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154. Epithelial endoplasmic reticulum stress orchestrates a protective IgA response

Author

Grootjans, Joep, Krupka, Niklas, Hosomi, Shuhei, Matute, Juan D, Hanley, Thomas, Saveljeva, Svetlana, Gensollen, Thomas, Heijmans, Jarom, Li, Hai, Limenitakis, Julien P, Ganal-Vonarburg, Stephanie C, Suo, Shengbao, Luoma, Adrienne M, Shimodaira, Yosuke, Duan, Jinzhi, Shih, David Q, Conner, Margaret E, Glickman, Jonathan N, Fuhler, Gwenny M, Palm, Noah W, de Zoete, Marcel R, van der Woude, C Janneke, Yuan, Guo-Cheng, Wucherpfennig, Kai W, Targan, Stephan R, Rosenstiel, Philip, Flavell, Richard A, McCoy, Kathy D, Macpherson, Andrew J, Kaser, Arthur, Blumberg, Richard S, Grootjans, Joep, Krupka, Niklas, Hosomi, Shuhei, Matute, Juan D, Hanley, Thomas, Saveljeva, Svetlana, Gensollen, Thomas, Heijmans, Jarom, Li, Hai, Limenitakis, Julien P, Ganal-Vonarburg, Stephanie C, Suo, Shengbao, Luoma, Adrienne M, Shimodaira, Yosuke, Duan, Jinzhi, Shih, David Q, Conner, Margaret E, Glickman, Jonathan N, Fuhler, Gwenny M, Palm, Noah W, de Zoete, Marcel R, van der Woude, C Janneke, Yuan, Guo-Cheng, Wucherpfennig, Kai W, Targan, Stephan R, Rosenstiel, Philip, Flavell, Richard A, McCoy, Kathy D, Macpherson, Andrew J, Kaser, Arthur, and Blumberg, Richard S

Abstract

Immunoglobulin A (IgA) is the major secretory immunoglobulin isotype found at mucosal surfaces, where it regulates microbial commensalism and excludes luminal factors from contacting intestinal epithelial cells (IECs). IgA is induced by both T cell-dependent and -independent (TI) pathways. However, little is known about TI regulation. We report that IEC endoplasmic reticulum (ER) stress induces a polyreactive IgA response, which is protective against enteric inflammation. IEC ER stress causes TI and microbiota-independent expansion and activation of peritoneal B1b cells, which culminates in increased lamina propria and luminal IgA. Increased numbers of IgA-producing plasma cells were observed in healthy humans with defective autophagy, who are known to exhibit IEC ER stress. Upon ER stress, IECs communicate signals to the peritoneum that induce a barrier-protective TI IgA response.

Published
2019

155. Epithelial endoplasmic reticulum stress orchestrates a protective IgA response

Author

dI&I I&I-2, LS Infectiebiologie (Bacteriologie), Grootjans, Joep, Krupka, Niklas, Hosomi, Shuhei, Matute, Juan D, Hanley, Thomas, Saveljeva, Svetlana, Gensollen, Thomas, Heijmans, Jarom, Li, Hai, Limenitakis, Julien P, Ganal-Vonarburg, Stephanie C, Suo, Shengbao, Luoma, Adrienne M, Shimodaira, Yosuke, Duan, Jinzhi, Shih, David Q, Conner, Margaret E, Glickman, Jonathan N, Fuhler, Gwenny M, Palm, Noah W, de Zoete, Marcel R, van der Woude, C Janneke, Yuan, Guo-Cheng, Wucherpfennig, Kai W, Targan, Stephan R, Rosenstiel, Philip, Flavell, Richard A, McCoy, Kathy D, Macpherson, Andrew J, Kaser, Arthur, Blumberg, Richard S, dI&I I&I-2, LS Infectiebiologie (Bacteriologie), Grootjans, Joep, Krupka, Niklas, Hosomi, Shuhei, Matute, Juan D, Hanley, Thomas, Saveljeva, Svetlana, Gensollen, Thomas, Heijmans, Jarom, Li, Hai, Limenitakis, Julien P, Ganal-Vonarburg, Stephanie C, Suo, Shengbao, Luoma, Adrienne M, Shimodaira, Yosuke, Duan, Jinzhi, Shih, David Q, Conner, Margaret E, Glickman, Jonathan N, Fuhler, Gwenny M, Palm, Noah W, de Zoete, Marcel R, van der Woude, C Janneke, Yuan, Guo-Cheng, Wucherpfennig, Kai W, Targan, Stephan R, Rosenstiel, Philip, Flavell, Richard A, McCoy, Kathy D, Macpherson, Andrew J, Kaser, Arthur, and Blumberg, Richard S

