Insights into IBD Pathogenesis

Cedars-Sinai Inflammatory Bowel Disease Center, Suite D4063, Los Angeles, CA 90048, USA.
Current Gastroenterology Reports 12/2009; 11(6):473-80. DOI: 10.1007/s11894-009-0072-9
Source: PubMed

ABSTRACT Inflammatory bowel disease (IBD), encompassing Crohn's disease (CD) and ulcerative colitis (UC), is a chronic inflammatory disorder caused by dysregulated immune responses in a genetically predisposed individual. Recent accumulating data, including genome-wide association studies, have identified more than 50 distinct genetic loci that confer susceptibility. We highlight the role of microbial-host interaction, particularly with respect to the overlap of common genetic and pathophysiologic mechanisms of CD and UC, interleukin-22-producing natural killer cells, autophagy, and TL1A, a member of the tumor necrosis factor (TNF) family, in gut homeostasis and IBD pathogenesis. This article focuses on the recent advances in understanding of IBD from the past year, including advances in genetics and immunobiology.

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    • "Human inflammatory bowel diseases (IBD) are autoimmune diseases that are characterized by chronic autoinflammatory processes within the intestinal mucosal lamina propria. TNF has been demonstrated to play a key role in human IBD [11], [12], [13] and in experimental models of autoimmune colitis in mice [14], [15], where TNF induces intestinal epithelial cell apoptosis during intestinal inflammation, thereby aggravating the disease [16]. Of note, CD137L signaling has been demonstrated to induce TNF secretion [17], [18], and TNF receptor 1 (TNFR1) acts as a coreceptor for CD137L and mediates CD137L signaling [19]. "
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    ABSTRACT: CD137 and its ligand (CD137L) are potent immunoregulatory molecules that influence activation, proliferation, differentiation and cell death of leukocytes. Expression of CD137 is upregulated in the lamina propria cells of Crohn's disease patients. Here, the role of CD137 in acute Dextran-Sodium-Sulfate (DSS)-induced colitis in mice was examined. We induced acute large bowel inflammation (colitis) via DSS administration in CD137(-/-) and wild-type (WT) mice. Colitis severity was evaluated by clinical parameters (weight loss), cytokine secretion in colon segment cultures, and scoring of histological inflammatory parameters. Additionally, populations of lamina propria mononuclear cells (LPMNC) and intraepithelial lymphocytes (IEL) were characterized by flow cytometry. In a subset of mice, resolution of intestinal inflammation was evaluated 3 and 7 days after withdrawal of DSS. We found that both CD137(-/-) and WT mice demonstrated a similar degree of inflammation after 5 days of DSS exposure. However, the resolution of colonic inflammation was impaired in the absence of CD137. This was accompanied by a higher histological score of inflammation, and increased release of the pro-inflammatory mediators granulocyte macrophage colony-stimulating factor (GM-CSF), CXCL1, IL-17 and IFN-γ. Further, there were significantly more neutrophils among the LPMNC of CD137(-/-) mice, and reduced numbers of macrophages among the IEL. We conclude that CD137 plays an essential role in the resolution of acute DSS-induced intestinal inflammation in mice.
    PLoS ONE 09/2013; 8(9):e73277. DOI:10.1371/journal.pone.0073277 · 3.23 Impact Factor
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    • "More recently, other investigators have published an informative review on the role of the TL1A-DR3 pathway in the pathogenesis of IBD [14]. Of note, TL1A expression is increased in the inflamed intestinal tissue of patients with CD [1]. "
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    ABSTRACT: This review identifies possible pharmacological targets for inflammatory bowel disease (IBD) within the IL-23/IL-17 axis. Specifically, there are several targets within the IL-23/IL-17 pathways for potential pharmacological intervention with antibodies or small molecule inhibitors. These targets include TL1A (tumor necrosis factor-like molecule), DR3 (death receptor 3), IL-23, IL-17 and the receptors for IL-23 and IL-17. As related to IBD, there are also other novel pharmacological targets. These targets include inhibiting specific immunoproteasome subunits, blocking a key enzyme in sphingolipid metabolism (sphingosine kinase), and modulating NF-κB/STAT3 interactions. Several good approaches exist for pharmacological inhibition of key components in the IL-23 and IL-17 pathways. These approaches include specific monoclonal antibodies to TL1A, IL-17 receptor, Fc fusion proteins, specific antibodies to IL-17F, and small molecule inhibitors of IL-17 like Vidofludimus. Also, other potential approaches for targeted drug development in IBD include specific chemical inhibitors of SK, specific small molecule inhibitors directed against catalytic subunits of the immunoproteasome, and dual inhibitors of the STAT3 and NF-κB signal transduction systems. In the future, well-designed preclinical studies are still needed to determine which of these pharmacological approaches will provide drugs with the best efficacy and safety profiles for entrance into clinical trials.
    03/2012; 2012(1):389404. DOI:10.1155/2012/389404
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    • "At least one AIDx has been identified for nearly every organ and tissue in the body. While some organs are attacked by multiple AIDx, the diseases affecting a single site often have distinct clinical and pathological presentations (Shih and Targan 2009; Westbrook, Szakmary, and Schiestl 2010), presumably as a result of divergent antigenic stimuli rather than anatomical and physiological differences among individuals. Burgeoning evidence suggests that other health conditions, including but not limited to amyotrophic lateral sclerosis (Niebroj-Dobosz, Dziewulska, and Janik 2006; Staines 2008), atherosclerosis (Ross 1990; Golovanova et al. 1998; Xu et al.1999), infertility (Fichorova and Boulanov 1996; Geva et al. 1997; Melner and Feltus 1999), post-menopausal osteoporosis (Pacifici 2007), and schizophrenia (Shinitzky et al. 1991; Spivak et al. 2009), may have an autoimmune component as well. "
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    ABSTRACT: Autoimmune disease (AIDx) results from failure to sustain tolerance to self molecules. Dozens of AIDx involving one or multiple organ systems afflict 3% or more of people worldwide (>75% women). Predisposing factors for AIDx include genetic background, hormonal status, pathogens, and xenobiotic exposures. The incidence of AIDx is higher in individuals living in developed nations, including recent immigrants. Patients may have several AIDx simultaneously. Certain AIDx can prevent other AIDx. A history of AIDx raises the risk for developing hematopoietic neoplasia. Some common mechanisms for losing self-tolerance include reduced deletion or enhanced activation of autoreactive CD4(+) T-helper (Th) lymphocytes, defective immunomodulation by CD4(+) regulatory (Treg) and CD8(+) suppressor (Ts) T-lymphocytes, dysregulated signaling (leading to a relative increase in pro-inflammatory cytokines), comparable structure between self-antigens and foreign molecules, or expression of new epitopes on previously hidden or xenobiotic-modified self proteins. Organ-specific AIDx is generally a cell-mediated (Th1 or Th17) process, while multi-organ AIDx also incorporates a robust autoantibody (Th2) component. Cytokine signatures of different AIDx overlap incompletely; for a given AIDx, different patients have divergent cytokine profiles. Newer anti-AIDx agents are based on our increasing knowledge of AIDx pathogenesis and usually attempt to reverse lymphocyte dysfunction, quell pro-inflammatory signaling, or restore self-tolerance.
    Toxicologic Pathology 11/2011; 40(2):216-29. DOI:10.1177/0192623311428481 · 2.14 Impact Factor
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