed, mice. Similar results were observed in Toll-like receptor 5 deficient mice, which are prone to develop microbiota-dependent colitis. Next, to examine the effect of guar gum on the epithelial injury model, mice were treated with DSS (1.4% w/v in drinking water) for seven days. The guar gum fed group developed severe colitis, including reduced body weight, diarrhea, rectal bleeding, shortening of colon length, and elevated levels of pro-inflammatory markers (Lcn2, KC, and SAA)compared to the control group. The last model to be tested was infection-induced colitis. Since inflammation is required to clear the infection, we hypothesized that guar gum fed mice might clear CR infection better than controls. To our surprise, guar gum fed WT mice shed higher numbers of CR in the feces than the cellulose group. The guar gum fed mice had lower body weights, colomegaly, an elevated level of colonic and serum Lcn2, and higher serum SAA than the control group. Collectively, guar gum failed to protect against CR-induced colonic pathology. Altogether, the work demonstrates that guar gum feeding may exacerbate colonic inflammation following immune-hyperactivation, chemical, and infectious injury. Cautioning IBD patients to monitor their consumption of guar gum fiber might be a way to reduce the severity of intestinal inflammation.
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Christophi, George P., Yeshika Sharma, Quader Farhan, Umang Jain, Ted Walker, Gregory S. Sayuk, and Deborah C. Rubin. "Erdheim-Chester Disease Presenting with Histiocytic Colitis and Cytokine Storm." Journal of Gastrointestinal and Liver Diseases 26, no. 2 (June 1, 2017): 183–87. http://dx.doi.org/10.15403/jgld.2014.1121.262.erd.
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Background: Non-Langerhans histiocytosis is a group of inflammatory lymphoproliferative disorders originating from non-clonal expansion of hematopoietic stem cells into cytokine-secreting dendritic cells or macrophages. Erdheim-Chester Disease (ECD) is a rare type of non-Langerhans cell histiocytosis characterized by tissue inflammation and injury caused by macrophage infiltration and histologic findings of foamy histiocytes. Often ECD involves the skeleton, retroperitoneum and the orbits. This is the first report documenting ECD manifesting as segmental colitis and causing cytokine-release syndrome.Case presentation: A 68-year old woman presented with persistent fever without infectious etiology and hematochezia. Endoscopy showed segmental colitis and pathology revealed infiltration of large foamy histiocytes CD3-/CD20-/CD68+/CD163+/S100- consistent with ECD. The patient was empirically treated with steroids but continued to have fever and developed progressive distributive shock.Conclusion: This case report describes the differential diagnosis of infectious and immune-mediated inflammatory and rheumatologic segmental colitis. Non-Langerhans histiocytosis and ECD are rare causes of gastrointestinal inflammation. Prompt diagnosis is imperative for the appropriate treatment to prevent hemodynamic compromise due to distributive shock or gastrointestinal bleeding. Importantly, gastrointestinal ECD might exhibit poor response to steroid treatment and other potential treatments including chemotherapy, and biologic treatments targeting IL-1 and TNF-alpha signaling should be considered.Abbreviations: AFB: acid-fast bacilli; ECD: Erdheim-Chester Disease; IBD: inflammatory bowel disease; PASD: periodic acid-Schiff with diastase; TB: tuberculosis
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Coccia, Margherita, Oliver J. Harrison, Chris Schiering, Mark J. Asquith, Burkhard Becher, Fiona Powrie, and Kevin J. Maloy. "IL-1β mediates chronic intestinal inflammation by promoting the accumulation of IL-17A secreting innate lymphoid cells and CD4+ Th17 cells." Journal of Experimental Medicine 209, no. 9 (August 13, 2012): 1595–609. http://dx.doi.org/10.1084/jem.20111453.
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Although very high levels of interleukin (IL)-1β are present in the intestines of patients suffering from inflammatory bowel diseases (IBD), little is known about the contribution of IL-1β to intestinal pathology. Here, we used two complementary models of chronic intestinal inflammation to address the role of IL-1β in driving innate and adaptive pathology in the intestine. We show that IL-1β promotes innate immune pathology in Helicobacter hepaticus–triggered intestinal inflammation by augmenting the recruitment of granulocytes and the accumulation and activation of innate lymphoid cells (ILCs). Using a T cell transfer colitis model, we demonstrate a key role for T cell–specific IL-1 receptor (IL-1R) signals in the accumulation and survival of pathogenic CD4+ T cells in the colon. Furthermore, we show that IL-1β promotes Th17 responses from CD4+ T cells and ILCs in the intestine, and we describe synergistic interactions between IL-1β and IL-23 signals that sustain innate and adaptive inflammatory responses in the gut. These data identify multiple mechanisms through which IL-1β promotes intestinal pathology and suggest that targeting IL-1β may represent a useful therapeutic approach in IBD.