Published
2019

165. 833a – Efficacy in Biologic-Failure and Nonbiologic-Failure Populations in a Phase 3 Study of Ustekinumab in Moderatesevere Ulcerative Colitis: Unifi

Author

Sands, Bruce E., primary, Peyrin-Biroulet, Laurent, additional, Marano, Colleen W., additional, O'Brien, Christopher D., additional, Zhang, Hongyan, additional, Johanns, Jewel, additional, Szapary, Philippe, additional, Rowbotham, David, additional, Leong, Rupert W., additional, Arasaradnam, Ramesh, additional, Danese, Silvio, additional, van Assche, Gert A., additional, Targan, Stephan R., additional, and Sandborn, William J., additional

Published
2019
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166. 833 – Efficacy and Safety of Ustekinumab As Maintenance Therapy in Ulcerative Colitis: Week 44 Results from Unifi

Author

Sands, Bruce E., primary, Sandborn, William J., additional, Panaccione, Remo, additional, O'Brien, Christopher D., additional, Zhang, Hongyan, additional, Johanns, Jewel, additional, Peyrin-Biroulet, Laurent, additional, van Assche, Gert A., additional, Danese, Silvio, additional, Targan, Stephan R., additional, Abreu, Maria T., additional, Hisamatsu, Tadakazu, additional, Szapary, Philippe, additional, and Marano, Colleen W., additional

Published
2019
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169. Su1879 – Novel Role for Death Receptor 3 (DR3) Expressed on Intestinal Epithelial Cells in Regulating Homeostatic Intestinal Permeability and Epithelial Cell Proliferation, As Well As Regeneration After Intestinal Mucosal Injury

Author

Shimodaira, Yosuke, primary, Abraham, Jay, additional, Hamade, Hussein, additional, Blackwood, Anna Y., additional, Thomas, Lisa, additional, Castanon, Sofi, additional, Shih, David Q., additional, Targan, Stephan R., additional, and Michelsen, Kathrin S., additional

Published
2019
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172. Tu1723 – Identification of Risk Factors Associated with Loss of Response to Ustekinumab in Crohn's Disease

Author

Hanauer, Stephen B., primary, Sands, Bruce E., additional, Feagan, Brian G., additional, Oortwijn, Alessandra, additional, van Kruchten, Roger, additional, Laliman, Victor A., additional, Izanec, James L., additional, Adedokun, Omoniyi J., additional, Gao, Long-Long, additional, Sloan, Sheldon, additional, Gasink, Christopher, additional, Targan, Stephan R., additional, de Villiers, Willem J., additional, Rutgeerts, Paul, additional, Colombel, Jean Frederic, additional, and Ghosh, Subrata, additional

Published
2019
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175. Sa1811 – Genotype and Posst-Operative Immunosuppression Impact Surgical Recurrence in Crohn's Disease

Author

Salem, Mark, primary, Li, Dalin, additional, Gerich, Mark E., additional, Yang, Shaohong, additional, Vasiliauskas, Eric, additional, Syal, Gaurav, additional, Ha, Christina, additional, Bonthala, Nirupama, additional, Rabizadeh, Shervin, additional, Zaghiyan, Karen, additional, Haritunians, Talin, additional, Melmed, Gil, additional, Targan, Stephan R., additional, Fleshner, Phillip, additional, and McGovern, Dermot, additional

Published
2019
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176. Tu1725 – Characterization of Patients with Delayed Response to Ustekinumab for Crohn's Disease

