122 results on '"Snapper S"'
Search Results
2. OP28 Defective STAT3 signaling in refractory Very Early Onset Inflammatory Bowel Disease is associated with a transcriptional signature which predicts response to anti-IL23-based therapies
- Author
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Collen, L, primary, Beckmann, N, additional, Mitsialis, V, additional, Eran, A, additional, Field, M, additional, Kim, D, additional, Bao, B, additional, Barends, J, additional, Saccocia, G, additional, Bresnahan, M, additional, Yang, J, additional, Combs, A, additional, Tuthill, M, additional, Bearup, R, additional, Okoroafor, I, additional, Patik, I, additional, Grushkin-Lerner, L, additional, Ouahed, J, additional, Muise, A, additional, Klein, C, additional, Horwitz, B, additional, Schadt, E, additional, Argmann, C, additional, and Snapper, S, additional
- Published
- 2024
- Full Text
- View/download PDF
3. OP17 IBD ulcers are characterized by bioactive interleukin-1 and transcriptomic hallmarks of stromal cell state reprogramming
- Author
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Mitsialis, V, primary, Losa, M, additional, Field, M, additional, Collen, L, additional, Barends, J, additional, Ringel, A, additional, Bresnahan, M, additional, Yang, J, additional, Tumminkatti, R, additional, Sveen, M, additional, Bearup, R, additional, Kotlarz, D, additional, Klein, C, additional, Argmann, C, additional, Schadt, E, additional, Muise, A, additional, Thiagarajah, J, additional, Eran, A, additional, Horwitz, B, additional, and Snapper, S, additional
- Published
- 2024
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- View/download PDF
4. Dissecting allele architecture of early onset IBD using high-density genotyping
- Author
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Heyman, Melvin, Rabizadeh, S, Noe, J, Snapper, S, Otley, A, Cohen, S, Oliva-Hemker, M, Kirschner, B, Ashish, P, Ziring, D, and Evans, J
- Abstract
Copyright © 2015 Cutler et al.Background: The inflammatory bowel diseases (IBD) are common, complex disorders in which genetic and environmental factors are believed to interact leading to chronic inflammatory responses against the gut microbiota. Earlier
- Published
- 2015
5. Immunobiology of T-Cells in Inflammatory Bowel Disease
- Author
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Snapper, S., Nguyen, D., Biswas, A., and Baumgart, Daniel C., editor
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- 2017
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- View/download PDF
6. DOP34 Human MD2 deficiency - an inborn error of immunity predisposing to early onset Inflammatory Bowel Disease
- Author
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Li, Y, primary, Yu, Z, additional, Schenk, M, additional, Lagovsky, I, additional, Illig, D, additional, Walz, C, additional, Rohlfs, M, additional, Conca, R, additional, Muise, A, additional, Snapper, S, additional, Uhlig, H, additional, Garty, B, additional, Klein, C, additional, and Kotlarz, D, additional
- Published
- 2023
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7. Author Correction: Somatic mosaicism and common genetic variation contribute to the risk of very-early-onset inflammatory bowel disease (Nature Communications, (2020), 11, 1, (995), 10.1038/s41467-019-14275-y)
- Author
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Serra E. G., Schwerd T., Moutsianas L., Cavounidis A., Fachal L., Pandey S., Kammermeier J., Croft N. M., Posovszky C., Rodrigues A., Russell R. K., Barakat F., Auth M. K. H., Heuschkel R., Zilbauer M., Fyderek K., Braegger C., Travis S. P., Satsangi J., Parkes M., Thapar N., Ferry H., Matte J. C., Gilmour K. C., Wedrychowicz A., Sullivan P., Moore C., Sambrook J., Ouwehand W., Roberts D., Danesh J., Baeumler T. A., Fulga T. A., Carrami E. M., Ahmed A., Wilson R., Barrett J. C., Elkadri A., Griffiths A. M., Zurek M., Strisciuglio C., Elawad M., Lo B., Arancibia-Carcamo C., Bailey A., Barnes E., Bird-Lieberman E. L., Brain O., Braden B., Collier J., East J., Howarth L., Keshav S., Klenerman P., Leedham S., Palmer R., Powrie F., Simmons A., Walker M., Tolkien Z., Kaptoge S., Allen D., Mehenny S., Mant J., Di Angelantonio E., Thompson S. G., Yilmaz B., Juillerat P., Geuking M., Wiest R., Macpherson A. J., Bravo F. D., Brugger L., Carstens O., Bigler U. G., Heimgartner B., Rusticeanu M., Schmid-Uebelhart S., Strebel B., Tatu A., Tutuian R., Oyas O., Ramon C., Stelling J., Franc Y., Fournier N., Pittet V. E. H., Burnand B., Egger M., Golay D., Marot A., Musso L., Rossel J. -B., Seematter V., Sommer J., Vulliamy R., Michetti P., Maillard M. H., Keller C., Nydegger A., Schoepfe A., Archanioti E., Ezri J., Fraga M., Schoepfer A., Muller C., Rogler G., Biedermann L., Blattmann M., Burk S., Dora B., Fried M., Misselwitz B., Mullhaupt B., Obialo N., Pohl D., Raschle N., Scharl M., Vavricka S., Von Kanel R., Zeitz J., Abdelrahman K., Ademi G., Borovicka J., Brand S., Frei R., Haarer J., Knellwolf-Grieger C., Krieger-Grubel C., Kunzler P., Meyenberger C., Meyer P., Rohrich N., Sawatzki M., Schelling M., Semadeni G. -M., Sulz M., Zimmermann D., Aepli P., Criblez D. H., Hess C., Richterich J. -P., Spalinger J., Staudenmann D., Stulz A., Wohrle S., Thomas A., Anderegg C., Kohler H., Kusche R., Antonino A. -T., Arrigoni E., Bengoa J. M., Cunningham S., de Saussure P., Girard L., de Jong D. B., Basturk P., Brunner S., Degen L., Hruz P., Bakker C. K. -D., Niess J., Balsiger B., Haldemann J., Saner G., Seibold F., Bauerfeind P., Becocci A., Belli D., Binek J., Hengstler P., Boehm S., Boldanov T., Buhr P., Koller R., Rueger V., Senning A., Burri E., Buyse S., Cao D. -T., D'Angelo F., Delarive J., Doerig C., Hessler R., Preissler C., Rentsch R., Risti B., Ritz M. A., Steuerwald M., Vogtlin J., Sagmeister M., Sauter B., Schibli S., Sokollik C., Schlauri H., Schnegg J. -F., Seirafi M., Spangenberger H., Stadler P., Staub P., Stenz V., Tempia-Caliera M., Thorens J., Truninger K., Urfer P., Viani F., Vouillamoz D., Zander S., Wyli T., Jostins L., Kennedy N. A., Ahmad T., Lamb C. A., Edwards C., Hart A., Hawkey C., Mansfield J. C., Mowat C., Newman W. G., Tremelling M., Lee J. C., Prescott N. J., Mathew C. G., Lees C. W., McGovern D. P. B., Targan S. R., Botwin G., Mengesha E., Fleshner P., Landers C., Li D., Rioux J. D., Bitton A., Cote-Daigneault J., Daly M. J., Xavier R., Morris K., Boucher G., Cho J. H., Abraham C., Merad M., Sands B., Peter I., Hao K., Itan