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Siciliani, E. A., T. Arai, L. Leroux, M. M. Stevenson, T. G. Geary, F. Lopes, and A. Jardim. "A52 ANALYSIS AND CHARACTERIZATION OF THE EXCRETED/SECRETED PRODUCTS OF PARASITIC HELMINTHS AS IMMUNOMODULATORS OF INFLAMMATORY BOWEL DISEASE (IBD)." Journal of the Canadian Association of Gastroenterology 4, Supplement_1 (March 1, 2021): 8–10. http://dx.doi.org/10.1093/jcag/gwab002.050.
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Abstract Background Parasitic helminths Trichuris suis and Ascaris suum are known to modulate host immune responses. This is thought to be mediated by the secretome, or excreted factors released by these parasites. We are interested in the excretory/secretory products (ESP, TsESP and AsESP) and mechanisms responsible for modulating immune disfunciton in autoinflammatory diseases. Aims This research studies the mechanisms of immune modulation by parasitic helminths in the context of IBD. We aim to describe the cellular response in vitro, as well as the systemic response in vivo, to better characterize the scope of immune modulation in ESP treatment. Methods ESPs were collected from T. suis or A. suum-conditioned media and proteins and metabolites were isolated. Bone marrow (BM) derived macrophages (BMDM) from C57BL6 mice, were treated with ESP fractions, stimulated with LPS, and secreted cytokines levels measured. Alternatively, undifferentiated BM was incubated with or without metabolites throughout the process of differentiation. Using a DSS-colitis model, mice were given 3% DSS or water, then treated with ESP or PBS once daily by IP injection. Colon lengths and TNFα mRNA levels were measured and histological preparations were scored to assess pathology. ESP with bioactivity were selected for further HPLC analysis. Fractions were collected and assayed for bioactivity. Results BMDM treated with T. suis or A. suum crude ESP decreased secretion of TNFα and increased IL-10. BMDM precursors incubated with A. suum metabolites during differentiation had fewer BMDM-like cells. Cytokine analysis showed decreased TNFα secretion. Experiments with Alamar suggested that metabolites remmodelled the BMDM metabolic pathways. These effects are being explored further. We found that metabolites released by A. suum improved DSS-colitis. Specifically, mice with DSS-induced colitis given IP metabolites had reduced colon shortening compared to PBS controls, a lower histologic damage score, as well as lower levels TNFα mRNA expression in gut epithelial cells. HPLC showed multiple peaks from crudes analyzed at 210 nm and 280 nm. HPLC fractions used to treat BMDM yielded varying secretion of TNFα. Bioactive fractions from HPLC coincide with the UV/Vis peaks, further suggesting they could be isolated and studied for immunomodulation. Conclusions These data suggested that ESP contains immunomodulators that may provide lead therapeutic compounds for patients with IBD. Helminth-derived components can immunologically polarize a response in vitro, as well as alter disease recovery in DSS colitis. HPLC fractionation and biological testing suggest that a bioactive molecule can be obtained. Further analysis must be done to determine structure using mass spectrometry and NMR analysis. Funding Agencies Natural Sciences and Engineering Research Council of Canada (NSERC) and Fonds de recherche nature et technologies Québec (FRQNT)
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Markandey, B., M. J. Beyak, S. Perez, P. Manley, and M. Ropeleski. "A195 A RARE CAUSE OF SEVERE REFRACTORY DIARRHEA IN A PATIENT WITH COMMON VARIABLE IMMUNE DEFICIENCY ASSOCIATED INTESTINAL ENTEROPATHY." Journal of the Canadian Association of Gastroenterology 4, Supplement_1 (March 1, 2021): 217–19. http://dx.doi.org/10.1093/jcag/gwab002.193.
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Abstract Background CVID is the most common type of severe antibody deficiency. Gastrointestinal manifestations affect approximately 20–50% of patients. Boland et al. described in a case series that 2/3 CVID patients were able to achieve clinical and endoscopic remission with Vedolizumab. This α4β7 integrin antagonist inhibits intestinal T cell translocation by blocking integrin interactions with mucosal vascular addressin cell adhesion molecule 1, reducing lymphocyte mediated inflammation. However, despite its novel use for this indication, limited data is available on the consequences of this therapy in patients with CVID. Aims To report on a case assessing the efficacy and outcomes of Vedolizumab for the treatment of CVID associated autoimmune enteropathy. Methods We present the case of a 50-year-old male presenting with severe refractory diarrhea and malnutrition. A colonoscopy demonstrated patchy ulceration and biopsies revealed ulcerated active colitis, negative for CMV. He was treated with Vedolizumab and Total Parental Nutrition (TPN). His diarrhea resolved, he gained 20 kg and he was weaned off TPN. In 2019, he re-presented with severe diarrhea. Subsequently endoscopic evaluation revealed patchy edematous colonic mucosa and biopsies demonstrated minimally active colitis, negative for CMV. He again responded to Vedolizumab re-induction, however shortly after, his diarrhea returned aggressively. CT enterography demonstrated active jejunal inflammation. Subsequently, an EGD revealed multiple duodenal ulcers and luminal narrowing. Biopsies of the small bowel were sent to histopathology. Results CMV superinfection was diagnosed on pathology (image 1). This patient’s diarrhea completely resolved with IV Gancyclovir and he was discharged on maintenance treatment with oral Valganciclovir. Conclusions This represents the first reported case of CMV enteritis secondary to Vedolizumab for the treatment of CVID associated autoimmune enteropathy. In this case, clinical and endoscopic remission was observed with Vedolizumab, however subsequently hampered by CMV reactivation. Hommel et al., published a positive correlation in a single centre retrospective cohort study of CMV reactivation in patients with ulcerative colitis treated with Vedolizumab. A large retrospective review of data from a multicenter consortium database of over 1000 Vedolizumab treated IBD patients reported CMV colitis in only 4 patients. CMV reactivation appears to be an exceptionally rare but important event in patients treated with Vedolizumab. Based on this report, patients with CVID associated enteropathy and refractory diarrhea should be carefully screened for CMV when treated with Vedolizumab. Further prospective data assessing the incidence of CMV reactivation in patients with Vedolizumab therapy is required to further define these findings. Funding Agencies None
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Yagudina, L. A., and D. M. Khakimova. "Common variable immune deficiency in clinical practice." Kazan medical journal 96, no. 2 (April 15, 2015): 249–52. http://dx.doi.org/10.17750/kmj2015-249.
