QRICH1 dictates the outcome of ER stress through transcriptional control of proteostasis.

Tissue homeostasis is perturbed in a diversity of inflammatory pathologies. These changes can elicit endoplasmic reticulum (ER) stress, protein misfolding, and cell death. ER stress triggers the unfolded protein response (UPR), which can promote recovery of ER proteostasis and cell survival or trigger programmed cell death.

Altered Intestinal ACE2 Levels Are Associated With Inflammation, Severe Disease, and Response to Anti-Cytokine Therapy in Inflammatory Bowel Disease.

Background And Aims: The host receptor for severe acute respiratory syndrome coronavirus 2, angiotensin-converting enzyme 2 (ACE2), is highly expressed in small bowel (SB). Our aim was to identify factors influencing intestinal ACE2 expression in Crohn's disease (CD), ulcerative colitis (UC), and non-inflammatory bowel disease (IBD) controls.

Methods: Using bulk RNA sequencing or microarray transcriptomics from tissue samples (4 SB and 2 colonic cohorts; n = 495; n = 387 UC; n = 94 non-IBD), we analyzed the relationship between ACE2 with demographics and disease activity and prognosis.

Epithelial Cell Biomarkers Are Predictive of Response to Biologic Agents in Crohn's Disease.

Background: Therapeutic efficacy of biologics has remained at about 50% for 2 decades. In Crohn's disease (CD) patients, we examined the predictive value of an epithelial cell biomarker, ileal microvillar length (MVL), for clinical response to ustekinumab (UST) and vedolizumab (VDZ) and its relationship to another biomarker, intestinal epithelial cell (IEC) pyroptosis, with respect to response to VDZ.

Method: Ileal biopsies from the UNITI-2 randomized controlled trial were analyzed for MVL as a predictor of clinical response to UST.

Abnormal Small Intestinal Epithelial Microvilli in Patients With Crohn's Disease.

Background & Aims: Crohn disease (CD) presents as chronic and often progressive intestinal inflammation, but the contributing pathogenic mechanisms are unclear. We aimed to identify alterations in intestinal cells that could contribute to the chronic and progressive course of CD.

Methods: We took an unbiased system-wide approach by performing sequence analysis of RNA extracted from formalin-fixed paraffin-embedded ileal tissue sections from patients with CD (n = 36) and without CD (controls; n = 32).

IL25 elicits a multipotent progenitor cell population that promotes T(H)2 cytokine responses.

CD4(+) T helper 2 (T(H)2) cells secrete interleukin (IL)4, IL5 and IL13, and are required for immunity to gastrointestinal helminth infections. However, T(H)2 cells also promote chronic inflammation associated with asthma and allergic disorders. The non-haematopoietic-cell-derived cytokines thymic stromal lymphopoietin, IL33 and IL25 (also known as IL17E) have been implicated in inducing T(H)2 cell-dependent inflammation at mucosal sites, but how these cytokines influence innate immune responses remains poorly defined.

New paradigms in basophil development, regulation and function.

Emerging evidence has shown that basophils perform essential, non-redundant functions in multiple models of acute and chronic Th2 cytokine-dependent immunity and inflammation. In particular, recent studies have shown that basophils are rapidly recruited to the lymph nodes, can function as antigen-presenting cells and are critical for the induction of Th2 cell differentiation and the associated inflammatory responses after exposure to helminth parasites or allergens. In this review, we discuss recent studies that provide new insights into the pathways that control basophil development, regulation and effector function.

MHC class II-dependent basophil-CD4+ T cell interactions promote T(H)2 cytokine-dependent immunity.

Dendritic cells can prime naive CD4+ T cells; however, here we demonstrate that dendritic cell-mediated priming was insufficient for the development of T helper type 2 cell-dependent immunity. We identify basophils as a dominant cell population that coexpressed major histocompatibility complex class II and interleukin 4 message after helminth infection. Basophilia was promoted by thymic stromal lymphopoietin, and depletion of basophils impaired immunity to helminth infection.

IL-31-IL-31R interactions limit the magnitude of Th2 cytokine-dependent immunity and inflammation following intestinal helminth infection.

IL-31 is a recently identified cytokine made predominantly by CD4(+) Th2 cells and its receptor, IL-31R, is expressed by a number of cell types including monocytes, epithelial cells, and T cells. Originally identified as a potential mediator of inflammation in the skin, we recently reported a novel function for endogenous IL-31R interactions in limiting type 2 inflammation in the lung. However, whether IL-31-IL-31R interactions regulate immunity or inflammation at other mucosal sites, such as the gut, is unknown.

Alternatively activated macrophage-derived RELM-{alpha} is a negative regulator of type 2 inflammation in the lung.

Differentiation and recruitment of alternatively activated macrophages (AAMacs) are hallmarks of several inflammatory conditions associated with infection, allergy, diabetes, and cancer. AAMacs are defined by the expression of Arginase 1, chitinase-like molecules, and resistin-like molecule (RELM) alpha/FIZZ1; however, the influence of these molecules on the development, progression, or resolution of inflammatory diseases is unknown. We describe the generation of RELM-alpha-deficient (Retnla(-/-)) mice and use a model of T helper type 2 (Th2) cytokine-dependent lung inflammation to identify an immunoregulatory role for RELM-alpha.

Commensal-dependent expression of IL-25 regulates the IL-23-IL-17 axis in the intestine.

Alterations in the composition of intestinal commensal bacteria are associated with enhanced susceptibility to multiple inflammatory diseases, including those conditions associated with interleukin (IL)-17-producing CD4(+) T helper (Th17) cells. However, the relationship between commensal bacteria and the expression of proinflammatory cytokines remains unclear. Using germ-free mice, we show that the frequency of Th17 cells in the large intestine is significantly elevated in the absence of commensal bacteria.

On the hunt for helminths: innate immune cells in the recognition and response to helminth parasites.

The generation of protective immunity to helminth parasites is critically dependent upon the development of a CD4(+) T helper type 2 cytokine response. However, the host-parasite interactions responsible for initiating this response are poorly understood. This review will discuss recent advances in our understanding of how helminth-derived products are recognized by innate immune cells.

IL-31-IL-31R interactions negatively regulate type 2 inflammation in the lung.

Interleukin (IL) 31Ralpha (glycoprotein 130-like monocyte receptor and glycoprotein 130-like receptor) heterodimerizes with oncostatin M receptor beta to bind IL-31, a cytokine expressed preferentially by CD4(+) T helper type 2 (Th2) cells. However, the functions of IL-31-IL-31R signaling in immune regulation remain unknown. Here, we identify a novel role for IL-31R in limiting type 2 inflammation in the lung.

Lack of association between EBV and breast carcinoma.

Multiple conflicting findings have been presented which indicate that EBV may be found in anywhere from 0% to 51% of breast carcinomas. When EBV has been found causally associated with other human cancers, its DNA and one or more of its viral products have been detected in most tumor cells of a given biopsy. To test whether EBV has such an association with breast cancer, we measured the number of viral DNA molecules per cell in matched normal and tumor biopsies from 45 patients using real-time quantitative PCR.

ZEB negatively regulates the lytic-switch BZLF1 gene promoter of Epstein-Barr virus.

Epstein-Barr virus (EBV) is a human herpesvirus capable of establishing a latent state in B lymphocytes. The product of the immediate-early BZLF1 gene, Zta, is a transcriptional transactivator essential for viral DNA amplification and virion production. Previously, we identified a negative cis-acting element within the BZLF1 promoter termed ZV.