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Crohn’s disease is a chronic inflammatory intestinal disease that is frequently accompanied by aberrant healing and stricturing complications. Crosstalk between activated myeloid and stromal cells is critical in the pathogenicity of Crohn’s disease 1 , 2 , and increases in intravasating monocytes are correlated with a lack of response to anti-TNF treatment 3 . The risk alleles with the highest effect on Crohn’s disease are loss-of-function mutations in NOD2 4 , 5 , which increase the risk of stricturing 6 . However, the mechanisms that underlie pathogenicity driven by NOD2 mutations and the pathways that might rescue a lack of response to anti-TNF treatment remain largely uncharacterized. Here we use direct ex vivo analyses of patients who carry risk alleles of NOD2 to show that loss of NOD2 leads to dysregulated homeostasis of activated fibroblasts and macrophages. CD14 + peripheral blood mononuclear cells from carriers of NOD2 risk alleles produce cells that express high levels of collagen, and elevation of conserved signatures is observed in nod2- deficient zebrafish models of intestinal injury. The enrichment of STAT3 regulation and gp130 ligands in activated fibroblasts and macrophages suggested that gp130 blockade might rescue the activated program in NOD2-deficient cells. We show that post-treatment induction of the STAT3 pathway is correlated with a lack of response to anti-TNF treatment in patients, and demonstrate in vivo in zebrafish the amelioration of the activated myeloid–stromal niche using the specific gp130 inhibitor bazedoxifene. Our results provide insights into NOD2-driven fibrosis in Crohn’s disease, and suggest that gp130 blockade may benefit some patients with Crohn’s disease—potentially as a complement to anti-TNF therapy. NOD2 deficiency drives fibrosis and stricturing complications in Crohn’s disease through dysregulated homeostasis of activated fibroblasts and macrophages, which is ameliorated by gp130 blockade in human cell and zebrafish models.

Eosinophilic gastritis (EG), defined by histological criteria as marked eosinophilia in the stomach, is rare, and large studies in children are lacking. We sought to describe the clinical, endoscopic, and histopathological features of EG, assess for any concurrent eosinophilia at other sites of the gastrointestinal (GI) tract, and evaluate response to dietary and pharmacological therapies. Pathology files at our medical center were searched for histological eosinophilic gastritis (HEG) with ≥70 gastric eosinophils per high-power field in children from 2005 to 2011. Pathology slides were evaluated for concurrent eosinophilia in the esophagus, duodenum, and colon. Medical records were reviewed for demographic characteristics, symptoms, endoscopic findings, comorbidities, and response to therapy. Thirty children with severe gastric eosinophilia were identified, median age 7.5 years, 14 of whom had both eosinophilia limited to the stomach and clinical symptoms, fulfilling the clinicopathological definition of EG. Symptoms and endoscopic features were highly variable. History of atopy and food allergies was common. A total of 22% had protein-losing enteropathy (PLE). Gastric eosinophilia was limited to the fundus in two patients. Many patients had associated eosinophilic esophagitis (EoE, 43%) and 21% had eosinophilic enteritis. Response to dietary restriction therapy was high (82% clinical response and 78% histological response). Six out of sixteen patients had persistent EoE despite resolution of their gastric eosinophilia; two children with persistent HEG post therapy developed de novo concurrent EoE. HEG in children can be present in the antrum and/or fundus. Symptoms and endoscopic findings vary, highlighting the importance of biopsies for diagnosis. HEG is associated with PLE, and with eosinophilia elsewhere in the GI tract including the esophagus. The disease is highly responsive to dietary restriction therapies in children, implicating an allergic etiology. Associated EoE is more resistant to therapy.

Common variable immune deficiency (CVID) and chronic granulomatous disease (CGD) are two of the well-characterized primary immune deficiencies with distinct pathologic defects. While CVID is predominantly a disorder of the adaptive immune system, in CGD, innate immunity is impaired. In both syndromes, the clinical manifestations include an increased susceptibility to infections and a number of non-infectious, inflammatory conditions including systemic autoimmunity, as well as organ-specific pathology. Among the organ-associated disorders, gastrointestinal (GI) manifestations are one of the most intractable. As such, non-infectious inflammatory disorders of the GI tract are clinically challenging as they have protean manifestations, often resembling inflammatory bowel disease (IBD) or celiac disease, are notoriously difficult to treat, and hence are associated with significant morbidity and mortality. Therefore, assessing the pathogenesis and defining appropriate therapeutic approaches for GI disease in patients with CVID and CGD is imperative.

