Charles L Bevins

Publications of Charles L Bevins

• Meeting report: A symposium on the evolution of common molecular pathways underlying innate immunity.

  Authors: Murray B Gardner, Nicole Baumgarth, Andy Fell, Stephen J McSorley, Jay V Solnick, Charles L Bevins

  Microbes and infection / Institut Pasteur. 04/2012;

  The University of California Davis hosted a symposium on innate immunity in January 2012. Professors Bruce Beutler, Jules Hoffmann, Luke O'Neill and Pamela Ronald discussed their research onThe University of California Davis hosted a symposium on innate immunity in January 2012. Professors Bruce Beutler, Jules Hoffmann, Luke O'Neill and Pamela Ronald discussed their research on mechanisms that multicellular organisms use to recognize microbes.

• Antimicrobial peptides: agents of border protection for companion animals.

  Authors: Brian C Leonard, Verena K Affolter, Charles L Bevins

  Veterinary dermatology. 03/2012;

  Over the past 20 years, there have been significant inroads into understanding the roles of antimicrobial peptides in homeostatic functions and their involvement in disease pathogenesis. In additionOver the past 20 years, there have been significant inroads into understanding the roles of antimicrobial peptides in homeostatic functions and their involvement in disease pathogenesis. In addition to direct antimicrobial activity, these peptides participate in many cellular functions, including chemotaxis, wound healing and even determination of canine coat colour. Various biological and genetic approaches have helped to elucidate the role of antimicrobial peptides with respect to innate immunity and host defense. Associations of antimicrobial peptides with various skin diseases, including psoriasis, rosacea and atopic dermatitis, have been documented in humans. In the longer term, therapeutic modulation of antimicrobial peptide expression may provide effective new treatments for disease. This review highlights current knowledge about antimicrobial peptides of the skin and circulating leukocytes, with particular focus on relevance to physiology and disease in companion animals.

• Bifidobacterium bifidum in a rat model of necrotizing enterocolitis: antimicrobial peptide and protein responses.

  Authors: Mark A Underwood, Anchasa Kananurak, Christine F Coursodon, Camille K Adkins-Reick, Hiutung Chu, Stephen H Bennett, Jan Wehkamp, Patricia A Castillo, Brian C Leonard, Daniel J Tancredi, Michael P Sherman, Bohuslav Dvorak, Charles L Bevins

  Pediatric research. 02/2012;

  Introduction:Necrotizing enterocolitis (NEC) is a devastating disease of premature infants. Probiotics decrease the risk of NEC in clinical and experimental studies. Antimicrobial peptides protectIntroduction:Necrotizing enterocolitis (NEC) is a devastating disease of premature infants. Probiotics decrease the risk of NEC in clinical and experimental studies. Antimicrobial peptides protect the gut against noxious microbes and shape the commensal microbiota, but their role in NEC remains unclear.Methods:To investigate the expression of antimicrobial peptides in experimental NEC and the impact of probiotics on their expression, premature rats were divided into three groups: dam fed (DF), hand fed with formula (FF), or hand fed with formula containing Bifidobacterium bifidum (FF + BIF). All groups were exposed to asphyxia and cold stress.Results:Like in human ontogeny, the rat pup has low expression of Paneth cell antimicrobials, which increases rapidly during normal development. The expression of lysozyme, secretory phospholipase A(2) (sPLA(2)), pancreatic-associated proteins 1 and 3 mRNA was elevated in the FF group with a high incidence of NEC, as compared with the DF and FF + BIF groups where the disease was attenuated.Discussion:We conclude that induction of antimicrobial peptides occurs in experimental NEC similar to that reported in human disease and is attenuated when disease is averted by probiotic B. bifidum. The induction of antimicrobial peptides is likely an adaptive mucosal response that is often not sufficient to prevent disease in the premature gut.

• Activity, Expression and Genetic Variation of Canine β-Defensin 103: A Multifunctional Antimicrobial Peptide in the Skin of Domestic Dogs.