Y., Duerr R. H., Konnikova L., Schwartz M. B., Proksell S., Johnston E., Miladinova V., Chen W., Brant S. R., Datta L., Silverberg M. S., Schumm L. P., Birch S., Giri M., Gettler K., Sharma Y., Stevens C., Lazarev M., Haritunians T., Snapper S. B., Shah N., Muise A. M., Wilson D. C., Uhlig H. H., Anderson C. A., Serra, E. G., Schwerd, T., Moutsianas, L., Cavounidis, A., Fachal, L., Pandey, S., Kammermeier, J., Croft, N. M., Posovszky, C., Rodrigues, A., Russell, R. K., Barakat, F., Auth, M. K. H., Heuschkel, R., Zilbauer, M., Fyderek, K., Braegger, C., Travis, S. P., Satsangi, J., Parkes, M., Thapar, N., Ferry, H., Matte, J. C., Gilmour, K. C., Wedrychowicz, A., Sullivan, P., Moore, C., Sambrook, J., Ouwehand, W., Roberts, D., Danesh, J., Baeumler, T. A., Fulga, T. A., Carrami, E. M., Ahmed, A., Wilson, R., Barrett, J. C., Elkadri, A., Griffiths, A. M., Zurek, M., Strisciuglio, C., Elawad, M., Lo, B., Arancibia-Carcamo, C., Bailey, A., Barnes, E., Bird-Lieberman, E. L., Brain, O., Braden, B., Collier, J., East, J., Howarth, L., Keshav, S., Klenerman, P., Leedham, S., Palmer, R., Powrie, F., Simmons, A., Walker, M., Tolkien, Z., Kaptoge, S., Allen, D., Mehenny, S., Mant, J., Di Angelantonio, E., Thompson, S. G., Yilmaz, B., Juillerat, P., Geuking, M., Wiest, R., Macpherson, A. J., Bravo, F. D., Brugger, L., Carstens, O., Bigler, U. G., Heimgartner, B., Rusticeanu, M., Schmid-Uebelhart, S., Strebel, B., Tatu, A., Tutuian, R., Oyas, O., Ramon, C., Stelling, J., Franc, Y., Fournier, N., Pittet, V. E. H., Burnand, B., Egger, M., Golay, D., Marot, A., Musso, L., Rossel, J. -B., Seematter, V., Sommer, J., Vulliamy, R., Michetti, P., Maillard, M. H., Keller, C., Nydegger, A., Schoepfe, A., Archanioti, E., Ezri, J., Fraga, M., Schoepfer, A., Muller, C., Rogler, G., Biedermann, L., Blattmann, M., Burk, S., Dora, B., Fried, M., Misselwitz, B., Mullhaupt, B., Obialo, N., Pohl, D., Raschle, N., Scharl, M., Vavricka, S., Von Kanel, R., Zeitz, J., Abdelrahman, K., Ademi, G., Borovicka, J., Brand, S., Frei, R., Haarer, J., Knellwolf-Grieger, C., Krieger-Grubel, C., Kunzler, P., Meyenberger, C., Meyer, P., Rohrich, N., Sawatzki, M., Schelling, M., Semadeni, G. -M., Sulz, M., Zimmermann, D., Aepli, P., Criblez, D. H., Hess, C., Richterich, J. -P., Spalinger, J., Staudenmann, D., Stulz, A., Wohrle, S., Thomas, A., Anderegg, C., Kohler, H., Kusche, R., Antonino, A. -T., Arrigoni, E., Bengoa, J. M., Cunningham, S., de Saussure, P., Girard, L., de Jong, D. B., Basturk, P., Brunner, S., Degen, L., Hruz, P., Bakker, C. K. -D., Niess, J., Balsiger, B., Haldemann, J., Saner, G., Seibold, F., Bauerfeind, P., Becocci, A., Belli, D., Binek, J., Hengstler, P., Boehm, S., Boldanov, T., Buhr, P., Koller, R., Rueger, V., Senning, A., Burri, E., Buyse, S., Cao, D. -T., D'Angelo, F., Delarive, J., Doerig, C., Hessler, R., Preissler, C., Rentsch, R., Risti, B., Ritz, M. A., Steuerwald, M., Vogtlin, J., Sagmeister, M., Sauter, B., Schibli, S., Sokollik, C., Schlauri, H., Schnegg, J. -F., Seirafi, M., Spangenberger, H., Stadler, P., Staub, P., Stenz, V., Tempia-Caliera, M., Thorens, J., Truninger, K., Urfer, P., Viani, F., Vouillamoz, D., Zander, S., Wyli, T., Jostins, L., Kennedy, N. A., Ahmad, T., Lamb, C. A., Edwards, C., Hart, A., Hawkey, C., Mansfield, J. C., Mowat, C., Newman, W. G., Tremelling, M., Lee, J. C., Prescott, N. J., Mathew, C. G., Lees, C. W., Mcgovern, D. P. B., Targan, S. R., Botwin, G., Mengesha, E., Fleshner, P., Landers, C., Li, D., Rioux, J. D., Bitton, A., Cote-Daigneault, J., Daly, M. J., Xavier, R., Morris, K., Boucher, G., Cho, J. H., Abraham, C., Merad, M., Sands, B., Peter, I., Hao, K., Itan, Y., Duerr, R. H., Konnikova, L., Schwartz, M. B., Proksell, S., Johnston, E., Miladinova, V., Chen, W., Brant, S. R., Datta, L., Silverberg, M. S., Schumm, L. P., Birch, S., Giri, M., Gettler, K., Sharma, Y., Stevens, C., Lazarev, M., Haritunians, T., Snapper, S. B., Shah, N., Muise, A. M., Wilson, D. C., Uhlig, H. H., and Anderson, C. A.
- Published
- 2022
8. DOP010 Activating PIK3CD mutations cause severe intestinal lymphonodular hyperplasia and an IBD-like phenotype
- Author
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Farachi, S, Werner, L, Konnikova, L, Rea, F, Vardi, I, Romeo, E, Barel, O, De Angelis, P, Dall’Oglio, L, Rechavi, G, Snapper, S, Somech, R, Weiss, B, Cancrini, C, and Shouval, D
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- 2018
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9. Spontaneous food allergy in Was−/− mice occurs independent of FcεRI‐mediated mast cell activation
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Lexmond, W. S., Goettel, J. A., Sallis, B. F., McCann, K., Rings, E. H. H. M., Jensen‐Jarolim, E., Nurko, S., Snapper, S. B., and Fiebiger, E.
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- 2017
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10. P356 Treatment with anakinra induces T cell production of IL22 and GI mucosal healing in an IL-10RA mutation patient
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Li, J., Shouval, D., Doty, A., Snapper, S., and Glover, S.
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- 2017
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11. DOP082 Enhanced TH17 responses in patients with IL10 receptor deficiency and history of infantile-onset IBD
- Author
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Shouval, D., Konnikova, L., Werner, L., Nunberg, M., Weiss, B., Glover, S., and Snapper, S.
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- 2017
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12. Development of BCG As a Recombinant Vaccine Vehicle
- Author
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Jacobs, W. R., Jr., Snapper, S. B., Lugosi, L., Bloom, B. R., Compans, R. W., editor, Cooper, M., editor, Koprowski, H., editor, McConnell, I., editor, Melchers, F., editor, Nussenzweig, V., editor, Oldstone, M., editor, Olsnes, S., editor, Saedler, H., editor, Vogt, P. K., editor, Wagner, H., editor, Wilson, I., editor, and Kaufmann, Stefan H. E., editor
- Published
- 1990
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- View/download PDF
13. Elevated levels of leukotriene C4 synthase mRNA distinguish a subpopulation of eosinophilic oesophagitis patients
- Author
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Lexmond, W. S., Pardo, M., Rooney, K., Goettel, J. A., Snapper, S. B., Yen, E. H., Dehlink, E., Nurko, S., and Fiebiger, E.