B cells, which are critical for intestinal homeostasis, remain understudied in ulcerative colitis (UC). In this study, we recruited three cohorts of patients with UC (primary cohort, n  = 145; validation cohort 1, n  = 664; and validation cohort 2, n  = 143) to comprehensively define the landscape of B cells during UC-associated intestinal inflammation. Using single-cell RNA sequencing, single-cell IgH gene sequencing and protein-level validation, we mapped the compositional, transcriptional and clonotypic landscape of mucosal and circulating B cells. We found major perturbations within the mucosal B cell compartment, including an expansion of naive B cells and IgG + plasma cells with curtailed diversity and maturation. Furthermore, we isolated an auto-reactive plasma cell clone targeting integrin αvβ6 from inflamed UC intestines. We also identified a subset of intestinal CXCL13-expressing TFH-like T peripheral helper cells that were associated with the pathogenic B cell response. Finally, across all three cohorts, we confirmed that changes in intestinal humoral immunity are reflected in circulation by the expansion of gut-homing plasmablasts that correlates with disease activity and predicts disease complications. Our data demonstrate a highly dysregulated B cell response in UC and highlight a potential role of B cells in disease pathogenesis. Multi-modal profiling reveals major alterations in colonic B cells in patients with ulcerative colitis, including reduced clonal diversity of plasma cells, and suggests that circulating gut-homing plasmablasts could serve as a biomarker for disease activity.

Abstract Background Histological response to treatment is an important outcome in patients with ulcerative colitis (UC). The accuracy of biopsy-based measurements of inflammation may be limited by error imposed by natural microscopic heterogeneity on the scale of individual biopsies. We determined the magnitude of this error, its histological correlates, and the density of biopsy sampling within mucosal regions of interest required to meet specified benchmarks for accuracy. Methods A total of 994 sequential 1-mm digital microscopic images (virtual biopsies) from consecutive colectomies from patients with clinically severe UC were scored by 2 pathologists. Agreement statistics for Geboes subscores and Nancy (NHI) and Robarts Histological Indices (RHI) between random samples from 1 to 10 biopsies and a reference mean score across a 2-cm region of mucosa were calculated using bootstrapping with 2500 iterations. Results The agreement statistics improved across all indices as the biopsy density increased, with the largest proportional gains occurring with addition of the second and third biopsies. One biopsy achieved moderate to good agreement with 95% confidence for NHI and RHI corresponding to scale-specific errors of 0.40 (0.25-0.66) and 3.02 (2.08-5.36), respectively; and 3 biopsies achieved good agreement with 95% confidence corresponding to scale-specific errors of 0.22 (0.14-0.39) and 1.87 (1.19-3.25), respectively. Of the individual histological features, erosions and ulcers had the greatest impact on the agreement statistics. Conclusions In the setting of active colitis, up to 3 biopsy samples per region of interest may be required to overcome microscopic heterogeneity and ensure accurate histological grading.

Increased expression of Interleukin (IL)-33 has been detected in intestinal samples of patients with ulcerative colitis, a condition associated with increased risk for colon cancer, but its role in the development of colorectal cancer has yet to be fully examined. Here, we investigated the role of epithelial expressed IL-33 during development of intestinal tumors. IL-33 expression was detected in epithelial cells in colorectal cancer specimens and in the Apc Min/ + mice. To better understand the role of epithelial-derived IL-33 in the intestinal tumorigenesis, we generated transgenic mice expressing IL-33 in intestinal epithelial cells ( V33 mice). V33 Apc Min/ + mice, resulting from the cross of V33 with Apc Min/ + mice, had increased intestinal tumor burden compared with littermate Apc Min/ + mice. Consistently, Apc Min/ + mice deficient for IL-33 receptor (ST2), had reduced polyp burden. Mechanistically, overexpression of IL-33 promoted expansion of ST2 + regulatory T cells, increased Th2 cytokine milieu, and induced alternatively activated macrophages in the gut. IL-33 promoted marked changes in the expression of antimicrobial peptides, and antibiotic treatment of V33 Apc Min/ + mice abrogated the tumor promoting-effects of IL-33 in the colon. In conclusion, elevated IL-33 signaling increases tumor development in the Apc Min/ + mice.

Cirrhosis and hepatocellular carcinoma are the prototypic complications of chronic hepatitis C virus infection in the liver. However, hepatitis C virus also affects a variety of other organs that may lead to significant morbidity and mortality. Extrahepatic manifestations of hepatitis C infection include a multitude of disease processes affecting the small vessels, skin, kidneys, salivary gland, eyes, thyroid, and immunologic system. The majority of these conditions are thought to be immune mediated. The most documented of these entities is mixed cryoglobulinemia. Morphologically, immune complex depositions can be identified in small vessels and glomerular capillary walls, leading to leukoclastic vasculitis in the skin and membranoproliferative glomerulonephritis in the kidney. Other HCV-associated entities include porphyria cutanea tarda, lichen planus, necrolytic acral erythema, membranous glomerulonephritis, diabetic nephropathy, B-cell non-Hodgkin lymphomas, insulin resistance, sialadenitis, sicca syndrome, and autoimmune thyroiditis. This paper highlights the histomorphologic features of these processes, which are typically characterized by chronic inflammation, immune complex deposition, and immunoproliferative disease in the affected organ.

