Inflammatory Bowel Diseases

BackgroundKeratins, a major subgroup of intermediate filament proteins, play a critical role in maintaining epithelial barrier and intracellular epithelial integrity. Studies have demonstrated possible links between inflammatory signaling and colonic keratins type II K8, and type I K18, K19 and K20, in animal models of colitis, and in patients with Inflammatory Bowel Disease (IBD). K7 is de novo expressed in patients with the IBD subtypes Ulcerative Colitis (UC) and Crohns Disease (CD). However, the histopathological roles of colonocyte keratins across IBD, microscopic colitis (MC), and Irritable Bowel Syndrome (IBS) remain poorly understood. Given the established utility as biomarkers in cancer diagnostics, we investigated whether keratin expression patterns could be used to distinguish inflammatory and functional colonic disorders. MethodsBiobank samples from patients with IBD (n=27), MC (n=18), IBS (n=32) and healthy controls (n=31), were collected and immunohistochemically stained for K7, K8, K18, K19, and K20. Digital image analysis quantified staining intensities, which were correlated with histopathological severity scores and clinical parameters. ResultsColonic keratin expression was significantly elevated in IBD, particularly in UC, while they were decreased in MC, and unaltered in IBS. Notably, K8 and K19 expression were strongly associated with areas of severe epithelial damage in IBD. Keratin expression was most pronounced in patients who had undergone colectomy due to treatment-resistant IBD. DiscussionKeratin changes in IBD and MC but not in IBS highlight their importance in maintaining barrier homeostasis. Whether these changes are causes or consequences for these diseases will warrant further research.

LIGHT, encoded by the TNFSF14 gene, is a cytokine belonging to the tumor necrosis factor superfamily. Upon binding to its receptors, HVEM and LTBR, it activates inflammatory responses. We used a single-molecule immunoassay to determine the circulating levels of free LIGHT in plasma from pediatric patients with Crohns disease (N = 183) and a panel of healthy pediatric reference samples (N = 9). LIGHT levels were greatly elevated in Crohns disease (average of 305 pg/ml versus 57 pg/ml in controls, P < 0.0001). We performed correlational analyses between LIGHT levels and the clinical characteristics of the Crohns cohort, including age, Montreal classification, family history, medical/surgical therapy, and routine blood test parameters. We found statistically significant correlation between white blood cell count and free LIGHT (P < 0.046). Our results support the hypothesis that elevated levels of the cytokine contribute to the pathology of Crohns disease and that therapies to neutralize free LIGHT with antibodies may be beneficial.

BackgroundPerianal Crohns disease (PCD) represents one of the most severe and refractory forms of pediatric inflammatory bowel disease (IBD). Constipation and colonic redundancy, particularly type 1 dolichocolon (T1-DC), may increase distal rectosigmoid pressure, and exacerbate perianal pathology. We hypothesized that T1-DC is more common in children with PCD than in those with uncomplicated ileocolonic Crohns disease (CD) or non-IBD controls. MethodsWe retrospectively analyzed 20 consecutive pediatric PCD cases (penetrating [B3p] or inflammatory [B1p]) and compared them with 20 patients with non-complicated ileocolonic CD (L3/B1) and 30 non-IBD trauma controls. DC type was determined radiographically using established criteria, focusing on T1- and T2-DC. Constipation history was abstracted from medical records under IRB-approved protocols. ResultsDC was significantly more prevalent in PCD than in ileocolonic CD or controls (p < 0.001), primarily due to T1-DC. The associations persisted (p<0.03) in PCD patients without a history of constipation. ConclusionsRectosigmoid redundancy (T1-DC) may represent an underrecognized anatomic co-morbidity in pediatric PCD, contributing to increased distal pressure and susceptibility to perianal complications. Identification of T1-DC could inform surgical decision-making and postoperative management. Targeted approaches--such as segmental resection during stoma reversal, structured bowel regimens, physical activity, and pelvic-floor biofeedback--may help reduce recurrence risk. Prospective studies are needed to define the mechanistic role of colonic redundancy in the pathogenesis of PCD.