  Authors: Brian C Leonard, Stanley L Marks, Catherine A Outerbridge, Verena K Affolter, Anchasa Kananurak, Amy Young, Peter F Moore, Danika L Bannasch, Charles L Bevins

  Journal of innate immunity. 01/2012;

  The skin functions as more than a physical barrier to infection. Epithelial cells of the skin can synthesize antimicrobial peptides, including defensins, which exhibit direct antimicrobial activity.The skin functions as more than a physical barrier to infection. Epithelial cells of the skin can synthesize antimicrobial peptides, including defensins, which exhibit direct antimicrobial activity. Here we characterize the expression pattern, genetic variation and activity of the major β-defensin expressed in canine skin, canine β-defensin 103 (CBD103). The gene encoding CBD103 exhibits two forms of polymorphism: a common 3-basepair deletion allele and a gene copy-number variation. Golden retrievers and Labrador retrievers were the only breeds that encoded the variant allele of CBD103, termed CBD103ΔG23. Both these breeds also exhibited a CBD103 gene copy-number polymorphism that ranged from 2 to 4 gene-copies per diploid genome. Recombinant CBD103 and CBD103ΔG23, as well as the human ortholog human β-defensin 3 (hBD3) and hBD3ΔG23, showed potent and comparable antimicrobial killing against both methicillin-susceptible and methicillin-resistant Staphylococcus pseudintermedius. Skin biopsy specimens from dogs with atopic dermatitis revealed CBD103 expression levels similar to those in healthy controls and comparable at lesional and nonlesional sites. This expression pattern in dogs differs from the previously reported reduced expression of the human ortholog in atopic dermatitis. Overall, the similarities of CBD103 and its human ortholog reported here support the notion that the domestic dog may serve as a valuable model for studying β-defensin biology in the skin.

• Intestinal bacterial translocation in rats with cirrhosis is related to compromised paneth cell antimicrobial host defense.

  Authors: Zora Teltschik, Reiner Wiest, Julia Beisner, Sabine Nuding, Claudia Hofmann, Juergen Schoelmerich, Charles L Bevins, Eduard F Stange, Jan Wehkamp

  Hepatology (Baltimore, Md.). 11/2011;

  Liver cirrhosis is associated with bacterial translocation (BT) and endotoxemia. Most translocating bacteria belong to the common intestinal microbiota, suggesting a breakdown of intestinal barrierLiver cirrhosis is associated with bacterial translocation (BT) and endotoxemia. Most translocating bacteria belong to the common intestinal microbiota, suggesting a breakdown of intestinal barrier function. We hypothesized that diminished mucosal antimicrobial host defense could predispose to BT. Two rodent models of portal hypertension with increased BT were used, CCl(4) -induced ascitic cirrhosis and 2-day portal vein-ligated (PVL) animals. BT was assessed by standard microbiological techniques on mesenteric lymph nodes. Total RNA was isolated systematically throughout the intestinal tract, and expression of Paneth cell α-cryptdins and β-defensins was determined by real-time quantitative polymerase chain reaction (qPCR). To determine functional consequences, mucosal antimicrobial activity was assessed with a fluorescence-activated cell sorting assay. BT was detectable in 40% of rats with cirrhosis. Compared with the group without BT, these animals exhibited diminished intestinal Paneth cell α-cryptdin 5 and 7 expression. In contrast, PVL was associated with BT in all animals but did not affect antimicrobial peptides. The decrease in Paneth cell antimicrobials was most pronounced in the ileum and the coecum. Other antimicrobials showed no changes or even an induction in the case of BT at different sites. Antimicrobial activity toward different commensal strains was reduced, especially in the distal ileum and the cecum in experimental cirrhosis with BT (excluding PVL). Conclusion: Compromised Paneth cell antimicrobial host defense seems to predispose to BT in experimental cirrhosis. Understanding this liver-gut axis including the underlying mechanisms could help us to find new treatment avenues. (HEPATOLOGY 2011).

• The potter's wheel: the host's role in sculpting its microbiota.

  Authors: Charles L Bevins, Nita H Salzman

  Cellular and molecular life sciences : CMLS. 11/2011; 68(22):3675-85.