Author

Sands, Bruce E., primary, Oortwijn, Alessandra, additional, Rijnders, Nicole, additional, Izanec, James L., additional, Gasink, Christopher, additional, Jacobstein, Douglas, additional, Adedokun, Omoniyi J., additional, Ma, Tony, additional, Gao, Long-Long, additional, Colombel, Jean Frederic, additional, Targan, Stephan R., additional, Ghosh, Subrata, additional, and Sandborn, William J., additional

Published
2019
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177. Tu1740 – Sustained Remission in Patients with Moderate to Severe Ulcerative Colitis: Results from the Phase 3 Unifi Maintenance Study

Author

Van Assche, Gert A., primary, Targan, Stephan R., additional, Baker, Thomas, additional, O'Brien, Christopher D., additional, Zhang, Hongyan, additional, Johanns, Jewel, additional, Szapary, Philippe, additional, Marano, Colleen W., additional, Leong, Rupert W., additional, Rowbotham, David, additional, Hisamatsu, Tadakazu, additional, Danese, Silvio, additional, Sands, Bruce E., additional, and Peyrin-Biroulet, Laurent, additional

Published
2019
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182. Ileal Gene Expression Data from Crohn’s Disease Small Bowel Resections Indicate Distinct Clinical Subgroups

Author

Potdar, Alka A, primary, Li, Dalin, additional, Haritunians, Talin, additional, VanDussen, Kelli L, additional, Fiorino, Marie F, additional, Liu, Ta-Chiang, additional, Stappenbeck, Thaddeus S, additional, Fleshner, Phillip, additional, Targan, Stephan R, additional, McGovern, Dermot P B, additional, and Bilsborough, Janine, additional

Published
2019
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183. Epithelial endoplasmic reticulum stress orchestrates a protective IgA response

Author

Grootjans, Joep, primary, Krupka, Niklas, additional, Hosomi, Shuhei, additional, Matute, Juan D., additional, Hanley, Thomas, additional, Saveljeva, Svetlana, additional, Gensollen, Thomas, additional, Heijmans, Jarom, additional, Li, Hai, additional, Limenitakis, Julien P., additional, Ganal-Vonarburg, Stephanie C., additional, Suo, Shengbao, additional, Luoma, Adrienne M., additional, Shimodaira, Yosuke, additional, Duan, Jinzhi, additional, Shih, David Q., additional, Conner, Margaret E., additional, Glickman, Jonathan N., additional, Fuhler, Gwenny M., additional, Palm, Noah W., additional, de Zoete, Marcel R., additional, van der Woude, C. Janneke, additional, Yuan, Guo-Cheng, additional, Wucherpfennig, Kai W., additional, Targan, Stephan R., additional, Rosenstiel, Philip, additional, Flavell, Richard A., additional, McCoy, Kathy D., additional, Macpherson, Andrew J., additional, Kaser, Arthur, additional, and Blumberg, Richard S., additional

Published
2019
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184. Prevalence and Associations of Avascular Necrosis of the Hip in a Large Well-characterized Cohort of Patients With Inflammatory Bowel Disease

Author

Rolston, Vineet S., primary, Patel, Anish V., additional, Learch, Thomas J., additional, Li, Dalin, additional, Karayev, Dmitry, additional, Williams, Chadwick, additional, Siddanthi, Madhavi L., additional, Targan, Stephan R., additional, Weisman, Michael H., additional, and McGovern, Dermot P.B., additional

Published
2019
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191. High-density mapping of the MHC identifies a shared role for HLA-DRB1*01:03 in inflammatory bowel diseases and heterozygous advantage in ulcerative colitis

