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. Key Messages: 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.

Expression of decorin in intestinal tissues of mice with inflammatory bowel disease and its correlation with autophagy

“…IBD usually occurs in young adults and is closely associated with inheritance, infection and immune function (3). IBD is harmful to health with characteristics including a high recurrence rate, high canceration rate and poor prognosis (4,5).…”

CCR6-CCL20 Axis in IBD: What have we learnt in the past 20 years?

“…Batf positive T cells are thought to actively contribute to the T cell mediated component of colitis. Further, unlike STAT3, the absence of Batf did not influence the intestinal homeostasis ex vivo [34].…”

Secreted protein acidic and rich in cysteine functions in colitis via IL17A regulation in mucosal CD4+ T cells

“…Recently, it was reported that not only neutrophils but also CD4 + T helper (Th) cells have important roles in the pathogenesis of IBD. These studies have focused on Th17 cells because the IL23/Th17/IL17A pathway is an important therapeutic target in IBD patients . However, the role of IL17A in colitis remains controversial.…”

“…These studies have focused on Th17 cells because the IL23/Th17/IL17A pathway is an important therapeutic target in IBD patients. [33][34][35] However, the role of IL17A in colitis remains controversial. The levels of IL17A produced by Th17 cells are increased in both the colonic mucosa and serum of IBD patients.…”