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Primary immunodeficiencies are rare but severe diseases. Out of all primary immunodeficiencies, most commonly diagnosed conditions belong to the group of common variable immune deficiencies. According to criteria of European Society for Immunodeficiencies (ESID) the diagnosis of common variable immune deficiency is extremely likely at considerable decrease (over 2 standard deviation values compared to median value) of two or three main isotypes of immunoglobulins (classes A, G, M). The mean prevalence of variable immune deficiency in general population ranges from 1:50 000 to 1:70 000. This disease has two age peaks of onset: the first peak is between the age of 6 and 10 years; the second peak - between the age of 26-30 years. Moreover, before the disease onset patients are considered as healthy. The range of clinical manifestations, which may help to suspect common variable immune deficiency, is very wide: some patients have repeated pneumonia, others have thrombocytopenic purpura, autoimmune hemolytic anemia or colitis. Low prevalence of primary immunodeficiency in population, a variety of its clinical forms, insufficient awareness of practical doctors dictate the need for detailed description of this pathology on a clinical example. The article presents a case of firstly diagnosed case of common variable immune deficiency in a 26 years old female. Issues of epidemiology, etiology, pathogenesis, clinical symptoms and diagnosis of this disease are described. It is necessary to draw the attention of doctors of various specialties to the fact that changes in the immune system, up to hereditary, genetically determined immunodeficiencies can often be the cause of recurrent inflammatory processes of different localization with a low response to conventional therapy.
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Ranasinghe, Ranmali, and Rajaraman Eri. "CCR6–CCL20-Mediated Immunologic Pathways in Inflammatory Bowel Disease." Gastrointestinal Disorders 1, no. 1 (August 21, 2018): 15–29. http://dx.doi.org/10.3390/gidisord1010003.
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Inflammatory bowel disease (IBD) has evoked significant interest in human immunobiology given its tactical immune evasion methodologies resulting in acute immune destabilization. IBD comprising Crohn’s disease and Ulcerative colitis manifests as chronic inflammation in the gut mucosa, leading to complexities involving immune dysregulation in the T helper lymphocyte arm, effecting disease pathogenicity. The mucosa of the alimentary canal is constantly exposed to a myriad of food antigens and luminal microorganisms for which a consistent host-protective mechanism is operative in healthy people. Lowered mucosal immune expression which allows penetration of the epithelial barrier by infective pathogenic microbes elicits both innate and adaptive immune responses in the gut, culminating in aberrant intestinal inflammation. Interestingly, the IBD leukocyte repertoire is significantly entwined with chemokine-assisted chemotactic navigation into the sites of inflammation, which is also thought to generate favorable immune-suppressive responses. The functions of the cognate chemokine receptor, CCR6, which binds with its unique ligand CCL20, are expected to tilt the balance between upregulation of homeostatic tolerance and inflammatory pathophysiology. This review aims to critically examine the CCR6-driven immune pathways: TH1/TH2, TH1/TH17, TH17/Treg, IL-23/IL-17, Akt/ERK-1/2, ILC3, and TH9/TH2 for systematic investigation of its underlying mechanisms in the future and to underpin its importance in resolving IBD pathology. Thus, CCR6 occupies an exclusive position in gut immunology which renders it an invaluable therapeutic tool for the production of novel medicaments to treat IBD.
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Abron, Jessica D., Narendra P. Singh, Manoj K. Mishra, Robert L. Price, Mitzi Nagarkatti, Prakash S. Nagarkatti, and Udai P. Singh. "An endogenous aryl hydrocarbon receptor ligand, ITE, induces regulatory T cells and ameliorates experimental colitis." American Journal of Physiology-Gastrointestinal and Liver Physiology 315, no. 2 (August 1, 2018): G220—G230. http://dx.doi.org/10.1152/ajpgi.00413.2017.
