scholarly journals The Possible Pathogenic Role of IgG4-Producing Plasmablasts in Stricturing Crohn’s Disease

Pathobiology ◽  
2022 ◽  
pp. 1-11
Author(s):  
Omar Bushara ◽  
David Joseph Escobar ◽  
Samuel Edward Weinberg ◽  
Leyu Sun ◽  
Jie Liao ◽  
...  

<b><i>Background:</i></b> Crohn’s disease (CD) is a condition on the spectrum of inflammatory bowel disease that affects up to 20 people per 100,000 in the US annually, and with incidence increasing. One of the most significant sources of morbidity in CD is the formation of strictures, with resultant intestinal blockage a common indication for hospitalization and surgical intervention in these patients. The pathophysiology of stricture formation is not fully understood. However, the fibroplasia that leads to fibrostenotic stricture formation may have shared pathophysiology with IgG4-related fibrosis. <b><i>Summary:</i></b> Initial intestinal inflammation recruits innate immune cells, such as neutrophils, that secrete IL-1β and IL-23, which induces a type 17 CD4+ T-helper T-cell (Th17)-mediated adaptive immune response. These CD4+ Th17 T cells also contribute to inflammation by secreting proinflammatory cytokines such as IL-17 and IL-21. IL-21 recruits and stimulates CD4+ T follicular helper (Tfh) cells, which secrete more IL-21. This causes ectopic germinal center formation, recruiting and stimulating naïve B cells. The IL-17 and IL-21 produced by Th17 cells and Tfh cells also induce IgG4 plasmablast differentiation. Finally, these IgG4-producing plasmablasts secrete platelet-derived growth factor (PDGF), which activates local PDGF-receptor expressing fibroblasts and myofibroblasts, resulting in uncontrolled fibroplasia.

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
M. Hornschuh ◽  
E. Wirthgen ◽  
M. Wolfien ◽  
K. P. Singh ◽  
O. Wolkenhauer ◽  
...  

AbstractEpigenetics has become a promising field for finding new biomarkers and improving diagnosis, prognosis, and drug response in inflammatory bowel disease. The number of people suffering from inflammatory bowel diseases, especially Crohn's disease, has increased remarkably. Crohn's disease is assumed to be the result of a complex interplay between genetic susceptibility, environmental factors, and altered intestinal microbiota, leading to dysregulation of the innate and adaptive immune response. While many genetic variants have been identified to be associated with Crohn's disease, less is known about the influence of epigenetics in the pathogenesis of this disease. In this review, we provide an overview of current epigenetic studies in Crohn's disease. In particular, we enable a deeper insight into applied bioanalytical and computational tools, as well as a comprehensive update toward the cell-specific evaluation of DNA methylation and histone modifications.


2021 ◽  
Vol 18 (1) ◽  
pp. 20-29
Author(s):  
S. A. Bulgakov ◽  
G. M. Chernakova ◽  
E. A. Kleshcheva ◽  
S. V. Simonova

Crohn’s disease and ulcerative colitis are chronic inflammatory bowel diseases, which are often accompanied by inflammation of other organs. This article presents modern data on etiology, pathogenesis and clinical course of inflammatory bowel diseases, as well as information on extraintestinal eye manifestations of nonspecific ulcerative colitis and Crohn’s disease. The role of microbiota, genetic factors, immune system defects in pathogenesis of intestinal inflammation and extraintestinal eye manifestations is considered. The possibility the development of ophthalmopathology not only against the background of intestinal inflammation, but also as a consequence of therapeutic and surgical methods of treatment of ulcerative colitis and Crohn’s disease is noted. The peculiarities of the course of episcleritis/scleritis, keratitis, uveitis, chorioretinitis, optical neuritis for patients with inflammatory bowel diseases are considered. The presence of these complications may reflect the activity of the underlying disease, which in some cases requires correction of therapy. Anterior uveitis and episcleritis/scleritis are the most common extraintestinal manifestations of inflammatory bowel disease. Inflammation of tissues of the posterior segment of the eye and optic nerve against the background of ulcerative colitis and Crohn’s disease are less common, but are of clinical importance, as they can catastrophically damage the structures of the eye and, as a consequence, lead to complete blindness. Considering the possibility of mild clinical symptoms and asymptomatic course of inflammation in the eye envelopes, the importance of ophthalmological examination of all patients with ulcerative colitis and Crohn’s disease is emphasized. Aspects of modern therapy of ophthalmopathology and background intestinal inflammation are highlighted. Biological preparations — antagonists of pro-inflammatory cytokines — have been identified as the most promising in the treatment of inflammatory intestinal diseases and extraintestinal manifestations. The important role of proper nutrition and biologically active supplements containing omega-3 fatty acids, vitamin D, microelements, was noted as auxiliary therapy of both intestinal and extraintestinal inflammation.