  Animals, ranging from basal metazoans to primates, are host to complex microbial ecosystems; engaged in a symbiotic relationship that is essential for host physiology and homeostasis. EpithelialAnimals, ranging from basal metazoans to primates, are host to complex microbial ecosystems; engaged in a symbiotic relationship that is essential for host physiology and homeostasis. Epithelial surfaces vary in the composition of colonizing microbiota as one compares anatomic sites, developmental stages and species origin. Alterations of microbial composition likely contribute to susceptibility to several distinct diseases. The forces that shape the colonizing microbial composition are the focus of much current investigation, and it is evident that there are pressures exerted both by the host and the external environment to mold these ecosystems. The focus of this review is to discuss recent studies that demonstrate the critical importance of host factors in selecting for its microbiome. Greater insight into host-microbiome interactions will be essential for understanding homeostasis at mucosal surfaces, and developing useful interventions when homeostasis is disrupted.

• A common mutation in the defensin DEFB126 causes impaired sperm function and subfertility.

  Authors: Theodore L Tollner, Scott A Venners, Edward J Hollox, Ashley I Yudin, Xue Liu, Genfu Tang, Houxun Xing, Robert J Kays, Tsang Lau, James W Overstreet, Xiping Xu, Charles L Bevins, Gary N Cherr

  Science translational medicine. 07/2011; 3(92):92ra65.

  A glycosylated polypeptide, β-defensin 126 (DEFB126), derived from the epididymis and adsorbed onto the sperm surface, has been implicated in immunoprotection and efficient movement of sperm inA glycosylated polypeptide, β-defensin 126 (DEFB126), derived from the epididymis and adsorbed onto the sperm surface, has been implicated in immunoprotection and efficient movement of sperm in mucosal fluids of the female reproductive tract. Here, we report a sequence variant in DEFB126 that has a two-nucleotide deletion in the open reading frame, which generates an abnormal mRNA. The allele frequency of this variant sequence was high in both a European (0.47) and a Chinese (0.45) population cohort. Binding of the Agaricus bisporus lectin to the sperm surface glycocalyx was significantly lower in men with the homozygous variant (del/del) genotype than in those with either a del/wt or a wt/wt genotype, suggesting an altered sperm glycocalyx with fewer O-linked oligosaccharides in del/del men. Moreover, sperm from del/del carriers exhibited an 84% reduction in the rate of penetration of a hyaluronic acid gel, a surrogate for cervical mucus, compared to the other genotypes. This reduction in sperm performance in hyaluronic acid gels was not a result of decreased progressive motility (average curvilinear velocity) or morphological deficits. Nevertheless, DEFB126 genotype and lectin binding were correlated with sperm performance in the penetration assays. In a prospective cohort study of newly married couples who were trying to conceive by natural means, couples were less likely to become pregnant and took longer to achieve a live birth if the male partner was homozygous for the variant sequence. This common sequence variation in DEFB126, and its apparent effect of impaired reproductive function, will allow a better understanding, clinical evaluation, and possibly treatment of human infertility.

• Paneth cells, antimicrobial peptides and maintenance of intestinal homeostasis.

  Authors: Charles L Bevins, Nita H Salzman

  Nature reviews. Microbiology. 03/2011; 9(5):356-68.

  Building and maintaining a homeostatic relationship between a host and its colonizing microbiota entails ongoing complex interactions between the host and the microorganisms. The mucosal immuneBuilding and maintaining a homeostatic relationship between a host and its colonizing microbiota entails ongoing complex interactions between the host and the microorganisms. The mucosal immune system, including epithelial cells, plays an essential part in negotiating this equilibrium. Paneth cells (specialized cells in the epithelium of the small intestine) are an important source of antimicrobial peptides in the intestine. These cells have become the focus of investigations that explore the mechanisms of host-microorganism homeostasis in the small intestine and its collapse in the processes of infection and chronic inflammation. In this Review, we provide an overview of the intestinal microbiota and describe the cell biology of Paneth cells, emphasizing the composition of their secretions and the roles of these cells in intestinal host defence and homeostasis. We also highlight the implications of Paneth cell dysfunction in susceptibility to chronic inflammatory bowel disease.