Author

Goyette, Philippe, Boucher, Gabrielle, Mallon, Dermot, Ellinghaus, Eva, Jostins, Luke, Huang, Hailiang, Ripke, Stephan, Gusareva, Elena S., Annese, Vito, Hauser, Stephen L., Oksenberg, Jorge R., Thomsen, Ingo, Leslie, Stephen, Daly, Mark J., Van Steen, Kristel, Duerr, Richard H., Barrett, Jeffrey C., Mcgovern, Dermot P. B., Schumm, L. Philip, Traherne, James A., Carrington, Mary N., Kosmoliaptsis, Vasilis, Karlsen, Tom H., Franke, Andre, Rioux, John D., Abraham, Clara, Achkar, Jean Paul, Ahmad, Tariq, Amininejad, Leila, Ananthakrishnan, Ashwin N., Andersen, Vibeke, Anderson, Carl A., Andrews, Jane M., Aumais, Guy, Baidoo, Leonard, Baldassano, Robert N., Balschun, Tobias, Bampton, Peter A., Barclay, Murray, Bayless, Theodore M., Bethge, Johannes, Bis, Joshua C., Bitton, Alain, Brand, Stephan, Brant, Steven R., Buning, Carsten, Chew, Angela, Cho, Judy H., Cleynen, Isabelle, Cohain, Ariella, Croft, Anthony, D'Amato, Mauro, Danese, Silvio, De Jong, Dirk, De Vos, Martine, Denapiene, Goda, Denson, Lee A., Devaney, Kathy L., Dewit, Olivier, D'Inca, Renata, Dubinsky, Marla, Edwards, Cathryn, Ellinghaus, David, Essers, Jonah, Ferguson, Lynnette R., Festen, Eleonora A., Fleshner, Philip, Florin, Tim, Franchimont, Denis, Fransen, Karin, Gearry, Richard, Georges, Michel, Gieger, Christian, Glas, Jurgen, Green, Todd, Griffiths, Anne M., Guthery, Stephen L., Hakonarson, Hakon, Halfvarson, Jonas, Hanigan, Katherine, Haritunians, Talin, Hart, Ailsa, Hawkey, Chris, Hayward, Nicholas K., Hedl, Matija, Henderson, Paul, Xinli, Hu, Hui, Ken Y., Imielinski, Marcin, Ippoliti, Andrew, Jonaitis, Laimas, Kennedy, Nicholas A., Khan, Mohammed Azam, Kiudelis, Gediminas, Kugathasan, Subra, Kupcinskas, Limas, Latiano, Anna, Laukens, Debby, Lawrance, Ian C., Lee, James C., Lees, Charlie W., Leja, Marcis, Van Limbergen, Johan, Lionetti, Paolo, Liu, Jimmy Z., Louis, Edouard, Mahy, Gillian, Mansfield, John, Massey, Dunecan, Mathew, Christopher G., Milgrom, Raquel, Mitrovic, Mitja, Montgomery, Grant, Mowat, Craig, Newman, Wwilliam, Aylwin, Ng, Siew C., Ng, Evelyn Ng, Sok Meng, Nikolaus, Susanna, Ning, Kaida, Nothen, Markus, Oikonomou, Ioannis, Palmieri, Orazio, Parkes, Miles, Phillips, Anne, Ponsioen, Cyriel Y., Potocnik, Uros, Prescott, Natalie J., Proctor, Deborah D., Radford Smith, Graham, Rahier, Jean Francois, Raychaudhur, Soumya, Regueiro, Miguel, Rieder, Florian, Roberts, Rebecca, Russell, Richard K., Sanderson, Jeremy D., Sans, Miquel, Satsangi, Jack, Schadt, Eric E., Schreiber, Stefan, Scott, Regan, Seielstad, Mark, Sharma, Yashoda, Silverberg, Mark S., Simms, Lisa A., Skieceviciene, Jurgita, Spain, Sarah L., Steinhart, A. Hillary, Stempak, Joanne M., Stronati, Laura, Sventoraityte, Jurgita, Targan, Stephan R., Taylor, Kirstin M., Ter Velde, Anje, Theatre, Emilie, Torkvist, Leif, Tremelling, Mark, Van Der Meulen, Andrea, Van Sommeren, Suzanne, Vasiliauskas, Eric, Vermeire, Severine, Verspaget, Hein W., Walters, Thomas, Wwang, Kai, Wwang, Ming Hsi, Wweersma, Rinse K., Wei, Zhi, Whiteman, David, Wijmenga, Cisca, Wilson, David C., Winkelmann, Juliane, Xavier, Ramnik J., Zeissig, Sebastian, Zhang, Bin, Zhang, Clarence K., Zhang, Hu, Zhang, Wwei, Zhao, Hongyu, Zhao, Zhen Z., Gastroenterology and Hepatology, Traherne, James [0000-0002-6003-8559], Kosmoliaptsis, Vasilis [0000-0001-7298-1387], and Apollo - University of Cambridge Repository

