Christopher J. Justinich

FGF9-induced proliferative response to eosinophilic inflammation in oesophagitis

Background: Oesophagitis is characterised by basal cell hyperplasia and activated eosinophils, which release mediators including major basic protein (MBP). MBP and its mimetic polyarginine activate the calcium sensing receptor (CaSR) on oesophageal epithelium. Fibroblast growth factor 9 (FGF9) is implicated in epithelial homeostasis and proliferative response to injury, but has not been characterised in the oesophagus. Objective: To characterise FGF9 in oesophageal epithelium and oesophagitis, as the result of MBP activation of the CaSR. Methods: Human oesophageal epithelial cells (HET-1A) were used to compare affects of calcium, polyarginine and MBP-peptide on FGF9. HET-1A were transfected with interfering RNA (siRNACaSR). FGF9, FGF receptors 2 and 3, bone morphogenetic protein (BMP)-2, BMP-4 and noggin mRNA expression were detected by reverse transcriptase polymerase chain reaction. FGF9 was measured from HET-1A and from normal, gastro-oesophageal reflux and eosinophilic oesophagitis (EoE) patient biopsies using ELISA and immunohistochemistry. HET-1A proliferation was studied using bromodeoxyuridine and MTT. Results: FGF9 was secreted by HET-1A cells treated with polyarginine and MBP-peptide, but not calcium. This effect was abrogated by siRNACaSR. FGF9 receptor mRNA was present. HET-1A cells proliferated following rhFGF9, but not MBP-peptide treatment, and rhFGF9 altered transcription of downstream proliferation-related genes (noggin, BMP-2 and BMP-4). FGF9 was increased in biopsies from patients with eosinophilic oesophagitis, which correlated with basal hyperplasia. Conclusion: Eosinophil-released MBP acts on the CaSR to increase FGF9 in oesophageal epithelial cells, leading to proliferation. Increased FGF9 is found in biopsies of EoE patients and may play a role in the pathogenesis of oesophagitis.

A tale of two diseases: The history of inflammatory bowel disease

Inflammatory bowel disease (IBD) sounds like a straightforward term - a disease of inflammation in the bowel. However, the history of IBD reveals a story of a nefariously complex set of idiopathic conditions. IBD defies definition, in part because its pathophysiology is not completely understood. For the same reason and despite substantial advances in research, IBD also defies cure. At best, IBD can be defined as a disease of disruption - disrupted physiology, microbiology, immunology and genetics. The term IBD is most often used to describe two separate conditions: ulcerative colitis (UC) and Crohns disease (CD). This paper reviews the history of IBD, considering the ever-evolving understanding of both UC and CD. Beyond its intrinsic interest, the history of IBD exemplifies a pattern that is becoming increasingly familiar in the 21st century - the story of a chronic, incurable disease that defies the best efforts to treat it.

Atopic and non-atopic eosinophilic oesophagitis are distinguished by immunoglobulin E-bearing intraepithelial mast cells

Mulder D J, Mak N, Hurlbut D J & Justinich C J u2028(2012) Histopathology 61, 810–822

Recurrent abdominal pain and weight loss in an adolescent: Celiac artery compression syndrome

Celiac artery compression syndrome is a rare cause of abdominal pain and weight loss, likely caused by compression of the celiac artery or plexus by the median arcuate ligament. A case of celiac artery compression syndrome in a 17-year-old male patient with severe postprandial pain and weight loss is described. Imaging techniques such as computed tomography, angiography and Doppler ultrasound identified the abnormality, which was corrected by laparoscopic surgery.

Expression of Toll-Like Receptors 2 and 3 on Esophageal Epithelial Cell Lines and on Eosinophils During Esophagitis

BackgroundThe chronic disease eosinophilic esophagitis may be mediated by the innate immune system. Activation of toll-like receptors (TLRs) in other tissues is known to initiate eosinophil infiltration, thus TLRs may be a potential mediator of esophageal eosinophilia. Little is known about TLRs in the esophagus.AimsThe purpose of this study was to identify the presence and activation of TLR2 and TLR3 on esophageal epithelial cell lines, primary epithelial cells and mucosal esophageal biopsies.MethodsTLR2 and TLR3 were identified by immunocytochemistry and immunoblot. PCR assessed alterations to gene expression by activation of TLR2 and TLR3. Immunohistochemistry co-localized eosinophils and TLR2/TLR3 on esophageal biopsies.ResultsTLR2 and TLR3 were expressed on the esophageal adenocarcinoma cell lines TE-1 and TE-7, but only TLR3 was present on the esophageal epithelial cell line HET-1A. Thymic stromal lymphopoietin gene expression was altered in response to ligands zymosan and polyI:C, demonstrating activation. Primary esophageal epithelial cells did not express TLR2 or TLR3. In esophageal biopsies, TLR2 and TLR3 expression was limited to eosinophils and other immune cells during esophagitis.ConclusionsTLR2 and TLR3 expression on cultured esophageal epithelial cells differs from TLR2 and TLR3 expression in esophageal biopsies, which is limited to immune cells during esophagitis.

Multiple squamous hyperplastic-fibrous inflammatory polyps of the oesophagus: a new feature of eosinophilic oesophagitis?

This report describes the unusual case of a 12-year-old boy with multiple polyps in the oesophagus and concurrent eosinophilic oesophagitis (EoE). Polyps were of a fibrous-inflammatory composition featuring eosinophils, mast cells, hyperplastic epithelium and fibrosis, which are all features described with EoE. EoE is an increasingly recognised clinicopathological disorder characterised by large numbers of eosinophils infiltrating the oesophageal mucosa. Polyps in the oesophagus are rare, have not previously been associated with EoE, and may represent a new feature of the disease.

B cells, IgE and mechanisms of type I hypersensitivity in eosinophilic oesophagitis

The pathogenesis of eosinophilic oesophagitis (EO) is unknown. EO has recently been defined as significantly elevated intraepithelial eosinophils (⩾15 per high-power field) throughout the oesophageal mucosa, coupled with clinical and endoscopic signs of oesophagitis that cannot be attributed to gastro-oesophageal reflux disease (GORD) or other causes.1 2 This inflammatory condition is more likely to occur in atopic individuals and is limited to the oesophagus where Th2 cytokines and mast cells are also abnormally elevated.1 Removal of specific protein or all proteins from the diet may resolve the inflammatory response in some patients.3 Animal models point to antigen exposure in lung or nasal mucosa leading to local inflammation and oesophagitis.4 EO may indeed be the manifestation of an oesophageal hypersensitivity response to food or environmental antigens, but since a systemic response is not present, local mucosal immune events may be important in this disease.nnPatients with EO have increased numbers of cells required for local immunoglobulin E (IgE) antibody production. Lucendo et al used sensitive immunohistochemical evaluation to quantify B cells (CD20+);5 however, very few intraepithelial B cells were detected in oesophagitis (EO and GORD), and the numbers did not reach statistical significance.nnMucosal mast cells are also increased in the oesophagus in EO, and these cells stain positively for IgE.5 6 7 …