• Expression and activity of a novel cathelicidin from domestic cats.

  Authors: Brian C Leonard, Hiutung Chu, Jennifer L Johns, Richard L Gallo, Peter F Moore, Stanley L Marks, Charles L Bevins

  PloS one. 01/2011; 6(4):e18756.

  Cathelicidins are small cationic antimicrobial peptides found in many species including primates, mammals, marsupials, birds and even more primitive vertebrates, such as the hagfish. Some animalsCathelicidins are small cationic antimicrobial peptides found in many species including primates, mammals, marsupials, birds and even more primitive vertebrates, such as the hagfish. Some animals encode multiple cathelicidins in their genome, whereas others have only one. This report identifies and characterizes feline cathelicidin (feCath) as the sole cathelicidin in domestic cats (Felis catus). Expression of feCath is predominantly found in the bone marrow, with lower levels of expression in the gastrointestinal tract and skin. By immunocytochemistry, feCath localizes to the cytoplasm of neutrophils in feline peripheral blood. Structurally, the mature feCath sequence is most similar to a subgroup of cathelicidins that form linear α-helices. feCath possesses antimicrobial activity against E. coli D31, Salmonella enterica serovar Typhimurium (IR715), Listeria monocytogenes and Staphylococcus pseudintermedius (clinical isolate) similar to that of the human ortholog, LL-37. In contrast, feCath lacks the DNA binding activity seen with LL-37. Given its similarity in sequence, structure, tissue expression, and antimicrobial activity, the cathelicidin encoded by cats, feCath, belongs to the subgroup of linear cathelicidins found not only in humans, but also non-human primates, dogs, mice, and rats.

• Gut inflammation provides a respiratory electron acceptor for Salmonella.

  Authors: Sebastian E Winter, Parameth Thiennimitr, Maria G Winter, Brian P Butler, Douglas L Huseby, Robert W Crawford, Joseph M Russell, Charles L Bevins, L Garry Adams, Renée M Tsolis, John R Roth, Andreas J Bäumler

  Nature. 09/2010; 467(7314):426-9.

  Salmonella enterica serotype Typhimurium (S. Typhimurium) causes acute gut inflammation by using its virulence factors to invade the intestinal epithelium and survive in mucosal macrophages. TheSalmonella enterica serotype Typhimurium (S. Typhimurium) causes acute gut inflammation by using its virulence factors to invade the intestinal epithelium and survive in mucosal macrophages. The inflammatory response enhances the transmission success of S. Typhimurium by promoting its outgrowth in the gut lumen through unknown mechanisms. Here we show that reactive oxygen species generated during inflammation react with endogenous, luminal sulphur compounds (thiosulphate) to form a new respiratory electron acceptor, tetrathionate. The genes conferring the ability to use tetrathionate as an electron acceptor produce a growth advantage for S. Typhimurium over the competing microbiota in the lumen of the inflamed gut. We conclude that S. Typhimurium virulence factors induce host-driven production of a new electron acceptor that allows the pathogen to use respiration to compete with fermenting gut microbes. Thus the ability to trigger intestinal inflammation is crucial for the biology of this diarrhoeal pathogen.

• Induction and rescue of Nod2-dependent Th1-driven granulomatous inflammation of the ileum.

  Authors: Amlan Biswas, Yuen-Joyce Liu, Liming Hao, Atsushi Mizoguchi, Nita H Salzman, Charles L Bevins, Koichi S Kobayashi

  Proceedings of the National Academy of Sciences of the United States of America. 08/2010; 107(33):14739-44.