ObjectiveThe impact of medications on COVID-19 vaccine efficacy in IBD patients is unknown, as patients with immunosuppressed states and/or treated with immunosuppressants were excluded from vaccine trials. To address this, we evaluated serological responses to COVID-19 vaccination with the SARS-CoV-2 spike (S) mRNA BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (NIH-Moderna) vaccines in IBD patients enrolled in an ongoing SARS-CoV-2 sero-survey at the Icahn School of Medicine at Mount Sinai in New York City. DesignWe obtained sera from 48 patients who had undergone vaccination with one or two vaccine doses. Sera were tested for SARS-CoV-2 anti-RBD total immunoglobulins and IgG (Siemens COV2T and sCOVG assays), anti-Spike IgG (in-house ELISA), and anti-nucleocapsid antibodies (Roche). ResultsAll IBD patients (15/15) who completed two-dose vaccine schedules achieved seroconversion to high levels. Two IBD patients with history of COVID-19 infections and who were seropositive at baseline seroconverted to high levels after the first dose. Concurrent biologic use was 85% (41/48), including 33% of patients (16) on TNF antagonist monotherapy, 42% (17) on vedolizumab monotherapy, 6% (3) on vedolizumab combination therapy with thiopurine, and 8% (4) ustekinumab; 1 patient was receiving guselkumab for psoriasis. Three patients (6%) were on oral steroids at the time of vaccination. ConclusionIBD patients receiving biologics can seroconvert with robust serological responses after complete Pfizer-BioNTech and NIH-Moderna COVID-19 vaccination. In IBD-patients with previous SARS-CoV-2 seroconversion, a single dose of either vaccine can induce high index values, mirroring findings from the general population.

IntroductionIntestinal barrier failure is a key characteristic of both kinds of inflammatory bowel disease (IBD), ulcerative colitis (UC) and Crohns disease (CD). The intestinal barrier, or gut mucosal barrier, is composed of mucus and a tightly interconnected single layer of intestinal epithelial cells (IEC) that line the gut. Together, these components work to contain the gut microbiota within the gut lumen and when they fail, microbes, microbial products, or microbial components cause damage, inflammation, and immune activation in host tissue. We previously reported that High mobility group box 1 (HMGB1) in colonic mucus aggregates bacteria, limits bacterial invasion through mucus, and prevents bacteria from adhering to host tissue. Epithelial surface-associated HMGB1 is decreased in active UC lesions and low levels of HMGB1 are associated with high levels of tissue-adherent bacteria expressing adhesins carrying the molecular target of HMGB1 (ToH1). The study reported here was designed to determine whether HMGB1 defense is also compromised in active lesions from CD patients. MethodsImmunofluorescence microscopy was used to visualize mucus and HMGB1 in tissue from colonic resections performed in CD and non-IBD control patients. ResultsActive CD lesions had areas where the IEC were absent or pulling away from underlying tissue along with areas of increased mucus thickness and goblet cells full of mucus highly positive for alpha-linked-fucose residues. The surface associated HMGB1 was also decreased in active CD lesions. ConclusionTissue from CD patients exhibited cellular and acellular intestinal barrier defects in comparison to control patients. We observed the previously reported loss of IEC barrier integrity and abnormalities in the amount and distribution of mucus in CD lesions. We also report for the first time that CD is associated with decreased HMGB1 defense at the colon surface.

