Research Article: Heat Shock Protein-Derived T-Cell Epitopes Contribute to Autoimmune Inflammation in Pediatric Crohn’s Disease

Date Published: November 2, 2009

Publisher: Public Library of Science

Author(s): Gisella L. Puga Yung, Meredith Fidler, Erika Albani, Naomi Spermon, Gijs Teklenburg, Robert Newbury, Nicole Schechter, Theo van den Broek, Berent Prakken, Rosario Billetta, Ranjan Dohil, Salvatore Albani, Christoph Kleinschnitz. http://doi.org/10.1371/journal.pone.0007714

Abstract: Pediatric Crohn’s disease is a chronic auto inflammatory bowel disorder affecting children under the age of 17 years. A putative etiopathogenesis of Crohn’s disease (CD) is associated with disregulation of immune response to antigens commonly present in the gut microenvironment. Heat shock proteins (HSP) have been identified as ubiquitous antigens with the ability to modulate inflammatory responses associated with several autoimmune diseases. The present study tested the contribution of immune responses to HSP in the amplification of autoimmune inflammation in chronically inflamed mucosa of pediatric CD patients. Colonic biopsies obtained from normal and CD mucosa were stimulated with pairs of Pan HLA-DR binder HSP60-derived peptides (human/bacterial homologues). The modulation of RNA and protein levels of induced proinflammatory cytokines were measured. We identified two epitopes capable of sustaining proinflammatory responses, specifically TNF〈 and IFN© induction, in the inflamed intestinal mucosa in CD patients. The responses correlated positively with clinical and histological measurements of disease activity, thus suggesting a contribution of immune responses to HSP in pediatric CD site-specific mucosal inflammation.

Partial Text: Crohn’s disease (CD) is a form of chronic auto-inflammatory bowel disease (IBD) characterized by patchy involvement of the intestinal tract. Although CD can involve any part of the intestine, ileo-colonic involvement is most common [1], [2]. Approximately 20–30 percent of all CD patients are children. Childhood presentation and subsequent treatment of CD may dramatically impact the patient’s growth, development and overall quality of life [1], [3]. CD is pathogenetically based on prolonged remitting/relapsing inflammation of immune origin, which generates damage at local mucosal sites and includes systemic involvement. Immunological, genetic and environmental factors could stochastically overlap in triggering and perpetuating the inflammatory processes [4]. This study addresses the hypothesis that local inflammation is the outcome of inappropriate immune responses to common environmental stimuli, and that such responses contribute to disease activity independently of the events that have triggered the disease [2], [4], [5]. Such antigens should be available within both the microbial flora and the target tissue, over-expressed at the site of inflammation [6], [7] and strongly antigenic [8], [9], [10]. A growing body of work [8], [11]–[14], including our own published findings [15]–[17], implicate that heat shock proteins (HSP) are among the antigens capable of sustaining such immune/autoimmune inflammation.

Despite of recent advances in the clinical understanding of CD, important questions concerning the immunopathology of this disease remain unanswered, particularly regarding the cause of persistent gut inflammation. A commonly held view is that the chronic inflammation is primarily the consequence of a disregulated adaptive immune system leading to an immunological imbalance with a resulting excess of proinflammatory cytokines [5], [23], [24].

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http://doi.org/10.1371/journal.pone.0007714

 

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