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- 2013
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14. Genetic and Transcriptomic Variation Linked to Neutrophil Granulocyte-Macrophage Colony-Stimulating Factor Signaling in Pediatric Crohn's Disease
- Author
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Denson, LA, Jurickova, I, Karns, R, Shaw, KA, Cutler, DJ, Okou, D, Alexander Valencia, C, Dodd, A, Mondal, K, Aronow, BJ, Haberman, Y, Linn, A, Price, A, Bezold, R, Lake, K, Jackson, K, Walters, TD, Griffiths, A, Baldassano, RN, Noe, JD, Hyams, JS, Crandall, WV, Kirschner, BS, Heyman, MB, Snapper, S, Guthery, SL, Dubinsky, MC, Leleiko, NS, Otley, AR, Xavier, RJ, Stevens, C, Daly, MJ, Zwick, ME, and Kugathasan, S
- Subjects
Adult ,Male ,Adolescent ,Neutrophils ,Clinical Sciences ,Crohn's Disease ,Autoimmune Disease ,Cytokine Receptor Common beta Subunit ,Young Adult ,Crohn Disease ,Clinical Research ,Receptors ,Genetics ,pediatric inflammatory bowel disease ,Humans ,2.1 Biological and endogenous factors ,whole-exome sequencing ,Aetiology ,Child ,Preschool ,STAT5 ,Gastroenterology & Hepatology ,Inflammatory Bowel Disease ,Granulocyte-Macrophage Colony-Stimulating Factor ,Infant ,neutrophil ,GM-CSF ,RNA sequencing ,Prognosis ,Case-Control Studies ,Mutation ,Female ,Missense ,Transcriptome ,Digestive Diseases ,Follow-Up Studies - Abstract
BACKGROUND:Granulocyte-macrophage colony-stimulating factor auto-antibodies (GMAbs) suppress neutrophil-extrinsic GM-CSF signaling and increase risk for stricturing behavior in Crohn's disease (CD). We aimed to define clinical, genomic, and functional associations with neutrophil-intrinsic GM-CSF signaling. METHODS:Missense mutations in CSF2RA, CSF2RB, JAK2, STAT5A, and STAT5B were identified using whole-exome sequencing in 543 pediatric inflammatory bowel disease (IBD) patients. Neutrophil-intrinsic GM-CSF signaling was defined using the GM-CSF-induced STAT5 stimulation index (GMSI) in 180 pediatric IBD patients and 26 non-IBD controls. Reduced GM-CSF signaling (GMSI-Lo) was defined as the 20th percentile within the control group. Variation in neutrophil phospho-protein abundance, bacterial killing, and the global pattern of gene expression with the GMSI was determined. RESULTS:We validated 18 potentially damaging missense mutations in CSF2RA and CSF2RB. CSF2RA A17G carriage increased from 10% in those with intact neutrophil GMSI to 32% in those with low GMSI (P = 0.02). The frequency of reduced Staphylococcus aureus killing increased from 17% in those with intact neutrophil GMSI to 35% in GMSI-Lo neutrophils (P = 0.043). Crohn's disease neutrophils with low GMSI exhibited specific alterations in phospho-protein networks and genes regulating cytokine production, wound healing, and cell survival and proliferation. Stricturing behavior increased from 7% in patients with both low GMAb and intact GMSI to 64% in patients with both elevated GMAb and low GMSI (P < 0.0001). CONCLUSIONS:Low/normal neutrophil-intrinsic GM-CSF signaling is associated with CSF2RA missense mutations, alterations in gene expression networks, and higher rates of disease complications in pediatric CD.
- Published
- 2019
15. Alpha kinase 1 controls intestinal inflammation by suppressing the IL-12/Th1 axis
- Author
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Ryzhakov, G, West, N, Franchini, F, Clare, S, Ilott, N, Sansom, S, Bullers, S, Pearson, C, Costain, A, Vaughan-Jackson, A, Goettel, J, Ermann, J, Horwitz, B, Buti, L, Lu, X, Mukhopadhyay, S, Snapper, S, and Powrie, FM
- Subjects
Male ,Colon ,Science ,Primary Cell Culture ,Bone Marrow Cells ,Interleukin-23 ,Helicobacter Infections ,Mice ,Animals ,Humans ,lcsh:Science ,Bone Marrow Transplantation ,Mice, Knockout ,Mice, Inbred BALB C ,Macrophages ,Th1 Cells ,Colitis ,Inflammatory Bowel Diseases ,Interleukin-12 ,Mice, Inbred C57BL ,Disease Models, Animal ,Radiation Chimera ,lcsh:Q ,Female ,Helicobacter hepaticus ,Protein Kinases - Abstract
Inflammatory bowel disease (IBD) are heterogenous disorders of the gastrointestinal tract caused by a spectrum of genetic and environmental factors. In mice, overlapping regions of chromosome 3 have been associated with susceptibility to IBD-like pathology, including a locus called Hiccs. However, the specific gene that controls disease susceptibility remains unknown. Here we identify a Hiccs locus gene, Alpk1 (encoding alpha kinase 1), as a potent regulator of intestinal inflammation. In response to infection with the commensal pathobiont Helicobacter hepaticus (Hh), Alpk1-deficient mice display exacerbated interleukin (IL)-12/IL-23 dependent colitis characterized by an enhanced Th1/interferon(IFN)-γ response. Alpk1 controls intestinal immunity via the hematopoietic system and is highly expressed by mononuclear phagocytes. In response to Hh, Alpk1−/− macrophages produce abnormally high amounts of IL-12, but not IL-23. This study demonstrates that Alpk1 promotes intestinal homoeostasis by regulating the balance of type 1/type 17 immunity following microbial challenge.
- Published
- 2018
16. A CASE OF VERY EARLY ONSET INFLAMMATORY BOWEL DISEASE, CHRONIC LUNG DISEASE, AND RECURRENT INFECTIONS
- Author
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Nawaz, S., primary, Goyal, A., additional, Farooqi, M., additional, Pai, S., additional, Snapper, S., additional, Raje, N., additional, and Field, M., additional
- Published
- 2018
- Full Text
- View/download PDF
17. Development of BCG As a Recombinant Vaccine Vehicle
- Author
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Jacobs, W. R., primary, Snapper, S. B., additional, Lugosi, L., additional, and Bloom, B. R., additional
- Published
- 1990
- Full Text
- View/download PDF
18. Insights into Immunoregulation and Pathogenesis from a Third World Disease
- Author
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Bloom, B. R., Salgame, P., Chan, J., Mehra, V., Snapper, S., Fan, X., Modlin, R., Rea, T., Brenner, M., Brennan, P., Convit, J., Jacobs, W. R., Jr., Melchers, Fritz, editor, Albert, E. D., editor, von Boehmer, H., editor, Dierich, M. P., editor, Du Pasquier, L., editor, Eichmann, K., editor, Gemsa, D., editor, Götze, O., editor, Kalden, J. R., editor, Kaufmann, S. H. E., editor, Kirchner, H., editor, Resch, K., editor, Riethmüller, G., editor, Schimpl, A., editor, Sorg, C., editor, Steinmetz, M., editor, Wagner, H., editor, and Zachau, H. G., editor
- Published
- 1989
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- View/download PDF
19. Spontaneous food allergy in Was −/− mice occurs independent of Fcε RI-mediated mast cell activation.
- Author
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Lexmond, W. S., Goettel, J. A., Sallis, B. F., McCann, K., Rings, E. H. H. M., Jensen‐Jarolim, E., Nurko, S., Snapper, S. B., and Fiebiger, E.