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Inflammatory bowel disease (IBD) is a chronic intestinal inflammatory condition that affects millions of people with high morbidity and health care costs. The precise etiology of IBD is unknown, but clear evidence suggests that intestinal inflammation is caused by an excessive immune response to mucosal antigens. Recent studies have shown that activation of the aryl hydrocarbon receptor (AhR) induces regulatory T cells (Tregs) and suppresses autoimmune diseases. In the current study, we investigated if a nontoxic ligand of AhR, 2-(1′ H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE), can attenuate dextran sodium sulfate-induced colitis. Our studies demonstrated that in mice that received ITE treatment in vivo, colitis pathogenesis, including a decrease in body weight, was significantly reversed along with the systemic and intestinal inflammatory cytokines. ITE increased the expression of Tregs in spleen, mesenteric lymph nodes (MLNs), and colon lamina propria lymphocytes (cLPL) of mice with colitis when compared with controls. This induction of Tregs was reversed by AhR antagonist treatment in vitro. ITE treatment also increased dendritic cells (CD11c+) and decreased macrophages (F4/80+) from the spleen, MLNs, and cLPL in mice with colitis. ITE also reversed the systemic and intestinal frequency of CD4+T cells during colitis and suppressed inflammatory cytokines including IFN-γ, TNF-α, IL-17, IL-6, and IL-1 as well as induced IL-10 levels. These findings suggest that ITE attenuates colitis through induction of Tregs and reduction in inflammatory CD4+T cells and cytokines. Therefore, our work demonstrates that the nontoxic endogenous AhR ligand ITE may serve as a therapeutic modality to treat IBD.NEW & NOTEWORTHY We report the novel finding that activation of the aryl hydrocarbon receptor with the nontoxic ligand 2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) induces regulatory T cells (Tregs) and suppresses inflammatory bowel disease (IBD). Our data suggest that ITE diminishes colitis pathology through induction of Tregs; reduces inflammatory cytokines, inflammation score, and macrophage frequency; and induces DCs resulting in amelioration of colitis. Therefore, nontoxic endogenous ITE promotes the induction of Tregs and may be useful for the treatment of IBD.
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Ukrainets, R. V., Yu S. Korneva, G. N. Alenina, and N. V. Doronina. "Morphofunctional features of mucosa-associated lymphoid tissue of intestine as an organ of immune system and its role in the development of diseases." Journal of Anatomy and Histopathology 9, no. 3 (October 10, 2020): 86–93. http://dx.doi.org/10.18499/2225-7357-2020-9-3-86-93.
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Reticuloendothelial system (RES) is considered one of the local immune response regulation centers. It takes part in most physiological and pathological processes, namely, in local homeostasis, in regulation of trophism and immunological responses of both primary and secondary immune responses. The main cell population of (RES) is a macrophage, which is a stationary cell that can move only within the tissue layer. Dendritic cells as representatives of (RES) as well are under direct control of macrophages. Up to 80% of all immunocompetent cells are concentrated in the intestinal mucosa. For adequate interaction with the intestinal microbiota and ensuring immunological tolerance to normal commensals, there is a lymphoid tissue associated with the intestinal mucosa (gut-associated lymphoid tissue – GALT), in which mononuclear phagocytes perform their most significant functions. When pathogenic microorganisms enter the mucosa, the network of resident macrophages as an immune barrier triggers an inflammatory response to further stabilize homeostasis. However, a pronounced microbial and antigenic load in the gut requires the mandatory presence of specific immune cells – lymphocytes, whose immature forms are located in GALT structures and specialize under the guidance of mononuclear phagocytes. After the final differentiation, lymphocytes expressing integrin α4β7 are able to return from the systemic bloodstream to the intestinal mucosa to perform highly specific functions. This phenomenon is called the homing effect. It was noted that in non-specific ulcerative colitis and Crohn's disease, both the number of regulatory T-lymphocytes and their expression of integrin α4β7 increases. The pathology of the homing effect, according to some researchers, explains the possibility of follow-up secondary lesions in chronic inflammatory bowel diseases with the development of systemic pathology.
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Seiffart, Virginia, Julia Zoeller, Robert Klopfleisch, Munisch Wadwa, Wiebke Hansen, Jan Buer, Christian Riedel, and Astrid M. Westendorf. "IL10-Deficiency in CD4+ T Cells Exacerbates the IFNγ and IL17 Response During Bacteria Induced Colitis." Cellular Physiology and Biochemistry 36, no. 4 (2015): 1259–73. http://dx.doi.org/10.1159/000430295.