The human IgA response is composed of two structurally different subclasses termed IgA1 and IgA2. Compared to IgA1, IgA2 has a shorter hinge region, which makes it more resistant to bacterial proteases. IgA1 is produced both systemically and in mucosal surfaces, whereas IgA2 is mostly confined to the intestines. While the overall IgA response is known to be involved in intestinal homeostasis, the specific contribution of IgA1 and IgA2 remains largely unknown (Chen 2020). Selective IgA deficiency (SIgAD) is the most prevalent primary immune deficiency. About half of SIgAD cases are associated with heterogeneous but generally mild clinical manifestations. Anecdotal evidence of IgA2 deficiency is available (van Loghem 1983, Ozawa 1986, Engstrom 1990), however no associations with clinical manifestations have been reported. Here, we describe the occurrence of a selective IgA2 deficiency in a patient (CD068) with small intestinal Crohns disease (CD). The patient had undetectable IgA2+ cells and secreted IgA2 antibody in both intestine and circulation. Among other features, patient CD068 presented with duodenal and ileal inflammation. To our knowledge, this is the first case of IgA2 deficiency with a potential link to IBD, which might shed new insights into potential IgA2-specific functions.

BackgroundInflammatory bowel disease (IBD) manifests systemically, yet most comorbidity studies rely on predominantly European populations. The All of Us Research Program enables investigation across demographically diverse groups. MethodsWe matched 5,094 IBD patients 1:4 with controls by age, gender, and race, analyzing comorbidities using logistic regression with Mantel-Haenszel adjustment. Multiple testing correction used false discovery rate (FDR) with significance thresholds of OR >1.5 or <0.5 and FDR <0.05. ResultsOur cohort included 29.2% non-White participants versus 10-15% in traditional studies. We identified 22 significant associations across seven organ systems. Three novel discoveries included delayed postmyocardial infarction pericarditis (adjusted OR = 4.80), contact dermatitis (adjusted OR = 1.84), and carotid artery aneurysm (adjusted OR = 2.21). Other significant associations included drug-induced lupus (adjusted OR = 4.32), autoimmune hepatitis (adjusted OR = 2.43), and restricting-type eating disorders (adjusted OR = 4.00). IBD patients showed decreased obesity-related conditions. ConclusionThis demographically diverse study discovered novel IBD comorbidities and confirmed established associations across racial groups. Findings support reconceptualizing IBD as a multisystem disorder requiring comprehensive management and demonstrate the importance of diverse research populations.

BackgroundDolichocolon (DC) is an underrecognized anatomic variant associated with constipation; its association with pediatric ulcerative colitis (UC) is unknown. MethodsWe retrospectively reviewed abdominal MRI and CT scans in pediatric UC, Crohns disease (CD), and non-IBD controls, classifying DC subtypes in 111 cases. ResultsDC prevalence was higher in UC than CD or controls. Type 1 DC predominated in proctitis/left-sided UC (E1/E2), while Type 2 DC was enriched in extensive/pancolitis (E3/E4). Complex DC (Types 1+2) was observed only in UC. DiscussionDC may modify UC distribution independent of constipation, representing a potential developmental modifier of pediatric UC phenotype and a nidus for prevention. Graphic abstractCreated with BioRender by D. Berens

BackgroundThe pro-hormone chromogranin A (CgA) and its bioactive cleavage product catestatin (CST) are both associated with inflammatory bowel disease (IBD) and dysregulated barrier functions, but their exact role has remained elusive. Here, we demonstrate that CST regulates the colonic mucus layer. MethodsCST levels were measured in feces of IBD patients. The mucus layer, goblet cells, and immune cell infiltration were analyzed by histology and electron microscopy in colon tissue from IBD patients and mice with selective deletion of the CST-coding region of the CgA gene. ResultsCST levels were elevated in feces of IBD patients compared to healthy controls. The thickness of the mucus layer was increased in non-affected, but not in inflamed, regions of the colon in IBD patients. The thickness of the mucus layer and concomitant mucus production were also increased in the CST-KO mouse. This mucus phenotype in CST-KO mice could be reversed by bone marrow transplantation from wildtype mice. ConclusionsCST produced by bone-marrow derived immune cells reduces production of the mucus layer in the intestine. This might contribute to the reduced mucus layer in inflamed colon regions of IBD patients. Additionally, CST feces levels might be a biomarker for IBD.