  Mutations in the NOD2 gene are strong genetic risk factors for ileal Crohn's disease. However, the mechanism by which these mutations predispose to intestinal inflammation remains a subject ofMutations in the NOD2 gene are strong genetic risk factors for ileal Crohn's disease. However, the mechanism by which these mutations predispose to intestinal inflammation remains a subject of controversy. We report that Nod2-deficient mice inoculated with Helicobacter hepaticus, an opportunistic pathogenic bacterium, developed granulomatous inflammation of the ileum, characterized by an increased expression of Th1-related genes and inflammatory cytokines. The Peyer's patches and mesenteric lymph nodes were markedly enlarged with expansion of IFN-gamma-producing CD4 and CD8 T cells. Rip2-deficient mice exhibited a similar phenotype, suggesting that Nod2 function likely depends on the Rip2 kinase in this model. Transferring wild-type bone marrow cells into irradiated Nod2-deficient mice did not rescue the phenotype. However, restoring crypt antimicrobial function of Nod2-deficient mice by transgenic expression of alpha-defensin in Paneth cells rescued the Th1 inflammatory phenotype. Therefore, through the regulation of intestinal microbes, Nod2 function in nonhematopoietic cells of the small intestinal crypts is critical for protecting mice from a Th1-driven granulomatous inflammation in the ileum. The model may provide insight into Nod2 function relevant to inflammation of ileal Crohn's disease.

• Defensin-barbed innate immunity: clinical associations in the pediatric population.

  Authors: Mark A Underwood, Charles L Bevins

  Pediatrics. 06/2010; 125(6):1237-47.

  Defensins and related antimicrobial peptides serve a central role in innate immunity in all species of plants and animals. In humans, defensins are widely expressed, including in neutrophils, skin,Defensins and related antimicrobial peptides serve a central role in innate immunity in all species of plants and animals. In humans, defensins are widely expressed, including in neutrophils, skin, and mucosal epithelia. Most defensins are potent antibiotics, and some have chemotactic and toxin-neutralizing activities. Results of recent studies on the homeostatic and disease-fighting activities of human defensins point to a key relevance in several pediatric disorders. Inherited variation in defensin gene expression may contribute to susceptibility to several diseases, including psoriasis and Crohn disease. We review here the recent discoveries in innate immunity that shed light on the potential roles of defensins, and other antimicrobial molecules, in the pathophysiology of common pediatric diseases such as atopic dermatitis, necrotizing enterocolitis, cystic fibrosis, and otitis media.

• A sweet target for innate immunity.

  Authors: Fu-Tong Liu, Charles L Bevins

  Nature medicine. 03/2010; 16(3):263-4.

• Life in the inflamed intestine, Salmonella style.

  Authors: Renato L Santos, Manuela Raffatellu, Charles L Bevins, L Garry Adams, Cagla Tükel, Renée M Tsolis, Andreas J Bäumler

  Trends in microbiology. 10/2009;

  The lower gastrointestinal tract is densely populated with resident microbial communities (microbiota), which do not elicit overt host responses but rather provide benefit to the host, includingThe lower gastrointestinal tract is densely populated with resident microbial communities (microbiota), which do not elicit overt host responses but rather provide benefit to the host, including niche protection from pathogens. However, introduction of bacteria into the underlying tissue evokes acute inflammation. Non-typhoidal Salmonella serotypes (NTS) elicit this stereotypic host response by actively penetrating the intestinal epithelium and surviving in tissue macrophages. Initial responses generated by bacterial host cell interaction are amplified in tissue through the interleukin (IL)-18/interferon-gamma and IL-23/IL-17 axes, resulting in the activation of mucosal barrier functions against NTS dissemination. However, the pathogen is adapted to survive antimicrobial defenses encountered in the lumen of the inflamed intestine. This strategy enables NTS to exploit inflammation to outcompete the intestinal microbiota, and promotes the Salmonella transmission by the fecal/oral route.

• Enteric defensins are essential regulators of intestinal microbial ecology.