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Background/Aims: IL10 is a key inhibitor of effector T cell activation and a mediator of intestinal homeostasis. In addition, IL10 has emerged as a key immunoregulator during infection with various pathogens, ameliorating the excessive T-cell responses that are responsible for much of the immunopathology associated with the infection. Because IL10 plays an important role in both intestinal homeostasis and infection, we studied the function of IL10 in infection-associated intestinal inflammation. Methods: Wildtype mice and mice deficient in CD4+ T cell-derived or regulatory T cells-derived IL10 were infected with the enteric pathogen Citrobacter (C.) rodentium and analyzed for the specific immune response and pathogloy in the colon. Results: We found that IL10 expression is upregulated in colonic tissue after infection with C. rodentium, especially in CD4+ T cells, macrophages and dendritic cells. Whereas the deletion of IL10 in regulatory T cells had no effect on C. rodentium induced colitis, infection of mice deficient in CD4+ T cell-derived IL10 exhibited faster clearance of the bacterial burden but worse colitis, crypt hyperplasia, and pathology than did WT mice. In addition, the depletion of CD4+ T cell-derived IL10 in infected animals was accompanied by an accelerated IFNγ and IL17 response in the colon. Conclusion: Thus, we conclude that CD4+ T cell-derived IL10 is strongly involved in the control of C. rodentium-induced colitis. Interference with this network could have implications for the treatment of infection-associated intestinal inflammation.
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Ryz, Natasha R., Scott J. Patterson, Yiqun Zhang, Caixia Ma, Tina Huang, Ganive Bhinder, Xiujuan Wu, et al. "Active vitamin D (1,25-dihydroxyvitamin D3) increases host susceptibility toCitrobacter rodentiumby suppressing mucosal Th17 responses." American Journal of Physiology-Gastrointestinal and Liver Physiology 303, no. 12 (December 15, 2012): G1299—G1311. http://dx.doi.org/10.1152/ajpgi.00320.2012.
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Vitamin D deficiency affects more that 1 billion people worldwide and is associated with an increased risk of developing a number of inflammatory/autoimmune diseases, including inflammatory bowel disease (IBD). At present, the basis for the impact of vitamin D on IBD and mucosal immune responses is unclear; however, IBD is known to reflect exaggerated immune responses to luminal bacteria, and vitamin D has been shown to play a role in regulating bacteria-host interactions. Therefore, to test the effect of active vitamin D on host responses to enteric bacteria, we gave 1,25(OH)2D3to mice infected with the bacterial pathogen Citrobacter rodentium, an extracellular microbe that causes acute colitis characterized by a strong Th1/Th17 immune response. 1,25(OH)2D3treatment of infected mice led to increased pathogen burdens and exaggerated tissue pathology. In association with their increased susceptibility, 1,25(OH)2D3-treated mice showed substantially reduced numbers of Th17 T cells within their infected colons, whereas only modest differences were noted in Th1 and Treg numbers. In accordance with the impaired Th17 responses, 1,25(OH)2D3-treated mice showed defects in their production of the antimicrobial peptide REG3γ. Taken together, these studies show that 1,25(OH)2D3suppresses Th17 T-cell responses in vivo and impairs mucosal host defense against an enteric bacterial pathogen.
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Murphy, Carola T., Lindsay J. Hall, Grainne Hurley, Aoife Quinlan, John MacSharry, Fergus Shanahan, Kenneth Nally, and Silvia Melgar. "The Sphingosine-1-Phosphate Analogue FTY720 Impairs Mucosal Immunity and Clearance of the Enteric Pathogen Citrobacter rodentium." Infection and Immunity 80, no. 8 (May 21, 2012): 2712–23. http://dx.doi.org/10.1128/iai.06319-11.
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ABSTRACTThe sphingosine-1-phosphate (S1P) analogue FTY720 is therapeutically efficacious in multiple sclerosis and in the prevention of transplant rejection. It prevents the migration of lymphocytes to sites of pathology by trapping them within the peripheral lymph nodes, mesenteric lymph nodes (MLNs), and Peyer's patches. However, evidence suggests that its clinical use may increase the risk of mucosal infections. We investigated the impact of FTY720 treatment on susceptibility to gastrointestinal infection with the mouse enteric pathogenCitrobacter rodentium. This attaching and effacing bacterium induces a transient bacterial colitis in immunocompetent mice that resembles human infection with pathogenicEscherichia coli. FTY720 treatment induced peripheral blood lymphopenia, trapped lymphocytes in the MLNs, and prevented the clearance of bacteria when mice were infected with luciferase-taggedC. rodentium. FTY720-treatedC. rodentium-infected mice had enhanced colonic inflammation, with significantly higher colon mass, colon histopathology, and neutrophil infiltration than vehicle-infected animals. In addition, FTY720-treated infected mice had significantly lower numbers of colonic dendritic cells, macrophages, and T cells. Gene expression analysis demonstrated that FTY720-treated infected mice had an impaired innate immune response and a blunted mucosal adaptive immune response, including Th1 cytokines. The data demonstrate that the S1P analogue FTY720 adversely affects the immune response to and clearance ofC. rodentium.
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Masuda, Junko, Chiho Umemura, Miki Yokozawa, Ken Yamauchi, Takuya Seko, Michiaki Yamashita, and Yumiko Yamashita. "Dietary Supplementation of Selenoneine-Containing Tuna Dark Muscle Extract Effectively Reduces Pathology of Experimental Colorectal Cancers in Mice." Nutrients 10, no. 10 (September 27, 2018): 1380. http://dx.doi.org/10.3390/nu10101380.
