Giulia Roda

Loss of Response to Anti-TNFs: Definition, Epidemiology, and Management

Tumor necrosis factor-α (TNFα) antagonists have advanced the management of inflammatory bowel diseases patients leading to an improvement of patient’s quality of life with the reduction of number of surgeries and hospitalizations. Despite these advances, many patients do not respond to the induction therapy (primary non-response—PNR) or lose response during the treatment (secondary loss of response—LOR). In this paper we will provide an overview of the definition, epidemiology and risk factors for PNR and LOR, as well as discuss the therapeutic options for managing LOR.

Cytokine Networks in Ulcerative Colitis

Ulcerative colitis (UC) is a relapsing inflammatory bowel disease whose pathogenesis has yet to be defined completely. A genetic predisposition is needed to develop the colitis, but environmental factors are necessary to trigger an exaggerated and aberrant immune response, which stands at the basis of the mucosal healing. Cytokines, small cell-signaling protein molecules secreted by various types of cells including immune and glia cells, are the main mediators of the mucosal healing in IBD; ulcerative colitis is characterized by a Th2 atypical immune response, since, beside the classical proinflammatory cytokines, such as IL-1, IL-6, and TNF-α, in the pathogenesis of UC, we find a complex network in which the Th2 cytokines, IL-10 and IL-13, play a key role, but little IL-4 was found. Our aim was to review the literature to point out the state of the art in terms of cytokines because the knowledge of cytokine network in UC could lead to the discovery of new therapeutical targets.

Defect in CEACAM family member expression in Crohn's disease IECs is regulated by the transcription factor SOX9.

Background: CEACAM1, CEACAM5, and CEACAM6 represent 3 of the CEACAM (carcinoembryonic antigen‐related cell adhesion molecule) subfamily members expressed on intestinal epithelial cells (IECs). Deficiency in their expression, as seen in inflammatory bowel disease (IBD), results in the lack of activation of CD8+ regulatory T cells in the mucosa. Since CEACAM expression was shown to be regulated by the transcription factor SOX9, we sought to determine whether the defect in CEACAM expression in IBD was related to aberrant SOX9 expression. Methods: IECs and lamina propria lymphocytes (LPLs) were freshly isolated from colonic tissues. T84 and HT29 16E cells were cocultured with LPLs. SOX9 and CEACAM subfamily member expression was assessed by real‐time polymerase chain reaction (PCR), Western blot, immunohistochemistry, and immunofluorescence. Results: In Crohns disease (CD) but not in ulcerative colitis (UC), a significant reduction in mRNA and protein expression for CEACAM1 and 5 was noted; in contrast, no difference in SOX9 mRNA expression was seen. However, nuclear SOX9 immunostaining was increased in CD IECs. Furthermore, SOX9 protein was reduced in the cytoplasm of LPL‐stimulated T84 and HT29 16E cells, while CEACAM5 expression was increased. Conclusions: The defect in CEACAM family members in CD IECs appears to be related to the aberrant nuclear localization of SOX9. Changes in SOX9 expression in the CD mucosa relate to the local microenvironment and altered IEC:LPL crosstalk. Inflamm Bowel Dis 2009

Mouse and human Notch-1 regulate mucosal immune responses

The Notch-1 signaling pathway is responsible for homeostatic tight junction expression in vitro, and promotes barrier function in vivo in the RAG1-adoptive transfer model of colitis. In this study, we sought to determine the role of colonic Notch-1 in the lymphoepithelial crosstalk in health and disease. We utilized in vivo and in vitro knockdown to target the expression of Notch-1. We identified that epithelial Notch-1 is required for appropriate activation of intestinal epithelial cells at steady state and upon inflammatory stimulus. Notch-1 expression modulates mucosal chemokine and cytokine secretion, and FoxP3 and effector T-cell responses. We showed that epithelial Notch-1 controls the immune function of the epithelium through crosstalk with the nuclear factor-κB (NF-κB)/mitogen-activated protein kinase (MAPK) pathways that, in turn, elicits T-cell responses. Overall, epithelial Notch-1 bridges innate and adaptive immunity in the gut. Our findings highlight an indispensable role for Notch-1-mediated signaling in the intricate epithelial-immune crosstalk, and validate that epithelial Notch-1 is necessary and sufficient to support protective epithelial proinflammatory responses.

Review article: non-malignant oral manifestations in inflammatory bowel diseases.

Patients with inflammatory bowel diseases (IBD) may present with lesions in their oral cavity. Lesions may be associated with the disease itself representing an extraintestinal manifestation, with nutritional deficiencies or with complications from therapy.

Anal Neoplasia in Inflammatory Bowel Disease Is Associated With HPV and Perianal Disease.