- Subjects
FOOD allergy ,MAST cells ,WISKOTT-Aldrich syndrome ,GENETIC disorders ,IMMUNOGLOBULIN E receptors - Abstract
Background Food allergies are a growing health problem, and the development of therapies that prevent disease onset is limited by the lack of adjuvant-free experimental animal models. We compared allergic sensitization in patients with food allergy or Wiskott-Aldrich syndrome ( WAS) and defined whether spontaneous disease in Was
−/− mice recapitulates the pathology of a conventional disease model and/or human food allergy. Methods Comparative Immuno CAP ISAC microarray was performed in patients with food allergy or WAS. Spontaneous food allergy in Was−/− mice was compared to an adjuvant-based model in wild-type mice ( WT- OVA/alum). Intestinal and systemic anaphylaxis was assessed, and the role of the high-affinity IgE Fc receptor (Fcε RI) in allergic sensitization was evaluated using Was−/− Fcer1a−/− mice. Results Polysensitization to food was detected in both WAS and food-allergic patients which was recapitulated in the Was−/− model. Oral administration of ovalbumin (OVA) in Was−/− mice induced low titers of OVA-specific IgE compared to the WT- OVA/alum model. Irrespectively, 79% of Was−/− mice developed allergic diarrhea following oral OVA challenge. Systemic anaphylaxis occurred in Was−/− mice (95%) with a mortality rate >50%. Spontaneous sensitization and intestinal allergy occurred independent of Fcε RI expression on mast cells (MCs) and basophils. Conclusions Was−/− mice provide a model of food allergy with the advantage of mimicking polysensitization and low food-antigen IgE titers as observed in humans with clinical food allergy. This model will facilitate studies on aberrant immune responses during spontaneous disease development. Our results imply that therapeutic targeting of the IgE/Fcε RI activation cascade will not affect sensitization to food. [ABSTRACT FROM AUTHOR]- Published
- 2017
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- View/download PDF
20. Elevated levels of leukotriene C4synthase mRNA distinguish a subpopulation of eosinophilic oesophagitis patients
- Author
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Lexmond, W. S., primary, Pardo, M., additional, Rooney, K., additional, Goettel, J. A., additional, Snapper, S. B., additional, Yen, E. H., additional, Dehlink, E., additional, Nurko, S., additional, and Fiebiger, E., additional
- Published
- 2013
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21. The Wiskott-Aldrich Syndrome protein alters Treg homeostasis via reduced strength of T cell receptor signaling.
- Author
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Boden, E, primary, Ahuja, V, additional, Moran, C, additional, Nguyen, D, additional, Mayer, L, additional, and Snapper, S, additional
- Published
- 2011
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22. Early-onset inflammatory bowel disease caused by mutant IL10 receptor
- Author
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Glocker, E O, primary, Kotlarz, D, additional, Boztug, K, additional, Gertz, E M, additional, Schäffer, A A, additional, Noyan, F, additional, Perro, M, additional, Diestelhorst, J, additional, Allroth, A, additional, Murugan, D, additional, Hätscher, N, additional, Pfeifer, D, additional, Sykora, K W, additional, Sauer, M, additional, Kreipe, H, additional, Lacher, M, additional, Nustede, R, additional, Woellner, C, additional, Baumann, U, additional, Salzer, U, additional, Koletzko, S, additional, Shah, N, additional, Segal, A W, additional, Sauerbrey, A, additional, Buderus, S, additional, Snapper, S B, additional, Grimbacher, B, additional, and Klein, C, additional
- Published
- 2010
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23. Early-onset inflammatory bowel disease caused by loss-of-function mutations in the IL10-receptor genes
- Author
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Glocker, E, primary, Kotlarz, D, additional, Boztug, K, additional, Gertz, E, additional, Schaffer, A, additional, Koletzko, S, additional, Shah, N, additional, Segal, A, additional, Snapper, S, additional, Grimbacher, B, additional, and Klein, C, additional
- Published
- 2009
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24. Regulatory T cell-based cellular therapy prevents colitis in WASP-deficient mice
- Author
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Maillard, M, primary, Nguyen, D, additional, Boden, E, additional, and Snapper, S, additional
- Published
- 2008
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25. Phosphoinositide 3-kinase knockout mice: role of p85α in B cell development and proliferation
- Author
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Fruman, D. A., primary, Snapper, S. B., additional, Yballe, C. M., additional, Alt, F. W., additional, and Cantley, L. C., additional
- Published
- 1999
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26. Elevated levels of leukotriene C4 synthase mRNA distinguish a subpopulation of eosinophilic oesophagitis patients.
- Author
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Lexmond, W. S., Pardo, M., Rooney, K., Goettel, J. A., Snapper, S. B., Yen, E. H., Dehlink, E., Nurko, S., and Fiebiger, E.
- Subjects
LEUKOTRIENES ,IMMUNE response ,ESOPHAGUS diseases ,DIAGNOSIS ,ALLERGIES ,PHENOTYPES - Abstract
Background Cysteinyl leukotrienes contribute to Th2-type inflammatory immune responses. Their levels in oesophageal tissue, however, do not distinguish patients with eosinophilic oesophagitis (EoE) from controls. Objective We asked whether mRNA levels of leukotriene C
4 synthase (LTC4 S), a key regulator of leukotriene production, could serve as a marker for EoE. Methods Digital mRNA expression profiling (nCounter® Technology) was performed on proximal and distal oesophageal biopsies of 30 paediatric EoE patients and 40 non-EoE controls. Expression data were confirmed with RT- qPCR. LTC4 S mRNA levels were quantified in whole blood samples. Leukotriene E4 was measured in urine. Results LTC4 S mRNA levels were elevated in proximal (2.6-fold, P < 0.001) and distal (2.9-fold, P < 0.001) oesophageal biopsies from EoE patients. Importantly, increased LTC4 S mRNA transcripts identified a subpopulation of EoE patients (28%). This patient subgroup had higher serum IgE levels (669 U/mL vs. 106 U/mL, P = 0.01), higher mRNA transcript numbers of thymic stromal lymphopoietin (TSLP) (1.6-fold, P = 0.009) and CD4 (1.4-fold, P = 0.04) but lower IL-23 mRNA levels (0.5-fold, P = 0.04). In contrast, elevated levels of IL-23 mRNA were found in oesophageal biopsies of patients with reflux oesophagitis. LTC4 S mRNA transcripts in whole blood and urinary excretion of leukotriene E4 were similar in EoE patient subgroups and non-EoE patients. Conclusion & Clinical Relevance Elevated oesophageal expression of LTC4 S mRNA is found in a subgroup of EoE patients, concomitant with higher serum IgE levels and an oesophageal transcriptome indicative of a more-pronounced allergic phenotype. Together with TSLP and IL-23 mRNA levels, oesophageal LTC4 S mRNA may facilitate diagnosis of an EoE subpopulation for personalized therapy. [ABSTRACT FROM AUTHOR]- Published
- 2013
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27. Identification of expression signals of the mycobacteriophages Bxb1, L1 and TM4 using the Escherichia-Mycobacterium shuttle plasmids pYUB75 and pYUB76 designed to create translational fusions to the lacZ gene
- Author
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Barletta, R. G., primary, Kim, D. D., additional, Snapper, S. B., additional, Bloom, B. R., additional, and Jacobs, W. R., additional
- Published
- 1992
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28. New use of BCG for recombinant vaccines
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Stover, C. K., primary, de la Cruz, V. F., additional, Fuerst, T. R., additional, Burlein, J. E., additional, Benson, L. A., additional, Bennett, L. T., additional, Bansal, G. P., additional, Young, J. F., additional, Lee, M. H., additional, Hatfull, G. F., additional, Snapper, S. B., additional, Barletta, R. G., additional, Jacobs, W. R., additional, and Bloom, B. R., additional
- Published
- 1991
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29. Isolation and characterization of efficient plasmid transformation mutants of Mycobacterium smegmatis
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Snapper, S. B., primary, Melton, R. E., additional, Mustafa, S., additional, Kieser, T., additional, and Jr, W. R.Jacobs, additional
- Published
- 1990
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30. Vaccine development On relating immunology to the Third World: some studies on leprosy.