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Selenoneine is an ergothioneine analog with greater antioxidant activity and is the major form of organic selenium in the blood, muscles, and other tissues of tuna. The aim of this study was to determine whether a selenoneine-rich diet exerts antioxidant activities that can prevent carcinogenesis in two types of colorectal cancer model in mice. We administrated selenoneine-containing tuna dark muscle extract (STDME) to mice for one week and used azoxymethane (AOM) and dextran sodium sulfate (DSS) for inducing colorectal carcinogenesis. Next, we examined the incidence of macroscopic polyps and performed functional analysis of immune cells from the spleen. We also studied tumor formation rates and median survival following the subcutaneous implantation of a colorectal cancer cell line. In the AOM/DSS-induced colitis-associated cancer (CAC) model, the oral administration of STDME significantly decreased tumor incidence and inhibited the accumulation of myeloid-derived suppressor cells (MDSCs) while also inhibiting the downregulation of interferon-γ (IFN-γ) production during carcinogenesis. These results suggest that dietary STDME may be an effective agent for reducing colorectal tumor progression.
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Yokoyama, Yoko, Ken Fukunaga, Hiroto Miwa, and Takayuki Matsumoto. "S1701 The Relevance of CD25HighCD4+ and the CD28-CD4+ T Cells to the Understanding of Immune Pathology in Patients with Ulcerative Colitis." Gastroenterology 136, no. 5 (May 2009): A—253. http://dx.doi.org/10.1016/s0016-5085(09)61147-1.
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Gonçalves, Nathalie S., Marjan Ghaem-Maghami, Giovanni Monteleone, Gad Frankel, Gordon Dougan, David J. M. Lewis, Cameron P. Simmons, and Thomas T. MacDonald. "Critical Role for Tumor Necrosis Factor Alpha in Controlling the Number of Lumenal Pathogenic Bacteria and Immunopathology in Infectious Colitis." Infection and Immunity 69, no. 11 (November 1, 2001): 6651–59. http://dx.doi.org/10.1128/iai.69.11.6651-6659.2001.
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ABSTRACT Infection of mice with the intestinal bacterial pathogenCitrobacter rodentium results in colonic mucosal hyperplasia and a local Th1 inflammatory response similar to that seen in mouse models of inflammatory bowel disease. In these latter models, and in patients with Crohn's disease, neutralization of tumor necrosis factor alpha (TNF-α) is of therapeutic benefit. Since there is no information on the role of TNF-α in either immunity to noninvasive bacterial pathogens or on the role of TNF-α in the immunopathology of infectious colitis, we investigated C. rodentiuminfection in TNFRp55−/− mice. In TNFRp55−/−mice, there were higher colonic bacterial burdens, but the organisms were cleared at the same rate as C57BL/6 mice, showing that TNF-α is not needed for protective antibacterial immunity. The most striking feature of infection in TNFRp55−/−mice, however, was the markedly enhanced pathology, with increased mucosal weight and thickness, increased T-cell infiltrate, and a markedly greater mucosal Th1 response. Interleukin-12 p40 transcripts were markedly elevated in C. rodentium-infected TNFRp55−/− mice, and this was associated with enhanced mucosal STAT4 phosphorylation. TNF-α is not obligatory for protective immunity to C. rodentium in mice; however, it appears to play some role in downregulating mucosal pathology and Th1 immune responses.
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Kudelka, Matthew R., Benjamin H. Hinrichs, Trevor Darby, Carlos S. Moreno, Hikaru Nishio, Christopher E. Cutler, Jianmei Wang, et al. "Cosmcis an X-linked inflammatory bowel disease risk gene that spatially regulates gut microbiota and contributes to sex-specific risk." Proceedings of the National Academy of Sciences 113, no. 51 (December 7, 2016): 14787–92. http://dx.doi.org/10.1073/pnas.1612158114.
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Inflammatory bowel disease (IBD) results from aberrant immune stimulation against a dysbiotic mucosal but relatively preserved luminal microbiota and preferentially affects males in early onset disease. However, factors contributing to sex-specific risk and the pattern of dysbiosis are largely unexplored. Core 1 β3GalT-specific molecular chaperone (Cosmc), which encodes an X-linked chaperone important for glycocalyx formation, was recently identified as an IBD risk factor by genome-wide association study. We deletedCosmcin mouse intestinal epithelial cells (IECs) and found marked reduction of microbiota diversity in progression from the proximal to the distal gut mucosa, but not in the overlying lumen, as seen in IBD. This loss of diversity coincided with local emergence of a proinflammatory pathobiont and distal gut restricted pathology. Mechanistically, we found that Cosmc regulates host genes, bacterial ligands, and nutrient availability to control microbiota biogeography. Loss of oneCosmcallele in males (IEC-Cosmc-/y) resulted in a compromised mucus layer, spontaneous microbe-dependent inflammation, and enhanced experimental colitis; however, females with loss of one allele and mosaic deletion ofCosmcin 50% of crypts (IEC-Cosmc+/−) were protected from spontaneous inflammation and partially protected from experimental colitis, likely due to lateral migration of normal mucin glycocalyx from WT cells over KO crypts. These studies functionally validateCosmcas an IBD risk factor and implicate it in regulating the spatial pattern of dysbiosis and sex bias in IBD.