Surveillance colonoscopy reduces colorectal cancer (CRC) risk in inflammatory bowel disease (IBD), but anecdotal evidence suggests a link between surveillance colonoscopy and symptoms flare, which may affect patient compliance with CRC surveillance. We investigated the effects of surveillance colonoscopy in quiescent IBD using a national database to conduct a retrospective, propensity score-matched (PSM) cohort study of 1,717 patients with IBD and 1,717 patients without IBD who underwent colonoscopy. Strict inclusion criteria were used to select patients with quiescent IBD undergoing surveillance colonoscopy. We demonstrated that patients with quiescent IBD prior to colonoscopy received significantly more post-colonoscopy steroid prescriptions compared to matched controls (OR 1.46 [1.20, 1.77], p<0.001). Steroid prescriptions were more likely in patients with IBD at longer follow-up intervals, suggesting a delayed mechanism of onset for post-colonoscopy inflammation. No significant differences between groups were observed for the other outcomes of post-procedure emergency room and hospital visits or enteric infections. Our results suggest a potential risk of symptom exacerbation, evidenced by increased steroid prescriptions, following surveillance colonoscopy. Given that nearly 25% of patients with IBD do not receive surveillance colonoscopy at the recommended intervals, active post-procedure symptoms may be a contributing factor that warrants further investigation.

Inflammatory bowel disease (IBD) treatments and pregnancy can independently modulate immune responses, but the combined effects on SARS-CoV-2 vaccine-induced immunity are poorly understood. This study explores the efficacy of SARS-CoV-2 vaccination and placental antibody transfer among pregnant women with IBD on biologic therapies. This observational study included pregnant women with and without IBD from the PIANO and PREVENT-COVID studies and their neonates. We assessed anti-SARS-CoV-2 neutralizing antibody titers (NT50) in maternal and cord blood post-vaccination using a pseudotype neutralization assay and calculated placental transfer ratios. A total of 32 pregnant women participated, and 27 were exposed to a biologic medication during pregnancy. Neutralizing antibody titers were similar between biologic-treated and non-treated groups, and biologic-exposed women demonstrated robust placental transfer of neutralizing antibodies. Corticosteroid use during pregnancy was significantly associated with reduced placental transfer efficiency, although this effect was not significant in a sensitivity analysis excluding patients treated with immunomodulators. Vaccination timing and previous SARS-CoV-2 infection impacted maternal and cord antibody levels, with higher titers observed in those vaccinated before pregnancy or infected during pregnancy. Overall, our findings suggest that pregnant women with IBD on biologic therapies mount effective SARS-CoV-2 neutralizing antibody responses similar to their non-biologic-exposed counterparts, with efficient placental transfer. These findings reassure the safety and efficacy of SARS-CoV-2 vaccination in this population, though further research is needed to explore the long-term protective effects of transferred antibodies in neonates. Corticosteroid use, immunomodulator use, and vaccination timing may influence antibody dynamics, underscoring the need for tailored clinical management in this vulnerable population.

BackgroundInterleukin (IL)-10 knockout (KO) mice, used as a model for inflammatory bowel disease (IBD), develop chronic enterocolitis. Endoscopy, the gold standard for evaluation of human mucosal health, is not widely available for murine models. We aimed to assess the natural history of left-sided colitis in IL-10 KO mice via serial endoscopies. MethodsBALB/cJ IL10 KO mice underwent regular endoscopic assessments from 2 up to 8 months of age. Procedures were recorded and blindly evaluated using a 4-component endoscopic score: mucosal wall transparency, intestinal bleeding, focal lesions and perianal lesions (0-3 points each). An endoscopic score [&ge;]1 point was considered as the presence of colitis/flare. ResultsIL-10 KO mice (N=40, 9 female) were assessed. Mean age at first endoscopy was 62.5{+/-}2.5 days; average number of procedures per mouse was 6.0{+/-}1.3. A total of 238 endoscopies were conducted every 24.8{+/-}8.3 days, corresponding to 124.1{+/-}45.2 days of surveillance per mouse (13.6 years cumulative surveillance). Thirty-three endoscopies in 24 mice (60%) detected colitis, mean endoscopy score 2.5{+/-}1.3 (range: 1-6.3). Nineteen mice (47.5%) had one episode of colitis and 5 (12.5%) had 2-3 episodes. All exhibited complete spontaneous healing on subsequent endoscopies. ConclusionsIn this largest endoscopic surveillance study of IL-10 KO mice, 40% of mice did not develop endoscopic left-sided colitis. Furthermore, IL-10 KO mice did not exhibit persistent colitis and universally exhibited complete spontaneous healing without treatment. The natural history of colitis in IL-10 KO mice may not be comparable with that of IBD in humans and requires careful consideration.