- Author
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Bloom, B. R., Salgame, P., Mehra, V., Kato, H., Modlin, R., Rea, T., Brennan, P., Convit, J., Lugozi, L., Snapper, S., and Jacobs, W.
- Subjects
IMMUNOLOGY ,HANSEN'S disease ,COMMUNICABLE diseases ,MYCOBACTERIAL diseases ,IMMUNITY ,ANTIGENS - Abstract
Leprosy is of interest to immunologists because the varied clinical manifestations of the disease correlate closely with the immunological spectrum. Resistance to infection is dependent on appropriate cell-mediated immunity, but patients with the lepromatous form fail to respond to antigens of M. leprae. In vitro studies have revealed the existence of T-suppressor cells of the phenotype CD8
+ , CD3+ , HLA-DR+ , FcR+ , 9·3- , which are restricted by major histocompatibility complex (MHC) class II antigens. Several new candidate vaccines against leprosy have been effective in breaking immunological unresponsiveness and engendering cell-mediated immunity in leproma- tous leprosy patients, including the combination of BCG + killed M. leprae. Because BCG has unique adjuvant properties, we have begun to use molecular genetic approaches to develop BCG into a multivaccine vehicle capable of immunizing simultaneously against several pathogens. Both phage- based and plasmid-based strategies have been successfully developed for introducing selectable markers into BCG for the first time. [ABSTRACT FROM AUTHOR]- Published
- 1989
31. Lysogeny and transformation in mycobacteria: stable expression of foreign genes.
- Author
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Snapper, S B, Lugosi, L, Jekkel, A, Melton, R E, Kieser, T, Bloom, B R, and Jacobs, W R
- Abstract
Requisite to a detailed understanding of the molecular basis of bacterial pathogenesis is a genetic system that allows for the transfer, mutation, and expression of specific genes. Because of the continuing importance of tuberculosis and leprosy worldwide, we initiated studies to develop a genetic system in mycobacteria and here report the use of two complementary strategies to introduce and express selectable genetic markers. First, an Escherichia coli cosmid was inserted into the temperate mycobacteriophage L1, generating shuttle phasmids replicating as plasmids in E. coli and phage capable of lysogenizing the mycobacterial host. These temperate shuttle phasmids form turbid plaques on Mycobacterium smegmatis and, upon lysogenization, confer resistance to superinfection and integrate within the mycobacterial chromosome. When an L1 shuttle phasmid containing a cloned gene conferring kanamycin resistance in E. coli was introduced into M. smegmatis, stable kanamycin-resistant colonies--i.e., lysogens--were obtained. Second, to develop a plasmid transformation system in mycobacteria, M. fortuitum/E. coli hybrid plasmids containing mycobacterial and E. coli replicons and a kanamycin-resistance gene were constructed. When introduced into M. smegmatis or BCG (Mycobacterium tuberculosis typus bovinus var. Bacille-Calmette-Guérin) by electroporation, these shuttle plasmids conferred stable kanamycin resistance upon transformants. These systems should facilitate genetic analyses of mycobacterial pathogenesis and the development of recombinant mycobacterial vaccines.
- Published
- 1988
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32. X. Challenges update workgroups
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Stenson, W. F., Snapper, S. B., Duerr, R. H., Cho, J. H., Kugathasan, S., Rioux, J. D., Sartor, R. B., Autenreith, I. B., Darfeuille-Michaud, A., Fox, J., Tannock, G. W., Versalovic, J., Young, V. B., Elson, C. O., Mayer, L. F., Weaver, C. T., Wayne Lencer, Colgan, S. P., Parkos, C. A., Silverberg, M. S., Targan, S. R., Rubin, D. T., Loftus, E. V., Vasiliauskas, E. A., Sands, B. E., Higgins, P., D Haens, G., Feagan, B. G., Hanauer, S. B., Sandborn, W. J., Steinhart, H., Fazio, V., Galandiuk, S., Koltun, W. A., Strong, S. A., Sylvester, F. A., Bousvaros, A., Dubinsky, M., Faubion, W. A., Griffiths, A. M., Guthery, S. L., Hyams, J. S., Polk, D. B., and Szigethy, E.
33. Activating PIK3CD mutations cause severe intestinal lymphonodular hyperplasia and an IBD-like phenotype
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Farachi, S., Werner, L., Konnikova, L., Rea, F., Vardi, I., Romeo, E., Barel, O., Angelis, P., Dall Oglio, L., Rechavi, G., Snapper, S., Somech, R., Weiss, B., Cancrini, C., and Daniel Shouval
34. Wiskott-Aldrich Syndrome Protein-Deficient Mice Reveal a Role for WASP in T but Not B Cell Activation
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SNAPPER, S
- Published
- 1998
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35. Clinical Genomics for the Diagnosis of Monogenic Forms of Inflammatory Bowel Disease: A Position Paper From the Paediatric IBD Porto Group of European Society of Paediatric Gastroenterology, Hepatology and Nutrition
- Author
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Simon Travis, Scott B. Snapper, Tobias Schwerd, Aleixo M. Muise, Dan Turner, Christoph Klein, Fabienne Charbit-Henrion, Caterina Strisciuglio, Frank M. Ruemmele, Richard K Russell, Marina Macchi, Johan L van Limbergen, David C. Wilson, Anne M. Griffiths, Dror S. Shouval, Lissy de Ridder, Daniel Kotlarz, Holm H. Uhlig, Paediatric Gastroenterology, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, APH - Digital Health, APH - Health Behaviors & Chronic Diseases, Pediatrics, Uhlig, H. H., Charbit-Henrion, F., Kotlarz, D., Shouval, D. S., Schwerd, T., Strisciuglio, C., de Ridder, L., van Limbergen, J., Macchi, M., Snapper, S. B., Ruemmele, F. M., Wilson, D. C., Travis, S. P. L., Griffiths, A. M., Turner, D., Klein, C., Muise, A. M., and Russell, R. K.