Pagetoid spread in esophageal squamous epithelium associated with underlying esophageal adenocarcinoma (EAC) has been well studied. Case reports describing pagetoid spread of esophageal squamous cell carcinomas (ESCC) also exist in the literature. The latter, however, has not been systematically studied. In this study, we report seven cases of pagetoid spread associated with ESCC. The clinical, morphologic, and immunophenotypic profiles of pagetoid spread in the context of ESCC and EAC are compared. Cases of pagetoid spread of ESCC were identified through computerized search of pathology archives at five institutions. Additional cases were identified through manual review of surgical resection cases of treatment naive ESCC in Mass General Brigham (MGB) pathology archive. Clinical history was collected via chart review. Immunohistochemistry for CK7, CK20, CDX2, p53, p63, and p40 was performed on selected cases. A computerized search of pathology archives of five institutions revealed only two cases. A manual review of 76 resected untreated ESCC revealed five additional cases with unequivocal pagetoid spread of ESCC, indicating the condition was not uncommon but rarely reported. Patient age ranged from 54 to 78 years (median, 65). There were six women and one man. One case had in situ disease, five had pT1 (1 pT1a and 4 pT1b), and one had pT3 disease. One of the patients with pT1 tumor had a positive lymph node, while the remaining six patients were all N0. Four tumors were in the proximal to mid esophagus, and three in the distal esophagus. Patient survival ranged from 25 months to more than 288 months. The pagetoid tumor cells demonstrated enlarged, hyperchromatic nuclei with variable amounts of eosinophilic cytoplasm. The cytoplasm was often condensed to the perinuclear area, creating peripheral clearing. By immunohistochemistry, the pagetoid cells were positive for p40 (6/6) and p63 (7/7) and negative for CDX2 (7/7). The tumor cells showed mutant-type staining for p53 in five of seven cases. One of the patients had pagetoid tumor cells at the resection margin and subsequently had recurrent disease 2 years later. All other patients had negative resection margins and did not have local recurrence. Four cases of pagetoid spread in the context of EAC were used as a comparison group. Previously published studies were also analyzed. These tumors were all located in the distal esophagus or gastroesophageal junction. All cases were associated with underlying invasive EAC. Pagetoid spread associated with EAC often had cytoplasmic vacuoles or mucin. They were more frequently positive for CK7 than pagetoid ESCC ( p  = 0.01). Both ESCC and EAC may give rise to pagetoid spread of tumor cells within surface squamous epithelium. Pagetoid spread from ESCC and EAC have overlapping morphologic features. P40 and p63 immunostains can facilitate the distinction between ESCC and EAC. P53 immunostain can aid in confirmation of malignancy. Understanding their overlapping pathologic features will help pathologists avoid pitfalls and diagnose these lesions correctly on biopsy specimens.

Serrated colorectal polyps, which, besides hyperplastic polyps, comprise sessile serrated adenomas/polyps and traditional serrated adenomas, are presumptive precursors of at least 20% of sporadic colorectal carcinomas; however, their significance in patients with inflammatory bowel disease is unclear. We retrospectively evaluated 78 serrated polyps, removed over a 14-year period from 6602 inflammatory bowel disease patients undergoing endoscopic surveillance, with respect to morphologic, clinicopathologic, and molecular features, and compared rates of advanced neoplasia (high-grade dysplasia and carcinoma) development following the index serrated polyp diagnosis to reference inflammatory bowel disease cohorts without serrated polyps. Serrated polyps negative for dysplasia, which morphologically resembled sporadic sessile serrated adenoma/polyps, occurred mainly in females, in the proximal colon, and contained BRAF mutations. Serrated polyps with low-grade dysplasia resembled sporadic traditional serrated adenomas and occurred mainly in males, in the distal colon, and contained KRAS mutations. Serrated polyps indefinite for dysplasia were morphologically heterogeneous, but similar to serrated polyps positive for low-grade dysplasia with respect to male predominance, left-sided location, and KRAS mutation rates. Rates of prevalent neoplasia associated with serrated polyps positive for low-grade dysplasia, indefinite for dysplasia, and negative for dysplasia were 76, 39, and 11%, respectively ( P <0.001). Actuarial 10-year rates of incident advanced neoplasia after an initial diagnosis of serrated polyp positive for low-grade dysplasia, indefinite for dysplasia, and negative for dysplasia were 17, 8, and 0%, respectively, the first and last being significantly different ( P =0.02) and comparable to those of corresponding reference populations of inflammatory bowel disease patients with and without low-grade dysplasia at baseline, respectively. We conclude that in serrated polyps from inflammatory bowel disease patients, dysplasia grade correlates with morphology, sex, anatomic location, BRAF and KRAS mutation status, prevalent conventional neoplasia, and rates of advanced neoplasia development.