title: Immunopathogenesis of IBD: Batf as a Key Driver of Disease Activity.
abstract: BACKGROUND
  Inflammatory bowel diseases (IBDs) represent a group of chronic immune-mediated disorders that are influenced by a genetic predisposition and additional environmental triggers. Genome-wide association studies strongly implicate that a number of immune system-related genetic variations are critically contributing to the initiation and promotion of intestinal inflammation. Especially the identification of the strong association of a series of single nucleotide polymorphisms including interleukin (IL)-23R, CCR6, signal transducer and activator of transcription 3 (Stat3) and Stat4 with IBD susceptibility point at a critical involvement of T cells and especially of IL-17a-producing Th17 cells in the immune pathogenesis of IBD. In line with this hypothesis, a series of preclinical studies have unequivocally established that T cells are key drivers of immune-mediated colitis. Interestingly, especially Th17 cells were identified to be highly prevalent in inflamed IBD tissues, a finding that seems to be functionally relevant as genetic inactivation studies in the mouse resulted in almost complete suppression of colitis development.
  
  
  CONCLUSIONS
  While targeting Th17 cell differentiation regulating transcription factors, as retinoic acid-related orphan receptor gamma t (RORγt) is effective in preventing murine colitis, one concern of drugs targeting RORγt in a clinical setting represents the large body of murine data unambiguously demonstrating that additional pathways within and outside the immune system are equally RORγt-dependent increasing the risk of undesirable side effects. The AP1 transcription factor Batf (B cell-activating transcription factor) appears to exclusively regulate pathways within lymphocytes. Importantly, Batf represents a central regulator of Th17 cell development and is strongly upregulated within IBD-affected tissues. Employing 2 acute colitis models, we demonstrate in this study that Batf-expressing T cells are critical drivers of T cell-mediated colitis while in contrast to Stat3 loss of Batf does not affect intestinal epithelial cell homeostasis ex vivo.
  
  
  CONCLUSIONS
  Targeting Batf in IBD emerges as an attractive therapeutic approach disabling colitogenic T cell activities while sparing off-target effects in the intestinal epithelial cell compartment.
authors.affiliation: Department of Medicine 1, University Hospital Erlangen, University of Erlangen-Nuremberg, Kussmaul Campus for Medical Research, Erlangen, Germany.
authors.forename: Kai
authors.initials: K
authors.lastname: Hildner
authors.forename: Elise
authors.initials: E
authors.lastname: Punkenburg
authors.forename: Benjamin
authors.initials: B
authors.lastname: Abendroth
authors.forename: Markus F
authors.initials: MF
authors.lastname: Neurath
mesh_terms: D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000037:antagonists & inhibitors / Q000502:physiology*; D002454:Cell Differentiation / Q000235:genetics; D003092:Colitis / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000139:chemically induced / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000473:pathology; D051379:Mice; D020641:Polymorphism, Single Nucleotide; D054399:Receptors, CCR6 / Q000235:genetics; D018123:Receptors, Interleukin / Q000235:genetics; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics; D050797:STAT4 Transcription Factor / Q000235:genetics; D058504:Th17 Cells / Q000502:physiology*; D000097768:Retinoic Acid Receptor gamma
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; D020381:Interleukin-17; D054399:Receptors, CCR6; D018123:Receptors, Interleukin; D018168:Receptors, Retinoic Acid; D050796:STAT3 Transcription Factor; D050797:STAT4 Transcription Factor; D000097768:Retinoic Acid Receptor gamma; C431772:Batf protein, mouse; C498126:CCR6 protein, mouse; C528688:interleukin-23 receptor, mouse