Background & AimsUlcerative colitis (UC) is an inflammatory bowel disease (IBD) where a defect in the colonic epithelial barrier elicits a chronic and unresolved inflammatory response against luminal microbiota. Mucins are heavily glycosylated proteins secreted by goblet cells that form gelatinous layers to protect the colonic epithelium. Whereas the role of the major colonic mucin, MUC2, is established in UC, few reports have analyzed MUC5B in this disease. In this study, we investigated MUC5B expression in colonic tissues and organoid cultures from UC patients and non-IBD controls. MethodsMUC5B transcripts were analyzed in colonic regions from UC patients and controls using RT-qPCR. MUC5B protein levels in colonic tissues were analyzed and quantified by immunohistochemistry. Patient-derived epithelial organoids were stained for MUC5B, E-cadherin and F-actin. Organoids were treated with interleukin 1 beta (IL-1{beta}) and MUC5B transcripts were analyzed by RT-qPCR. MUC5B proteins were assessed in IL-1{beta}-treated organoids by immunofluorescent microscopy. ResultsMUC5B transcripts and proteins were expressed in the healthy colon and their levels were decreased in UC tissues. MUC5B proteins were reduced in organoids derived from UC tissues. IL-1{beta} treatment of control organoids stimulated expression of acidic mucins, MUC5B transcripts and MUC5B proteins. MUC5B transcripts were not induced by IL-1{beta} in UC-derived organoids. ConclusionsMUC5B levels are reduced in UC colons and its expression is induced by the IL-1{beta} pro-inflammatory cytokine. These results suggest that MUC5B contributes to the protective colonic mucin layer and that this function is likely compromised in UC.

Patients with immune-mediated inflammatory diseases (IMIDs) and acquired and genetic immunodeficiencies receiving therapeutic infusions are considered high risk for SARS-CoV-2 infection. However, the seroprevalance in this group and the safety of routine administrations at outpatient infusion centers are unknown. To determine the infection rate and clinical-social factors related to SARS-CoV-2 in asymptomatic patients with IMIDs and immunodeficiencies receiving routine non-cancer therapeutic infusions, we conducted a seroprevalence study at our outpatient infusion center. We report the first prospective SARS-CoV-2 sero-surveillance of 444 IBD/IMID, immunodeficiency, and immune competent patients at an outpatient infusion center in the U.S. showing lower seroprevalence in patients compared with the general population and provide clinical and social characteristics associated with seroprevalence in this group. These data suggest that patients can safely continue infusions at outpatient centers.

Inflammatory Bowel Disease (IBD), which includes Crohns disease (CD) and Ulcerative Colitis (UC), is a complex and multifactorial condition marked by chronic inflammation of the gastrointestinal tract. This study leverages genome-wide association studies (GWAS) and gene expression data from the Genotype-Tissue Expression (GTEx) project to investigate IBDs genetic and expression profiles and subtypes. We examined 207 studies related to IBD, 71 specific to CD, and 66 focused on UC, identifying both shared and unique genetic factors among these conditions. GWAS meta-analysis revealed the top IBD-associated genes, which include IL23R, NOD2, ATG16L1, HLA-DRB9, and more. Pathway enrichment analyses identified consistently enriched pathways such as the NF-kappa B signaling pathway, JAK-STAT signaling pathway, and cytokine-cytokine receptor interaction, all of which play critical roles in immune responses and inflammation. Gene Ontology (GO) term analysis highlighted processes like cytokine production, cell activation, and leukocyte activation, reinforcing their involvement in the pathogenesis of IBD. Gene expression analysis showed that genes associated with IBD are expressed not only in the gastrointestinal tract but also in various regions of the brain, suggesting potential links between IBD and neurological functions. Our study further explored the genetic overlap between IBD and several neurological disorders, including schizophrenia, depression, autism spectrum disorder, and attention-deficit/hyperactivity disorder, uncovering a shared genetic architecture. These findings emphasize the systemic nature of IBD and its potential neurological implications, paving the way for targeted therapeutic strategies that address both gastrointestinal and neurological aspects of the disease.