- Subjects
medicine.medical_specialty ,very early-onset inflammatory bowel disease ,MEDLINE ,primary immunodeficiency ,digestive system ,Article ,ulcerative coliti ,03 medical and health sciences ,0302 clinical medicine ,030225 pediatrics ,Internal medicine ,Medicine ,Humans ,Family history ,Young adult ,Intensive care medicine ,Child ,Exome ,Genetic testing ,medicine.diagnostic_test ,business.industry ,Gastroenterology ,Genomics ,Hepatology ,Colitis ,Inflammatory Bowel Diseases ,digestive system diseases ,Crohn's disease ,Systematic review ,Pediatrics, Perinatology and Child Health ,Genomic ,Position paper ,030211 gastroenterology & hepatology ,genetic ,business ,Child Nutritional Physiological Phenomena ,exome sequencing ,Coliti ,Human - Abstract
BACKGROUND: It is important to identify patients with monogenic IBD as management may differ from classical IBD. In this position statement we formulate recommendations for the use of genomics in evaluating potential monogenic causes of IBD across age groups. METHODS: The consensus included paediatric IBD specialists from the Paediatric IBD Porto group of the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and specialists from several monogenic IBD research consortia. We defined key topics and performed a systematic literature review to cover indications, technologies (targeted panel, exome and genome sequencing), gene panel setup, cost-effectiveness of genetic screening, and requirements for the clinical care setting. We developed recommendations that were voted upon by all authors and Porto group members (32 voting specialists). RESULTS: We recommend next-generation DNA-sequencing technologies to diagnose monogenic causes of IBD in routine clinical practice embedded in a setting of multidisciplinary patient care. Routine genetic screening is not recommended for all IBD patients. Genetic testing should be considered depending on age of IBD-onset (infantile IBD, very early-onset IBD, paediatric or young adult IBD), and further criteria, such as family history, relevant comorbidities, and extraintestinal manifestations. Genetic testing is also recommended in advance of hematopoietic stem cell transplantation. We developed a diagnostic algorithm that includes a gene panel of 75 monogenic IBD genes. Considerations are provided also for low resource countries. CONCLUSIONS: Genomic technologies should be considered an integral part of patient care to investigate patients at risk for monogenic forms of IBD.
- Published
- 2021
36. Defects in Nicotinamide-adenine Dinucleotide Phosphate Oxidase Genes NOX1 and DUOX2 in Very Early Onset Inflammatory Bowel Disease
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Sandeep S. Dhillon, Billy Bourke, Anne M. Griffiths, Conghui H. Guo, Dermot P.B. McGovern, James H. Doroshow, Inga Peter, Luis Alvarez, Lidija Kovačič, Abdul Elkadri, Scott B. Snapper, Aleixo M. Muise, Ken Y. Hui, Judy H. Cho, Gabriella Aviello, Steven R. Brant, Cornelia Thoeni, Kim O’Neill, Holm H. Uhlig, John H. Brumell, PK Hayes, Ulla G. Knaus, Mark S. Silverberg, Hayes, P., Dhillon, S., O'Neill, K., Thoeni, C., Hui, K. Y., Elkadri, A., Guo, C. H., Kovacic, L., Aviello, G., Alvarez, L. A., Griffiths, A. M., Snapper, S. B., Brant, S. R., Doroshow, J. H., Silverberg, M. S., Peter, I., Mcgovern, D. P. B., Cho, J., Brumell, J. H., Uhlig, H. H., Bourke, B., Muise, A. M., and Knaus, U. G.
- Subjects
WT, wild type ,NADPH Oxidase ,Inflammatory bowel disease ,0302 clinical medicine ,Chronic granulomatous disease ,Cellular localization ,Original Research ,NOX1, NADPH oxidase 1 ,VEOIBD, very early onset inflammatory bowel disease ,0303 health sciences ,NADPH oxidase ,IBD, inflammatory bowel disease ,HA, human influenza hemagglutinin ,Gastroenterology ,NADPH Oxidase 1 ,NADPH, nicotinamide-adenine dinucleotide phosphate ,3. Good health ,medicine.anatomical_structure ,NOX1 ,cardiovascular system ,030211 gastroenterology & hepatology ,SNP, single-nucleotide polymorphism ,Reactive Oxygen Specie ,AJ, Ashkenazi Jewish ,PMA, phorbol 12-myristate 13-acetate ,PBS, phosphate-buffered saline ,Biology ,MAF, minor allele frequency ,Microbiology ,03 medical and health sciences ,PAS, periodic acid–Schiff ,ROS, reactive oxygen species ,medicine ,lcsh:RC799-869 ,DUOX2 ,VEOIBD ,030304 developmental biology ,DUOX2, dual oxidase 2 ,FAD, flavin adenine nucleotide ,Hepatology ,Inflammatory Bowel Disease ,CGD, chronic granulomatous disease ,Dual oxidase 2 ,medicine.disease ,UC, ulcerative colitis ,Immunology ,Paneth cell ,biology.protein ,lcsh:Diseases of the digestive system. Gastroenterology ,Reactive Oxygen Species - Abstract
Background & Aims: Defects in intestinal innate defense systems predispose patients to inflammatory bowel disease (IBD). Reactive oxygen species (ROS) generated by nicotinamide-adenine dinucleotide phosphate (NADPH) oxidases in the mucosal barrier maintain gut homeostasis and defend against pathogenic attack. We hypothesized that molecular genetic defects in intestinal NADPH oxidases might be present in children with IBD. Methods: After targeted exome sequencing of epithelial NADPH oxidases NOX1 and DUOX2 on 59 children with very early onset inflammatory bowel disease (VEOIBD), the identified mutations were validated using Sanger Sequencing. A structural analysis of NOX1 and DUOX2 variants was performed by homology in silico modeling. The functional characterization included ROS generation in model cell lines and in in vivo transduced murine crypts, protein expression, intracellular localization, and cell-based infection studies with the enteric pathogens Campylobacter jejuni and enteropathogenic Escherichia coli. Results: We identified missense mutations in NOX1 (c.988G>A, p.Pro330Ser; c.967G>A, p.Asp360Asn) and DUOX2 (c.4474G>A, p.Arg1211Cys; c.3631C>T, p.Arg1492Cys) in 5 of 209 VEOIBD patients. The NOX1 p.Asp360Asn variant was replicated in a male Ashkenazi Jewish ulcerative colitis cohort. Patients with both NOX1 and DUOX2 variants showed abnormal Paneth cell metaplasia. All NOX1 and DUOX2 variants showed reduced ROS production compared with wild-type enzymes. Despite appropriate cellular localization and comparable pathogen-stimulated translocation of altered oxidases, cells harboring NOX1 or DUOX2 variants had defective host resistance to infection with C. jejuni. Conclusions: This study identifies the first inactivating missense variants in NOX1 and DUOX2 associated with VEOIBD. Defective ROS production from intestinal epithelial cells constitutes a risk factor for developing VEOIBD. Keywords: Inflammatory Bowel Disease, NADPH Oxidase, NOX1, DUOX2, Reactive Oxygen Species, VEOIBD
- Published
- 2015
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37. Fatal autoimmunity in mice reconstituted with human hematopoietic stem cells encoding defective FOXP3
- Author
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Edda Fiebiger, Scott B. Snapper, Jodie Ouahed, Maria Grazia Roncarolo, Wayne A. Marasco, Bruce H. Horwitz, Bonny Patel, Diane Mathis, Luigi D. Notarangelo, Subhabrata Biswas, Rosa Bacchetta, Aleixo M. Muise, Katelyn McCann, Jiusong Sun, Sung-Yun Pai, Ada Yeste, Laura Passerini, Jeremy A. Goettel, Dror S. Shouval, Christoph Klein, Francisco J. Quintana, Edgar L. Milford, Siyoung Yang, Willem S. Lexmond, Goettel, J. A., Biswas, S., Lexmond, W. S., Yeste, A., Passerini, L., Patel, B., Yang, S., Sun, J., Ouahed, J., Shouval, D. S., Mccann, K. J., Horwitz, B. H., Mathis, D., Milford, E. L., Notarangelo, L. D., Roncarolo, M., Fiebiger, E., Marasco, W. A., Bacchetta, R., Quintana, F. J., Pai, S. -Y., Klein, C., Muise, A. M., and Snapper, S. B.