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Zhang, A., Y. Pang, S. Menzies, and L. M. Sly. "A6 THE ROLE OF TUFT CELLS IN INTESTINAL HOMEOSTASIS." Journal of the Canadian Association of Gastroenterology 4, Supplement_1 (March 1, 2021): 6–7. http://dx.doi.org/10.1093/jcag/gwab002.005.
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Abstract Background Intestinal epithelial cells may actively regulate homeostasis by recognizing and responding to extracellular signals. One of these cell types, tuft cells, has been proposed to have a role in secretion, absorption, and reception. However, their role in the intestine has not been fully characterized. We have found that tuft cells express the SH2 domain-containing inositol 5’-phosphatase (SHIP), which was formerly thought to be restricted to hematopoietic cells. SHIP negatively regulates PI3K-mediated cell growth, proliferation, and activation. Tuft cells secrete IL-25, which activates group 2 innate lymphoid cells (ILC2s), leading to type 2 immune responses. Tuft cells may contribute to inflammation in the intestine by increasing ILC2 numbers and/or activation, leading to type II inflammation. Aims My hypothesis is that SHIP inhibits tuft cell responses to innate immune stimuli by limiting PI3K activation. Moreover, SHIP deficiency will increase tuft cell responses to commensal microbes, causing ILC2-mediated type II inflammation. To investigate the role of SHIP in tuft cell responses in vivo, I will use a tuft cell-specific SHIP deficient mouse in the dextran sodium sulfate (DSS)-induced colitis model. Methods We created a mouse deficient in SHIP only in intestinal tuft cells (Fabpcre x SHIPfl/fl) to investigate the impact of SHIP deficiency in tuft cells on responses to luminal microbes. Tuft cell-specific SHIP deficient mice (8-week-old) and their wild type littermates were subjected to DSS-induced colitis for 7 days. Clinical disease activity was monitored daily and gross pathology, including total colon length, was examined at the experimental endpoint. The concentrations of pro-inflammatory type I and type II cytokines were assessed in colonic tissue homogenates via ELISA. Results During DSS-induced colitis, mice with SHIP deficient tuft cells had increased disease activity compared to their wild type littermates, particularly evident in their weight loss. Mice with SHIP deficient tuft cells also had significantly shorter colons than their wild type littermates. IL-25 concentrations (produced by tuft cells) were increased in full thickness colon homogenates from mice with SHIP deficient tuft cells. In contrast, pro-inflammatory cytokines IL-1β, IL-6, and TNF did not differ between genotypes. Thus, increased tuft cell activity due to SHIP deficiency correlated with increased disease severity during DSS-induced colitis. Conclusions SHIP deficiency in intestinal tuft cells leads to increased tuft cell activity and exacerbated colitis during DSS treatment. Tuft cells may contribute to inflammation via IL-25 production, leading to increased type II inflammation by ILC2s. In future studies, we will target IL-25 in this model to determine whether increased tuft cell IL-25 production plays a causal role in disease exacerbation. Funding Agencies NSERC
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Maye, H., S. Ekaterina, and A. Schoepfer. "P806 Increasing incidence of microscopic colitis in a population-based cohort study in a French speaking region of Switzerland." Journal of Crohn's and Colitis 14, Supplement_1 (January 2020): S630—S631. http://dx.doi.org/10.1093/ecco-jcc/jjz203.934.
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Abstract Background Microscopic colitis (MC) is a chronic inflammatory disease of the colon presenting with watery diarrhoea. It encompasses two entities, namely lymphocytic colitis (LC) and collagenous colitis (CC). Population-based epidemiologic data the frequency and natural history of microscopic colitis are scarce. We evaluated the clinical presentation at diagnosis, incidence and prevalence of MC in Cantons of Vaud and Fribourg, Switzerland. Methods Cantons of Vaud and Fribourg lie in the French-speaking, Western part of Switzerland. As of 12/2017, both cantons together had a population of 1,109,230 inhabitants. We contacted all Pathology institutes (n = 6) in both cantons in order to identify patients that have been diagnosed with microscopic colitis. We then performed a chart review in all adult and paediatric gastroenterology practices in order to identify MC patients and to assess the incidence, prevalence, their clinical, endoscopic, and histological characteristics as well as natural history. Results Out of 252 patients, a total of 218 fulfilled the diagnostic criteria for MC, whereof 123 had LC and 95 had CC. Age at first diagnosis of MC was 63.2 ± 14.3 years (62.8 ± 14.3 for LC, 63.7 ± 14.4 years) and median diagnostic delay was 1.1 ± 3.1 years. Symptoms leading to MC diagnosis were diarrhoea (100%), abdominal pain (31.7%), weight loss (31.2%), bloating (20.6%), fatigue (9.6%), and nausea/vomiting (3.2%). The following risk factors were found in MC patients: statins (27.1%), aspirine (23.4%), proton pump inhibitors (22.5%), serotonine reuptake inhibitors (22.5%), smoking (20.2%), non steroidal anti-inflammatory drugs (14.2%), and neuroleptics (4.1%). Median exposure time to risk factors was 55 months (IQR 33–78, range 1–280 months). Associated auto-immune diseases (celiac disease, type 1 diabetes, autoimmune gastritis, autoimmune thyroiditis, rheumatoid arthritis) were found in 14 patients (6.4%). No patient was diagnosed with MC prior to 1994. Incidence of MC significantly increased from 0.36/100,000 inhabitants in 1994–1997 to 6.85/100,000 inhabitants in 2017 (p = 0.025). The cumulative prevalence of MC, LC, and CC in 2017 was 19.65/100,000, 11.09/100,000, and 8.56/100,000, respectively. Conclusion The incidence and cumulative prevalence of MC shows a steady increase in an indicator region of roughly 1 million inhabitants in French speaking part of Switzerland.