  Authors: Nita H Salzman, Kuiechun Hung, Dipica Haribhai, Hiutung Chu, Jenny Karlsson-Sjöberg, Elad Amir, Paul Teggatz, Melissa Barman, Michael Hayward, Daniel Eastwood, Maaike Stoel, Yanjiao Zhou, Erica Sodergren, George M Weinstock, Charles L Bevins, Calvin B Williams, Nicolaas A Bos

  Nature immunology. 10/2009;

  Antimicrobial peptides are important effectors of innate immunity throughout the plant and animal kingdoms. In the mammalian small intestine, Paneth cell alpha-defensins are antimicrobial peptidesAntimicrobial peptides are important effectors of innate immunity throughout the plant and animal kingdoms. In the mammalian small intestine, Paneth cell alpha-defensins are antimicrobial peptides that contribute to host defense against enteric pathogens. To determine if alpha-defensins also govern intestinal microbial ecology, we analyzed the intestinal microbiota of mice expressing a human alpha-defensin gene (DEFA5) and in mice lacking an enzyme required for the processing of mouse alpha-defensins. In these complementary models, we detected significant alpha-defensin-dependent changes in microbiota composition, but not in total bacterial numbers. Furthermore, DEFA5-expressing mice had striking losses of segmented filamentous bacteria and fewer interleukin 17 (IL-17)-producing lamina propria T cells. Our data ascribe a new homeostatic role to alpha-defensins in regulating the makeup of the commensal microbiota.

• Lipocalin-2 resistance confers an advantage to Salmonella enterica serotype Typhimurium for growth and survival in the inflamed intestine.

  Authors: Manuela Raffatellu, Michael D George, Yuko Akiyama, Michael J Hornsby, Sean-Paul Nuccio, Tatiane A Paixao, Brian P Butler, Hiutung Chu, Renato L Santos, Thorsten Berger, Tak W Mak, Renée M Tsolis, Charles L Bevins, Jay V Solnick, Satya Dandekar, Andreas J Bäumler

  Cell host & microbe. 06/2009; 5(5):476-86.

  In response to enteric pathogens, the inflamed intestine produces antimicrobial proteins, a process mediated by the cytokines IL-17 and IL-22. Salmonella enterica serotype Typhimurium thrives in theIn response to enteric pathogens, the inflamed intestine produces antimicrobial proteins, a process mediated by the cytokines IL-17 and IL-22. Salmonella enterica serotype Typhimurium thrives in the inflamed intestinal environment, suggesting that the pathogen is resistant to antimicrobials it encounters in the intestinal lumen. However, the identity of these antimicrobials and corresponding bacterial resistance mechanisms remain unknown. Here, we report that enteric infection of rhesus macaques and mice with S. Typhimurium resulted in marked Il-17- and IL-22-dependent intestinal epithelial induction and luminal accumulation of lipocalin-2, an antimicrobial protein that prevents bacterial iron acquisition. Resistance to lipocalin-2, mediated by the iroBCDE iroN locus, conferred a competitive advantage to the bacterium in colonizing the inflamed intestine of wild-type but not of lipocalin-2-deficient mice. Thus, resistance to lipocalin-2 defines a specific adaptation of S. Typhimurium for growth in the inflamed intestine.

• Contribution of flagellin pattern recognition to intestinal inflammation during Salmonella enterica serotype Typhimurium infection.

  Authors: Sebastian E Winter, Parameth Thiennimitr, Sean-Paul Nuccio, Takeshi Haneda, Maria G Winter, R Paul Wilson, Joseph M Russell, Thomas Henry, Quynh T Tran, Sara D Lawhon, Gabriel Gomez, Charles L Bevins, Holger Rüssmann, Denise M Monack, L Garry Adams, Andreas J Bäumler

  Infection and immunity. 03/2009;