2021 ◽  
Author(s):  
Anjana Bali ◽  
Monika Rani

The initiation of Crohn’s disease, an inflammatory bowel disease, has been primarily associated with crypt inflammation and abscesses, which further progresses towards the development of mucosal lesion and ulcers followed by mucosal edema. Despite many years of research for the confirmatory role of inflammation in this disease, various pathways and diagnosis for this inflammatory cascade is still unrevealed, which in fact is of utmost importance in the assessment of disease activity and for tailoring the therapy. Till now, various histopathological as well as endoscopic examinations has been found to be effectively and accurately assess inflammatory activity, but they are invasive, time consuming and expensive and therefore are unsuitable for routine use. Consequently, the latest research is focusing on various biomarkers of intestinal inflammation and the corresponding biological therapy. So, this chapter will cover the recent advances in diagnosis and pharmacological therapies for the same.


2021 ◽  
Vol 12 (1) ◽  
pp. 56-66
Author(s):  
Toumi Ryma ◽  
Arezki Samer ◽  
Imene Soufli ◽  
Hayet Rafa ◽  
Chafia Touil-Boukoffa

Inflammatory Bowel Disease (IBD) is a term used to describe a group of complex disorders of the gastrointestinal (GI) tract. IBDs include two main forms: Crohn’s Disease (CD) and Ulcerative Colitis (UC), which share similar clinical symptoms but differ in the anatomical distribution of the inflammatory lesions. The etiology of IBDs is undetermined. Several hypotheses suggest that Crohn’s Disease and Ulcerative Colitis result from an abnormal immune response against endogenous flora and luminal antigens in genetically susceptible individuals. While there is no cure for IBDs, most common treatments (medication and surgery) aim to reduce inflammation and help patients to achieve remission. There is growing evidence and focus on the prophylactic and therapeutic potential of probiotics in IBDs. Probiotics are live microorganisms that regulate the mucosal immune system, the gut microbiota and the production of active metabolites such as Short-Chain Fatty Acids (SCFAs). This review will focus on the role of intestinal dysbiosis in the immunopathogenesis of IBDs and understanding the health-promoting effects of probiotics and their metabolites.


2021 ◽  
Vol 12 (9) ◽  
Author(s):  
Fan Zhao ◽  
Tao Zheng ◽  
Wenbin Gong ◽  
Jie Wu ◽  
Haohao Xie ◽  
...  

AbstractCrohn’s disease (CD) is an intestinal immune-dysfunctional disease. Extracellular vesicles (EVs) are membrane-enclosed particles full of functional molecules, e.g., nuclear acids. Recently, EVs have been shown to participate in the development of CD by realizing intercellular communication among intestinal cells. However, the role of EVs carrying double-strand DNA (dsDNA) shed from sites of intestinal inflammation in CD has not been investigated. Here we isolated EVs from the plasma or colon lavage of murine colitis and CD patients. The level of exosomal dsDNA, including mtDNA and nDNA, significantly increased in murine colitis and active human CD, and was positively correlated with the disease activity. Moreover, the activation of the STING pathway was verified in CD. EVs from the plasma of active human CD triggered STING activation in macrophages in vitro. EVs from LPS-damaged colon epithelial cells were also shown to raise inflammation in macrophages via activating the STING pathway, but the effect disappeared after the removal of exosomal dsDNA. These findings were further confirmed in STING-deficient mice and macrophages. STING deficiency significantly ameliorated colitis. Besides, potential therapeutic effects of GW4869, an inhibitor of EVs release were assessed. The application of GW4869 successfully ameliorated murine colitis by inhibiting STING activation. In conclusion, exosomal dsDNA was found to promote intestinal inflammation via activating the STING pathway in macrophages and act as a potential mechanistic biomarker and therapeutic target of CD.


2021 ◽  
Vol 19 (3) ◽  
pp. 70-82
Author(s):  
T.E.Borovik T.E.Borovik ◽  
◽  
A.S.Potapov A.S.Potapov ◽  
E.A.Roslavtseva E.A.Roslavtseva ◽  
A.I.Khavkin A.I.Khavkin ◽  
...  

The characteristics of the diet traditionally recommended for Crohn’s disease often reduce patients’ consumption of essential nutrients. Therefore, an important role belongs to nutritional support with specialized formulas, the effectiveness of which has been proven both for inducing remission and optimizing the parameters of physical development and puberty, bone mineralization. Nutritional support should be provided for patients with newly diagnosed Crohn’s disease in the form of full enteral nutrition, and subsequently in remission, exacerbation, in the pre- and postoperative periods as an addition to the standard diet. Of particular interest is the CDED ModuLife program, which is based on a combination of enteral nutrition with specially selected foods aimed at reducing the activity of intestinal inflammation in Crohn’s disease. Key words: inflammatory bowel disease, Crohn’s disease, full enteral nutrition, partial enteral nutrition, enteral nutrition formulas


2005 ◽  
Vol 288 (2) ◽  
pp. G169-G174 ◽  
Author(s):  
Gert Van Assche ◽  
Paul Rutgeerts