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Mann, Elizabeth R., Jialu You, Verena Horneffer-van der Sluis, David Bernardo, Hafid Omar Al-Hassi, Jon Landy, Simon T. Peake, et al. "Dysregulated Circulating Dendritic Cell Function in Ulcerative Colitis Is Partially Restored by Probiotic StrainLactobacillus caseiShirota." Mediators of Inflammation 2013 (2013): 1–12. http://dx.doi.org/10.1155/2013/573576.
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Background. Dendritic cells regulate immune responses to microbial products and play a key role in ulcerative colitis (UC) pathology. We determined the immunomodulatory effects of probiotic strainLactobacillus caseiShirota (LcS) on human DC from healthy controls and active UC patients.Methods. Human blood DC from healthy controls (control-DC) and UC patients (UC-DC) were conditioned with heat-killed LcS and used to stimulate allogeneic T cells in a 5-day mixed leucocyte reaction.Results. UC-DC displayed a reduced stimulatory capacity for T cells (P<0.05) and enhanced expression of skin-homing markers CLA and CCR4 on stimulated T cells (P<0.05) that were negative for gut-homing markerβ7. LcS treatment restored the stimulatory capacity of UC-DC, reflecting that of control-DC. LcS treatment conditioned control-DC to induce CLA on T cells in conjunction withβ7, generating a multihoming profile, but had no effects on UC-DC. Finally, LcS treatment enhanced DC ability to induce TGFβproduction by T cells in controls but not UC patients.Conclusions. We demonstrate a systemic, dysregulated DC function in UC that may account for the propensity of UC patients to develop cutaneous manifestations. LcS has multifunctional immunoregulatory activities depending on the inflammatory state; therapeutic effects reported in UC may be due to promotion of homeostasis.
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Notararigo, Sara, Manuel Martín-Pastor, Juan E. Viñuela-Roldán, Adriano Quiroga, J. Enrique Dominguez-Munoz, and Manuel Barreiro-de Acosta. "Targeted 1H NMR metabolomics and immunological phenotyping of human fresh blood and serum samples discriminate between healthy individuals and inflammatory bowel disease patients treated with anti-TNF." Journal of Molecular Medicine 99, no. 9 (May 21, 2021): 1251–64. http://dx.doi.org/10.1007/s00109-021-02094-y.
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Abstract Inflammatory bowel disease is a multifactorial etiology, associated with environmental factors that can trigger both debut and relapses. A high level of tumor necrosis factor-α in the gut is the main consequence of immune system imbalance. The aim of treatment is to restore gut homeostasis. In this study, fresh blood and serum samples were used to identify biomarkers and to discriminate between Crohn’s disease and ulcerative colitis patients under remission treated with anti-TNF. Metabolomics based on Nuclear Magnetic Resonance spectroscopy (NMR) was used to detect unique biomarkers for each class of patients. Blood T lymphocyte repertories were characterized, as well as cytokine and transcription factor profiling, to complement the metabolomics data. Higher levels of homoserine-methionine and isobutyrate were identified as biomarkers of Crohn’s disease with ileocolic localization. For ulcerative colitis, lower levels of creatine-creatinine, proline, and tryptophan were found that reflect a deficit in the absorption of essential amino acids in the gut. T lymphocyte phenotyping and its functional profiling revealed that the overall inflammation was lower in Crohn’s disease patients than in those with ulcerative colitis. These results demonstrated that NMR metabolomics could be introduced as a high-throughput evaluation method in routine clinical practice to stratify both types of patients related to their pathology. Key messages NMR metabolomics is a non-invasive tool that could be implemented in the normal clinical practice for IBD to assess beneficial effect of the treatment. NMR metabolomics is a useful tool for precision medicine, in order to sew a specific treatment to a specific group of patients. Finding predictors of response to IFX would be desirable to select patients affected by IBD. Immunological status of inflammations correlates with NMR metabolomics biomarkers.