OBJECTIVES:Literature describing the risk factors predisposing inflammatory bowel disease (IBD) patients to anal squamous neoplasia is very scarce. Case reports and small case series have implicated perianal Crohn’s disease (CD), long-standing IBD, human papillomavirus (HPV) infection, and immunosuppressive treatment. In this study, we retrospectively examined the association between HPV infection and anal squamous neoplastic lesions among IBD patients from our center.METHODS:We reviewed the pathology records and slides of IBD patients diagnosed with anal squamous cell carcinomas (SCCs), high-grade squamous intraepithelial lesions (HSILs), and low-grade squamous intraepithelial lesions (LSILs) who presented at our center between 1 March 1994 and 9 September 2014. The HPV status of the neoplasms was assessed histologically, by immunohistochemical staining for p16 overexpression, and by global and type-specific HPV PCR.RESULTS:SCCs, HSILs, LSILs, and small cell carcinoma were identified, respectively, in six, nine, two, and one IBD patients. All six patients with SCC had CD with perianal involvement. HPV-related neoplasia was identified in 3/6 cases of SCC (all HPV-16), 1/1 small cell carcinoma (HPV-18), and 9/9 HSIL (7 HPV-16, 2 not typed); 2/2 LSILs were negative for high-risk HPV.CONCLUSIONS:In our experience, anal squamous neoplastic lesions in IBD are associated with HPV infection and SCC seem to be associated with perianal CD. Prospective studies are needed to confirm these results.

Critical function of the necroptosis adaptor RIPK3 in protecting from intestinal tumorigenesis.

Necroptosis is a programmed form of non-apoptotic cell death that requires the kinase activity of the receptor interacting protein kinase 3 (RIPK3). Although in vitro data suggests that cancer cells lacking expression of RIPK3 are invasive, the physiological role of RIPK3 in a disease-relevant setting remains unknown. Here we provide evidence that RIPK3 has a critical role in suppressing colorectal cancer (CRC). RIPK3-deficient mice were highly susceptible to colitis-associated CRC and exhibited greater production of pro-inflammatory mediators and tumor promoting factors. Tumorigenesis in RIPK3-deficiency resulted from uncontrolled activation of NF-κB, STAT3, AKT and Wnt-β-catenin signaling pathways that enhanced the ability of intestinal epithelial cells (IECs) to aberrantly proliferate in the face of the sustained inflammatory microenvironment and promote CRC. We found that RIPK3 expression is reduced in tumors from patients with inflammatory bowel diseases, and further confirmed that expression of RIPK3 is downregulated in human CRC and correlated with cancer progression. Thus, our results reveal that the necroptosis adaptor RIPK3 has key anti-inflammatory and anti-tumoral functions in the intestine, and define RIPK3 as a novel colon tumor suppressor.

Systematic review with meta‐analysis: proximal disease extension in limited ulcerative colitis

Disease extent in ulcerative colitis is one of the major factors determining prognosis over the long‐term. Disease extent is dynamic and a proportion of patients presenting with limited disease progress to more extensive forms of disease over time.

Oral Cancer and Oral Precancerous Lesions in Inflammatory Bowel Diseases: A Systematic Review

Oral cancer is historically linked to well-known behavioural risk factors such as tobacco smoking and alcohol consumption. Other risk factors include age over 40, male sex, several dietary factors, nutritional deficiencies, viruses, sexually transmitted infections, human papillomavirus, chronic irritation, and possibly genetic predisposition. Precancerous lesions in the oral cavity include leukoplakia, erythroplakia, and lichen planus. Histology of oral cancer varies widely but the great majority are squamous cell carcinomas.Epidemiological studies and cancer registries have shown a consistently increased risk of oral malignancies in kidney, bone marrow, heart, or liver transplantation, in graft vs host disease, and in patients with HIV infection. Because of the increasing use of immunosuppressive drugs in patients with inflammatory bowel disease, it is useful to more accurately delineate the consequences of chronic immunosuppression to the oral cavity. Oral cancer and precancerous oral lesions in patients with inflammatory bowel disease [IBD] have been scarcely reported and reviews on the topic are lacking.We conducted a literature search using the terms and variants of all cancerous and precancerous oral manifestations of inflammatory bowel diseases. By retrieving the existing literature, it is evident that patients with IBD belong to the high-risk group of developing these lesions, a phenomenon amplified by the increasing HPV prevalence. Education on modifiable risk behaviours in patients with oral cancer is the cornerstone of prevention.Oral screening should be performed for all IBD patients, especially those who are about to start an immunosuppressant or biological drug.

Characterizing CEACAM5 interaction with CD8α and CD1d in intestinal homeostasis.

Normal intestinal epithelial cells (IECs) could act as non-professional antigen-presenting cells, selectively activating CD8+-suppressor T cells. An epithelial cell surface glycoprotein, gp180, recognized by monoclonal antibodies B9 and L12 was determined to be critical in this process. Purification and sequence analysis of mAb B9 reactive material revealed amino-acid sequence homology with CEACAM5. We demonstrate that CEACAM5 has properties attributed to gp180, such as CD8α binding and activation of CD8-associated Lck. CEACAM5 is the only CEACAM member interacting with CD1d through the B3 domain. Its N domain (recognized by B9) is required for CD8α binding. Removal of the N-domain glycosylated residues reduces B9 recognition, CD8α binding affinity, and activation of LcK. Therefore, conformational changes in CEACAM5 glycosylation site are critical for its interaction with CD8α. CEACAM5-activated CD8+ T cells acquire the ability to suppress the proliferation of CD4+ T cells in vitro in the presence of interleukin (IL)-15 or IL-7. We provide new insights into the role of CEACAM5 and define its specific immunoregulatory properties among the CEACAMs expressed on IECs. We suggest that unique set of interactions between CEACAM5, CD1d, and CD8 render CD1d more class I-like molecule, facilitating antigen presentation and activation of CD8+-suppressor regulatory T cells.