Adhesion molecules regulate the influx of leukocytes in normal and inflamed gut. They are also involved in local lymphocyte stimulation and antigen presentation within the intestinal mucosa. In intestinal inflammation, many adhesion molecules are upregulated, but α4-integrins most likely hold a key position in directing leukocytes into the inflamed bowel wall. Therapeutic compounds directed against trafficking of leukocytes have been designed and are being developed as a novel class of drugs in the treatment of Crohn's disease and ulcerative colitis. This review deals with the immunological aspects of leukocyte trafficking focused on gut homing of T cells. Second, the changes in adhesion molecules and T cell trafficking during intestinal inflammation are discussed. Finally, we review the clinical data that have been gathered with respect to the therapeutic potential and the safety of antiadhesion molecule treatment. Antegren, or natalizumab, a humanized anti-α4 integrin IgG4 antibody, has been most extensively evaluated and may be close to registration. A more specific humanized α4β7-integrin MLN-02 has shown preliminary clinical efficacy in ulcerative colitis, and both antergren and MLN-02 appear to be very safe. Trials with the anti-ICAM-1 antisense oligonucleotide ISIS-2302 in steroid refractory Crohn's disease have provided conflicting efficacy data. In the near future, some of these novel biological agents may prove valuable therapeutic tools in the management of refractory inflammatory bowel disease, although it is too early to define the patient population that will benefit most from these agents.


2020 ◽  
Vol 13 ◽  
pp. 175628482097120
Author(s):  
Xinyun Qiu ◽  
Xiaojing Zhao ◽  
Xiufang Cui ◽  
Xiaqiong Mao ◽  
Nana Tang ◽  
...  

Intestinal microbiota dysbiosis has been described in inflammatory bowel disease (IBD), but data from China are limited. In this study, we performed molecular analysis of the fecal microbial community from 20 healthy Chinese subjects and 25 patients with Crohn’s disease (CD), and evaluated associations with bacterial and fungal compositions. Decreased richness and diversity of bacterial composition was observed in the CD group compared with healthy (H) subjects. Significant structural differences in bacterial (but not fungal) composition among healthy controls and CD patients were found. A reduction in Firmicutes and Actinobacteria abundance, and overrepresentation of Proteobacteria were observed in the CD patients compared with the H group. The Escherichia-Shigella genus was overrepresented in the CD group, whereas Faecalibacterium, Gemmiger, Bifidobacterium, Romboutsia, Ruminococcus, Roseburia, and Fusicatenibacter abundance were decreased in the CD group compared with H subjects. Differences in fungal microbiota between the H and CD groups were observed at the genus rather than at the phylum level. The Candida genus was overrepresented in the CD (active disease) group compared with the H group, whereas no difference between CD (remission) and H groups was observed. Aspergillus, unclassified_Sordariomycetes, and Penicillium genera had greater representation in the H subjects compared with the CD group. Bacterial and fungal intra- and inter-kingdom correlations were observed between the H and CD groups. Therefore, fecal bacterial and fungal microbiome communities differed considerably between H and CD patients, and between Chinese and Western populations. The role of gut microbiota in homeostasis and in gastrointestinal disorders should be investigated further.


2020 ◽  
pp. 135910532090987 ◽  
Author(s):  
Shirley Regev ◽  
Shmuel Odes ◽  
Vered Slonim-Nevo ◽  
Michael Friger ◽  
Doron Schwartz ◽  
...  

Patients with Crohn’s disease, an inflammatory bowel disease, struggle with chronic somatic symptoms that could bring about emotional distress. This study assessed the relative role of somatization, and depressive and anxiety symptoms in disease activity among 619 Crohn’s patients (18–79 years; 58.3% women). Structural equation modeling revealed that somatization was the only unique predictor of disease activity beyond depression and anxiety. In addition, the effect of somatization on disease activity was stronger in men compared to women. Findings suggest that somatization represents a distinct domain of psychological distress that may play a role in the health of patients with Crohn’s disease.


1990 ◽  
Vol 4 (7) ◽  
pp. 404-406 ◽  
Author(s):  
D Grant Gall

As no curative therapy exists, supportive measures play an important role in the management of patients with inflammatory bowel disease (IBO). Aminosalicylic acid (ASA) compounds and corticosteroids remain the mainstay of medical therapy. Aminosalicylates are recommended for therapy of mild to moderate active ulcerative colitis and for the maintenance of remission in ulcerative colitis. The role of 5-ASA preparations in Crohn's disease is less clear. In granulomatous colitis, 5-ASA therapy is recommended. With the development of new delivery systems, the role for 5-ASA in the treatment of small bowel Crohn's disease is under investigation. Prednisone remains the drug of choice in severe ulcerative colitis and active Crohn's disease. The role of immunosuppressive drugs in pediatric patients is unclear. Nutritional therapy has been an important advance in the treatment of children with Crohn's disease, especially those with growth failure. Nutritional therapy can consist of combined total parenteral and enteral nutrition or enteral nutrition alone. An initial period of total parenteral nutrition followed by a six to eight week course of enteral therapy with a semisynthetic diet has been shown to be effective in the management of patients with severe active disease and growth failure.


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