Subjects
Heterozygote, Genotype, Genotyping Techniques, Genetic Linkage, Ulcerative, Human leukocyte antigen, Biology, Major histocompatibility complex, Polymorphism, Single Nucleotide, Article, Primary sclerosing cholangitis, Major Histocompatibility Complex, Alleles, Chromosome Mapping, Colitis, Ulcerative, Crohn Disease, Genetic Predisposition to Disease, Genome-Wide Association Study, HLA-DRB1 Chains, Humans, Inflammatory Bowel Diseases, Phenotype, Genetics, medicine, HLA-DR, Polymorphism, Colitis, HLA-DRB1, Crohn's disease, Single Nucleotide, medicine.disease, Ulcerative colitis, digestive system diseases, Immunology, biology.protein
Abstract

Genome-wide association studies of the related chronic inflammatory bowel diseases (IBD) known as Crohn's disease and ulcerative colitis have shown strong evidence of association to the major histocompatibility complex (MHC). This region encodes a large number of immunological candidates, including the antigen-presenting classical human leukocyte antigen (HLA) molecules. Studies in IBD have indicated that multiple independent associations exist at HLA and non-HLA genes, but they have lacked the statistical power to define the architecture of association and causal alleles. To address this, we performed high-density SNP typing of the MHC in >32,000 individuals with IBD, implicating multiple HLA alleles, with a primary role for HLA-DRB1*01:03 in both Crohn's disease and ulcerative colitis. Noteworthy differences were observed between these diseases, including a predominant role for class II HLA variants and heterozygous advantage observed in ulcerative colitis, suggesting an important role of the adaptive immune response in the colonic environment in the pathogenesis of IBD.

Published
2015
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192. Pre-pouch Ileitis is Associated with Development of Crohn's Disease-like Complications and Pouch Failure.

Author

Syal, Gaurav, Shemtov, Ron, Bonthala, Nirupama, Vasiliauskas, Eric A, Feldman, Edward J, Zaghiyan, Karen, Ha, Christina Y, McGovern, Dermot P B, Targan, Stephan R, Melmed, Gil Y, and Fleshner, Phillip R

Abstract

Background and Aims It is unclear whether pre-pouch ileitis heralds an aggressive inflammatory pouch disease in patients with ileal pouch-anal anastomosis [IPAA]. We compared outcomes of patients with pouchitis and concomitant pre-pouch ileitis with those with pouchitis alone. Methods Patients undergoing IPAA surgery for inflammatory bowel disease, who subsequently developed pouchitis with concomitant pre-pouch ileitis [pre-pouch ileitis group], were matched by year of IPAA surgery and preoperative diagnosis [ulcerative colitis or inflammatory bowel disease-unclassified] with patients who developed pouchitis alone [pouchitis group]. Primary outcomes were development of Crohn's disease [CD]-like complications [non-anastomotic strictures or perianal disease >6 months after ileostomy closure] and pouch failure. Secondary outcomes were need for surgical/endoscopic interventions and immunosuppressive therapy. Log-rank testing was used to compare outcome-free survival, and Cox regression was performed to identify predictors of outcomes. Results There were 66 patients in each group. CD-like complications and pouch failure developed in 36.4% and 7.6% patients in the pre-pouch ileitis group and 10.6% and 1.5% in pouchitis group, respectively. CD-like complications-free survival [log-rank p = 0.0002] and pouch failure-free survival [log-rank p = 0.046] were significantly lower in the pre-pouch ileitis group. The pre-pouch ileitis group had a higher risk of requiring surgical/endoscopic interventions [log-rank p = 0.0005] and immunosuppressive therapy [log-rank p <0.0001]. Pre-pouch ileitis was independently associated with an increased risk of CD-like complications (hazard ratio [HR] 3.8; p = 0.0007), need for surgical/endoscopic interventions [HR 4.1; p = 0.002], and immunosuppressive therapy [HR 5.0; p = 0.0002]. Conclusions Pre-pouch ileitis is associated with a higher risk of complicated disease and pouch failure than pouchitis. It should be considered a feature of CD. [ABSTRACT FROM AUTHOR]

Published
2021
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