- Subjects
Immunology ,Transplantation, Heterologous ,chemical and pharmacologic phenomena ,Autoimmunity ,Enzyme-Linked Immunosorbent Assay ,Human leukocyte antigen ,Biology ,medicine.disease_cause ,Biochemistry ,Immunophenotyping ,Mice ,Immune system ,medicine ,Animals ,Humans ,Mice, Knockout ,Reverse Transcriptase Polymerase Chain Reaction ,Autoantibody ,Hematopoietic Stem Cell Transplantation ,Immunologic Deficiency Syndromes ,FOXP3 ,Forkhead Transcription Factors ,Cell Biology ,Hematology ,biochemical phenomena, metabolism, and nutrition ,Immune dysregulation ,Flow Cytometry ,Immunohistochemistry ,Disease Models, Animal ,Delayed hypersensitivity ,Humanized mouse ,bacteria ,Stem cell - Abstract
Mice reconstituted with a human immune system provide a tractable in vivo model to assess human immune cell function. To date, reconstitution of murine strains with human hematopoietic stem cells (HSCs) from patients with monogenic immune disorders have not been reported. One obstacle precluding the development of immune-disease specific “humanized” mice is that optimal adaptive immune responses in current strains have required implantation of autologous human thymic tissue. To address this issue, we developed a mouse strain that lacks murine major histocompatibility complex class II (MHC II) and instead expresses human leukocyte antigen DR1 (HLA-DR1). These mice displayed improved adaptive immune responses when reconstituted with human HSCs including enhanced T-cell reconstitution, delayed-type hypersensitivity responses, and class-switch recombination. Following immune reconstitution of this novel strain with HSCs from a patient with immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, associated with aberrant FOXP3 function, mice developed a lethal inflammatory disorder with multiorgan involvement and autoantibody production mimicking the pathology seen in affected humans. This humanized mouse model permits in vivo evaluation of immune responses associated with genetically altered HSCs, including primary immunodeficiencies, and should facilitate the study of human immune pathobiology and the development of targeted therapeutics.
- Published
- 2014
38. Catalyzing change: Implementing standardised reporting in monogenic inflammatory bowel disease research.
- Author
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Yeh PJ, Nash K, Charlesworth JEG, Collen LV, Snapper S, and Uhlig HH
- Subjects
- Humans, Age of Onset, Phenotype, Genetic Predisposition to Disease, Inflammatory Bowel Diseases genetics, Crohn Disease
- Published
- 2024
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39. Progression of Pediatric Crohn's Disease Is Associated With Anti-Tumor Necrosis Factor Timing and Body Mass Index Z-Score Normalization.
- Author
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Geem D, Hercules D, Pelia RS, Venkateswaran S, Griffiths A, Noe JD, Dotson JL, Snapper S, Rabizadeh S, Rosh JR, Baldassano RN, Markowitz JF, Walters TD, Ananthakrishnan A, Sharma G, Denson LA, Hyams JS, and Kugathasan S
- Subjects
- Child, Humans, Body Mass Index, Risk Factors, Tumor Necrosis Factor-alpha, Constriction, Pathologic etiology, Necrosis, Disease Progression, Retrospective Studies, Crohn Disease complications
- Abstract
Background & Aims: The evolution of complicated pediatric Crohn's disease (CD) in the era of anti-tumor necrosis factor (aTNF) therapy continues to be described. Because CD progresses from inflammatory to stricturing (B2) and penetrating (B3) disease behaviors in a subset of patients, we aimed to understand the risk of developing complicated disease behavior or undergoing surgery in relation to aTNF timing and body mass index z-score (BMIz) normalization., Methods: Multicenter, 5-year longitudinal data from 1075 newly diagnosed CD patients were analyzed. Descriptive statistics, univariate and stepwise multivariate Cox proportional hazard regression (CPHR), and log-rank analyses were performed for risk of surgery and complicated disease behaviors. Differential gene expression from ileal bulk RNA sequencing was correlated with outcomes., Results: Stricturing complications had the largest increase: from 2.98% to 10.60% over 5 years. Multivariate CPHR showed aTNF exposure within 3 months from diagnosis (hazard ratio [HR], 0.33; 95% CI, 0.15-0.71) and baseline L2 disease (HR, 0.29; 95% CI, 0.09-0.92) to be associated with reduced B1 to B2 progression. For children with a low BMIz at diagnosis (n = 294), multivariate CPHR showed BMIz normalization within 6 months of diagnosis (HR, 0.47; 95% CI, 0.26-0.85) and 5-aminosalicyclic acid exposure (HR, 0.32; 95% CI, 0.13-0.81) were associated with a decreased risk for surgery while B2 (HR, 4.20; 95% CI, 1.66-10.65) and B2+B3 (HR, 8.24; 95% CI, 1.08-62.83) at diagnosis increased surgery risk. Patients without BMIz normalization were enriched for genes in cytokine production and inflammation., Conclusions: aTNF exposure up to 3 months from diagnosis may reduce B2 progression. In addition, lack of BMIz normalization within 6 months of diagnosis is associated with increased surgery risk and a proinflammatory transcriptomic profile., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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40. Intestinal microbiome and metabolome signatures in patients with chronic granulomatous disease.
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Chandrasekaran P, Han Y, Zerbe CS, Heller T, DeRavin SS, Kreuzberg SA, Marciano BE, Siu Y, Jones DR, Abraham RS, Stephens MC, Tsou AM, Snapper S, Conlan S, Subramanian P, Quinones M, Grou C, Calderon V, Deming C, Leiding JW, Arnold DE, Logan BR, Griffith LM, Petrovic A, Mousallem TI, Kapoor N, Heimall JR, Barnum JL, Kapadia M, Wright N, Rayes A, Chandra S, Broglie LA, Chellapandian D, Deal CL, Grunebaum E, Lim SS, Mallhi K, Marsh RA, Murguia-Favela L, Parikh S, Touzot F, Cowan MJ, Dvorak CC, Haddad E, Kohn DB, Notarangelo LD, Pai SY, Puck JM, Pulsipher MA, Torgerson TR, Kang EM, Malech HL, Segre JA, Bryant CE, Holland SM, and Falcone EL
- Subjects
- Humans, NADPH Oxidases, Cross-Sectional Studies, Granulomatous Disease, Chronic genetics, Gastrointestinal Microbiome, Inflammatory Bowel Diseases
- Abstract
Background: Chronic granulomatous disease (CGD) is caused by defects in any 1 of the 6 subunits forming the nicotinamide adenine dinucleotide phosphate oxidase complex 2 (NOX2), leading to severely reduced or absent phagocyte-derived reactive oxygen species production. Almost 50% of patients with CGD have inflammatory bowel disease (CGD-IBD). While conventional IBD therapies can treat CGD-IBD, their benefits must be weighed against the risk of infection. Understanding the impact of NOX2 defects on the intestinal microbiota may lead to the identification of novel CGD-IBD treatments., Objective: We sought to identify microbiome and metabolome signatures that can distinguish individuals with CGD and CGD-IBD., Methods: We conducted a cross-sectional observational study of 79 patients with CGD, 8 pathogenic variant carriers, and 19 healthy controls followed at the National Institutes of Health Clinical Center. We profiled the intestinal microbiome (amplicon sequencing) and stool metabolome, and validated our findings in a second cohort of 36 patients with CGD recruited through the Primary Immune Deficiency Treatment Consortium., Results: We identified distinct intestinal microbiome and metabolome profiles in patients with CGD compared to healthy individuals. We observed enrichment for Erysipelatoclostridium spp, Sellimonas spp, and Lachnoclostridium spp in CGD stool samples. Despite differences in bacterial alpha and beta diversity between the 2 cohorts, several taxa correlated significantly between both cohorts. We further demonstrated that patients with CGD-IBD have a distinct microbiome and metabolome profile compared to patients without CGD-IBD., Conclusion: Intestinal microbiome and metabolome signatures distinguished patients with CGD and CGD-IBD, and identified potential biomarkers and therapeutic targets., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
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41. Identifying high-impact variants and genes in exomes of Ashkenazi Jewish inflammatory bowel disease patients.