Background & AimsCrohns disease (CD) is a highly morbid chronic inflammatory disease. The majority of CD patients also develop fibrostenosing complications. Despite this, there are no medical therapies for intestinal fibrosis. This is in part due to lack of high-fidelity biomimetic models to enhance understanding and drug development. There is a need to develop in vivo models of inflammatory bowel disease-related intestinal fibrosis. We sought to determine if the TNF{Delta}ARE mouse, a model of ileal inflammation, may also develop intestinal fibrosis. MethodsSeveral clinically relevant outcomes were studied including features of structural fibrosis, histological fibrosis, and gene expression. These include the use of a luminal casting technique we developed, traditional histological outcomes, use of second harmonic imaging, and quantitative PCR. These features were studied in aged TNF{Delta}ARE mice as well as in cohorts of numerous ages. ResultsAt ages of 24+ weeks, TNF{Delta}ARE mice develop structural, histological, and genetic changes of ileal fibrosis. Genetic expression profiles have changes as early as six weeks, followed by histological changes occurring as early as 14-15 weeks, and overt structural fibrosis delayed until after 24 weeks. DiscussionThe TNF{Delta}ARE mouse is a viable and highly tractable model of intestinal fibrosis. This model and the techniques employed can be leveraged for both mechanistic studies and therapeutic development for the treatment of intestinal fibrosis.

Background and AimsStem cell-derived organoids are promising platforms for therapeutic screening in inflammatory bowel disease (IBD), but identifying functional organoid readouts with translational utility is challenging. Colon epithelial organoids from patients with ulcerative colitis (UC) overexpress chemokines CXCL1, CXCL11, CCL2, and CCL28, yet whether these inflammatory signatures correlate with disease activity and treatment response is unknown. This short report investigates whether organoid-retained chemokines correlate with disease activity and therapeutic outcomes. MethodsWe interrogated three bulk and two single-cell transcriptomic datasets from IBD clinical trials encompassing anti-TNF and anti-integrin therapies to determine whether epithelial chemokines retained in UC organoids track clinical response and distinguish treatment responders from non-responders to biologic therapy across multiple IBD patient cohorts. ResultsIn bulk transcriptomic data, CXCL1, CXCL11, and CCL2 were elevated in active UC and normalized only in patients achieving clinical remission, independent of therapy class, with persistent chemokine overexpression in non-responders. Single-cell analysis demonstrated widespread chemokine overexpression in UC epithelial clusters, with consistent normalization of CXCL1, CXCL11, and CCL28 in LGR5-positive stem compartment of patients who achieved clinical remission, but not in non-responders. In Crohns disease, the resolution of these epithelial chemokines was not associated with clinical response. ConclusionsEpithelial chemokines, particularly CXCL1, CXCL11, and CCL28, track clinical remission in UC and represent candidate biomarkers and functional endpoints for epithelial-directed therapeutic strategies using stem cell-derived UC organoid models.