  Salmonella enterica serotype Typhimurium causes acute inflammatory diarrhea in humans. Flagella contribute to intestinal inflammation but the mechanism remains unclear since most mutations abrogatingSalmonella enterica serotype Typhimurium causes acute inflammatory diarrhea in humans. Flagella contribute to intestinal inflammation but the mechanism remains unclear since most mutations abrogating pattern recognition of flagellin also prevent motility and reduce bacterial invasion. To determine the contribution of flagellin pattern recognition to the generation of innate immune responses, we compared in two animal models a non-motile, but flagellin expressing and secreting serotype Typhimurium strain (flgK mutant) to a non-motile, non-flagellin expressing strain (flgK fliC fljB mutant). In vitro, caspase-1 can be activated by cytosolic delivery of flagellin, resulting in release of the interferon gamma inducing factor interleukin-18 (IL-18). Experiments with streptomycin-pretreated caspase-1 deficient mice suggested that induction of interferon gamma expression in the murine cecum early (12 hours) after serotype Typhimurium infection was caspase-1-dependent but independent of flagellin pattern recognition. In addition, mRNA levels of the CXC chemokines macrophage inflammatory protein 2 and keratinocyte-derived chemokine were markedly increased early after serotype Typhimurium infection of streptomycin-pretreated wild-type mice regardless of flagellin expression. In contrast, in bovine ligated ileal loops, flagellin pattern recognition contributed to increased mRNA levels of macrophage inflammatory protein 3 alpha and more fluid accumulation at 2 hours after infection. Collectively, our data suggest that pattern recognition of flagellin contributes to early innate host responses in the bovine ileal mucosa, but not in the murine cecal mucosa.

• Genetic variants of Wnt transcription factor TCF-4 (TCF7L2) putative promoter region are associated with small intestinal Crohn's disease.

  Authors: Maureen J Koslowski, Irmgard Kübler, Mathias Chamaillard, Elke Schaeffeler, Walter Reinisch, Guoxing Wang, Julia Beisner, Alexander Teml, Laurent Peyrin-Biroulet, Stefan Winter, Klaus R Herrlinger, Paul Rutgeerts, Séverine Vermeire, Rachel Cooney, Klaus Fellermann, Derek Jewell, Charles L Bevins, Matthias Schwab, Eduard F Stange, Jan Wehkamp

  PLoS ONE. 02/2009; 4(2):e4496.

  Reduced expression of Paneth cell antimicrobial alpha-defensins, human defensin (HD)-5 and -6, characterizes Crohn's disease (CD) of the ileum. TCF-4 (also named TCF7L2), a Wnt signalling pathwayReduced expression of Paneth cell antimicrobial alpha-defensins, human defensin (HD)-5 and -6, characterizes Crohn's disease (CD) of the ileum. TCF-4 (also named TCF7L2), a Wnt signalling pathway transcription factor, orchestrates Paneth cell differentiation, directly regulates the expression of HD-5 and -6, and was previously associated with the decrease of these antimicrobial peptides in a subset of ileal CD. To investigate a potential genetic association of TCF-4 with ileal CD, we sequenced 2.1 kb of the 5' flanking region of TCF-4 in a small group of ileal CD patients and controls (n = 10 each). We identified eight single nucleotide polymorphisms (SNPs), of which three (rs3814570, rs10885394, rs10885395) were in linkage disequilibrium and found more frequently in patients; one (rs3814570) was thereby located in a predicted regulatory region. We carried out high-throughput analysis of this SNP in three cohorts of inflammatory bowel disease (IBD) patients and controls. Overall 1399 healthy individuals, 785 ulcerative colitis (UC) patients, 225 CD patients with colonic disease only and 784 CD patients with ileal involvement were used to determine frequency distributions. We found an association of rs3814570 with ileal CD but neither with colonic CD or UC, in a combined analysis (allele positivity: OR 1.27, 95% CI 1.07 to 1.52, p = 0.00737), which was the strongest in ileal CD patients with stricturing behaviour (allele frequency: OR 1.32, 95% CI 1.08 to1.62, p = 0.00686) or an additional involvement of the upper GIT (allele frequency: OR 1.38, 95% CI 1.03 to1.84, p = 0.02882). The newly identified genetic association of TCF-4 with ileal CD provides evidence that the decrease in Paneth cell alpha-defensins is a primary factor in disease pathogenesis.

• IL-23 orchestrates mucosal responses to Salmonella enterica serotype Typhimurium in the intestine.

  Authors: Ivan Godinez, Manuela Raffatellu, Hiutung Chu, Tatiane A Paixão, Takeshi Haneda, Renato L Santos, Charles L Bevins, Renée M Tsolis, Andreas J Bäumler

  Infection and immunity. 11/2008;

  Salmonella enterica serotype Typhimurium causes an acute inflammatory reaction in the cecum of streptomycin pre-treated mice that involves T cell-dependent induction of interferon (Ifn)-gamma,Salmonella enterica serotype Typhimurium causes an acute inflammatory reaction in the cecum of streptomycin pre-treated mice that involves T cell-dependent induction of interferon (Ifn)-gamma, interleukin (Il)-22 and Il-17 expression. Here we investigated the role of IL-23 in initiating these inflammatory responses using the streptomycin pre-treated mouse model. Compared to wild type mice, expression of Il-17 was abrogated, Il-22 expression was markedly reduced but Ifn-gamma expression was normal in the cecum of IL-23 p19 deficient mice during serotype Typhimurium infection. IL-23 p19 deficient mice also exhibited a markedly reduced expression of regenerating islet-derived 3 gamma (Reg3g), keratinocyte-derived cytokine (Kc), and reduced neutrophil recruitment into the cecal mucosa during infection. Analysis of CD3(+) lymphocytes in the intestinal mucosa by flow cytometry revealed that alphabeta T cells were the predominant cell type expressing the IL-23 receptor in naïve mice. However, a marked increase in the number of IL-23 receptor expressing gammadelta T cells was observed in the lamina propria during serotype Typhimurium infection. Compared to wild type mice, gammadelta T cell receptor deficient mice exhibited blunted expression of Il-17 during serotype Typhimurium infection while Ifn-gamma expression was normal. These data suggested that gammadelta T cells are a significant, but not the sole source of IL-17 in the acutely inflamed cecal mucosa of mice. Collectively our results point to IL-23 as an important player in initiating a T cell-dependent amplification of inflammatory responses in the intestinal mucosa during serotype Typhimurium infection.

• Family history of Crohn's disease is associated with an increased risk for Crohn's disease of the pouch.

  Authors: Bo Shen, Feza H Remzi, Jeffrey P Hammel, Bret A Lashner, Charles L Bevins, Ian C Lavery, Jan Wehkamp, Victor W Fazio

  Inflammatory bowel diseases. 10/2008;

  Background: Crohn's disease (CD) of the pouch can occur in patients with restorative proctocolectomy and ileal pouch-anal anastomosis originally performed for a preoperative diagnosis of ulcerativeBackground: Crohn's disease (CD) of the pouch can occur in patients with restorative proctocolectomy and ileal pouch-anal anastomosis originally performed for a preoperative diagnosis of ulcerative colitis (UC). CD of the pouch was often observed in patients with a family history of CD. The purpose was to determine whether the family history of CD increased the risk for CD of the pouch in patients who underwent restorative proctocolectomy.Methods: A total of 558 eligible patients seen in the Pouchitis Clinic were enrolled, including 116 patients with CD of the pouch and 442 patients with a normal pouch or other pouch disorders. Demographic and clinical variables were included in the study. Multivariable logistic regression analyses were performed.Results: The adjusted multivariate logistic analyses revealed that the risk for CD of the pouch was increased in patients with a family history of CD, with an odds ratio (OR) of 3.22 (95% confidence interval [CI] 1.56-6.67), or with a first-degree relative with CD (OR = 4.18, 95% CI, 1.48-11.8), or with a greater number of family members with CD (OR = 2.00 per family member, 95% CI, 1.19-3.37), adjusting for age, gender, smoking status, duration of IBD, duration of having a pouch, and a preoperation diagnosis of indeterminate colitis or CD. In addition, patients of younger age and longer duration of having a pouch had a higher risk for CD of the pouch. A diagnosis of CD of the pouch was associated with a poor outcome, with a greater than 5-fold estimated increased odds of pouch failure (OR = 5.58, 95% CI, 2.74-11.4).Conclusions The presence of a family history of CD is associated with an increased risk for CD of the pouch, which in turn has a high risk for pouch failure.(Inflamm Bowel Dis 2008).