BACKGROUND & AIMSAcute severe ulcerative colitis (ASUC) is a life-threatening presentation of ulcerative colitis requiring prompt treatment. Infliximab (IFX) rescue therapy can prevent colectomy in patients with ASUC. METHODSWe performed a cohort study of adult patients hospitalized with ASUC between 01/2014 - 02/2021 who received infliximab rescue therapy. Using multivariable logistic regression, baseline and longitudinal laboratory predictors of colectomy within 90 days of index hospitalization were identified and used to develop a risk prediction model and prognostic scoring system to identifying patients at risk for colectomy. Model performance was assessed using area under the receiver operator characteristic curve (AUC) analysis. RESULTS166 patients with ASUC who received infliximab rescue therapy were identified. Overall, 24.7% (n=41) underwent colectomy within 90 days. Multivariate analysis revealed that colectomy within 90 days could be predicted by having a calculated IFX clearance of >53L/d (OR 2.28, 95% CI 0.99, 5.22), a day 0 absolute C-reactive protein (CRP) > 91mg/L (OR 3.49, 95% CI 1.58 to 8.08), a decrease in CRP of < 43% from day 0 to day 3 (OR 4.13, 95% CI 1.84 to 9.94), and a decrease in CRP of < 9% from the day of IFX administration to one day post-IFX administration (OR 4.20, 95% CI 1.74 to 10.4). Using these predictors, two highly accurate prognostic scoring system were developed to identify patients at risk for requiring colectomy both prior to administering infliximab (AUC 0.76) and after administer infliximab rescue therapy (AUC 0.81). CONCLUSIONWe identified important baseline and longitudinal laboratory predictors of colectomy within 90-days among patients with ASUC receiving infliximab rescue therapy and developed accurate prognostic scores to determine risk of colectomy. These scores can be used risk-stratify patients and facilitate personalized management.

BackgroundUlcerative Colitis (UC) is characterized by chronic, relapsing and remitting inflammation in the colon and rectum. Pathogenic T cell activity is thought to play a major role in this process. T cell effector function is determined by the T cell receptor (TCR) and the antigen it recognizes. Examining the TCR repertoire can provide key insights into the adaptive immune response. ObjectiveTo characterize the longitudinal TCR repertoire of patients with UC across disease activity to determine if recurrent antigen(s) are responsible for active inflammation. DesignBulk TCR V{beta} sequencing was done on colon tissue of 20 patients with UC across multiple time points of disease. Corresponding clinical metadata was also obtained over the same time period for each patient to map their clinical disease course. The top ten most highly abundant clones from each time point were longitudinally tracked and correlated with disease phenotype. ResultsSeventy-five percent of patients did not have overlapping abundant TCR clones across multiple time points of disease. The remaining 25% of patients had one to five TCR clones present in high abundance in their tissue during every time point analyzed. ConclusionThese results demonstrate that most patients with UC do not share a similar TCR repertoire over time, indicating that times of inflammation are associated with unique antigen exposures. A smaller group of patients have persistent, private TCR clones with high abundance, 60% of whom had more unremitting, active disease.

Background and AimsT lymphocytes are found in abnormally large numbers in the bowel in Crohns disease. This has led to the assumption by some that these cells play a causal role in the pathogenesis of what has been labelled an autoimmune disease. An alternative explanation for their presence is that, as part of the adaptive immune system, the accumulation of these cells is not a primary phenomenon, but is a secondary adaptive immune response to faecal material in the bowel wall. To distinguish between these two processes we compared the T-cell repertoire in the bowel in Crohns with that in diverticulitis, where the primary pathology is mechanical, with a subsequent immune response to the accumulated faecal material. MethodsSix cases of Crohns disease and six patients with diverticulitis were studied. Dewaxed sections of bowel were stained with Anti-CD4, Anti-CD8, Anti-FOXP3 and Anti-CD25 to identify cytotoxic T-cells, NK-Tcells; T-helper and T-reg T-cells. ResultsNo differences were found in the distribution of the different T-cell markers in either the mucosa or in areas of inflammation in the two conditions. ConclusionThe accumulation of T-lymphocytes in the bowel in Crohns disease is likely to be a sign of an adaptive immune response to faecal material within the bowel rather than an indication of a primary causal immune attack on the bowel that produces the disease.