- Author
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Wu Y, Gettler K, Kars ME, Giri M, Li D, Bayrak CS, Zhang P, Jain A, Maffucci P, Sabic K, Van Vleck T, Nadkarni G, Denson LA, Ostrer H, Levine AP, Schiff ER, Segal AW, Kugathasan S, Stenson PD, Cooper DN, Philip Schumm L, Snapper S, Daly MJ, Haritunians T, Duerr RH, Silverberg MS, Rioux JD, Brant SR, McGovern DPB, Cho JH, and Itan Y
- Subjects
- Adult, Humans, Exome genetics, Risk Assessment, Genetic Predisposition to Disease, Jews genetics, Inflammatory Bowel Diseases genetics
- Abstract
Inflammatory bowel disease (IBD) is a group of chronic digestive tract inflammatory conditions whose genetic etiology is still poorly understood. The incidence of IBD is particularly high among Ashkenazi Jews. Here, we identify 8 novel and plausible IBD-causing genes from the exomes of 4453 genetically identified Ashkenazi Jewish IBD cases (1734) and controls (2719). Various biological pathway analyses are performed, along with bulk and single-cell RNA sequencing, to demonstrate the likely physiological relatedness of the novel genes to IBD. Importantly, we demonstrate that the rare and high impact genetic architecture of Ashkenazi Jewish adult IBD displays significant overlap with very early onset-IBD genetics. Moreover, by performing biobank phenome-wide analyses, we find that IBD genes have pleiotropic effects that involve other immune responses. Finally, we show that polygenic risk score analyses based on genome-wide high impact variants have high power to predict IBD susceptibility., (© 2023. The Author(s).)
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- 2023
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42. Inflammatory Bowel Disease and Cardiovascular Diseases.
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Chen B, Collen LV, Mowat C, Isaacs KL, Singh S, Kane SV, Farraye FA, Snapper S, Jneid H, Lavie CJ, and Krittanawong C
- Subjects
- Humans, Prospective Studies, Retrospective Studies, Chronic Disease, Cardiovascular Diseases epidemiology, Cardiovascular Diseases etiology, Colitis, Ulcerative, Crohn Disease complications, Coronary Artery Disease, Atrial Fibrillation epidemiology, Atrial Fibrillation etiology, Inflammatory Bowel Diseases complications, Heart Failure, Atherosclerosis
- Abstract
Background: Emerging data showed patients with chronic inflammatory disorders, including inflammatory bowel disease, are more likely to develop atherosclerotic cardiovascular diseases, heart failure, and atrial fibrillation. This article aims to review the evidence of those associations., Methods: PubMed was searched from inception to January 2022 using the keywords, including inflammatory bowel diseases, Crohn disease, ulcerative colitis, atherosclerotic cardiovascular disease, coronary artery disease, cardiovascular disease, atrial fibrillation, heart failure, and premature coronary artery disease. Relevant literature, including retrospective/prospective cohort studies, clinical trials, meta-analyses, and guidelines, were reviewed and summarized., Results: Both ulcerative colitis and Crohn disease are associated with an increased risk of atherosclerotic cardiovascular diseases, cerebrovascular accidents, premature coronary artery disease, and atrial fibrillation. Ulcerative colitis is associated with an increased risk of heart failure. The increased atrial fibrillation occurred during inflammatory bowel disease flares and persistent activity but not during periods of remission. Hypotheses for the mechanism underlying the association of inflammatory bowel disease and atherosclerotic cardiovascular diseases include shared risk factors (ie, obesity, diabetes, smoking, diet) and pathophysiology (gut microbiome dysfunction) or adverse effects from inflammatory bowel disease itself or its treatment (ie, chronic inflammation, dyslipidemia, thrombocytosis, steroids)., Conclusion: Inflammatory bowel disease is associated with an increased risk of atherosclerotic cardiovascular diseases, heart failure, and atrial fibrillation. A multidisciplinary team with gastroenterologists and cardiologists is needed to optimize the care for patients with inflammatory bowel disease and associated cardiac diseases., (Copyright © 2022 Elsevier Inc. All rights reserved.)
- Published
- 2022
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43. Utilization of Antitumor Necrosis Factor Biologics in Very Early Onset Inflammatory Bowel Disease: A Multicenter Retrospective Cohort Study From North America.
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Kerur B, Fiedler K, Stahl M, Hyams J, Stephens M, Lu Y, Pfefferkorn M, Alkhouri R, Strople J, Kelsen J, Siebold L, Goyal A, Rosh JR, LeLeiko N, Van Limbergen J, Guerrerio AL, Maltz RM, Karam L, Crowley E, Griffiths AM, Heyman MB, Deneau M, Benkov K, Noe J, Moulton D, Pappa H, Galanko J, Snapper S, Muise AM, Kappelman MD, and Benchimol EI
- Subjects
- Adalimumab therapeutic use, Adolescent, Child, Child, Preschool, Cohort Studies, Humans, Infant, Infant, Newborn, Infliximab therapeutic use, Necrosis, Retrospective Studies, Tumor Necrosis Factor Inhibitors, Tumor Necrosis Factor-alpha, Biological Products therapeutic use, Colitis, Ulcerative drug therapy, Crohn Disease drug therapy, Inflammatory Bowel Diseases drug therapy
- Abstract
Background: Research on the utilization and effectiveness of antitumor necrosis factor (TNF) biologics in children with very early onset inflammatory bowel disease (VEOIBD) is urgently needed. Here we describe anti-TNF use and durability in a multicenter cohort., Methods: We performed a retrospective cohort study of patients diagnosed with VEOIBD (<6 years) between 2008 and 2013 at 25 North American centers. We performed chart abstraction at diagnosis and 1, 3, and 5 years after diagnosis. We examined the rate of initiation and durability of infliximab and adalimumab and evaluated associations between treatment durability and the following covariates with multivariate Cox proportional hazard regression: age at diagnosis, sex, disease duration, disease classification, and presence of combined immunomodulatory treatment versus monotherapy., Results: Of 294 children with VEOIBD, 120 initiated treatment with anti-TNF therapy and 101 had follow-up data recorded [50% Crohn disease (CD), 31% ulcerative colitis (UC), and 19% IBD unclassified (IBD-U)]. The cumulative probability of anti-TNF treatment was 15% at 1 year, 30% at 3 years, and 45% at 5 years from diagnosis; 56 (55%) were treated between 0 and 6 years old. Anti-TNF durability was 90% at 1 year, 75% at 3 years, and 55% at 5 years. The most common reason for discontinuation of anti-TNF were loss of response in 24 (57%) children. Children with UC/IBD-U had lower durability than those with CD (hazard ratio [HR] 0.17; 95% confidence interval [CI], 0.06-0.51; P = 0.001)., Conclusions: Utilization and durability of anti-TNF in VEOIBD is relatively high and comparable with older children. Having Crohn disease (compared with UC/IBD-U) is associated with greater durability., (Copyright © 2022 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)
- Published
- 2022
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44. Pediatric Gastrointestinal Histopathology in Patients With Tetratricopeptide Repeat Domain 7A (TTC7A) Germline Mutations: A Rare Condition Leading to Multiple Intestinal Atresias, Severe Combined Immunodeficiency, and Congenital Enteropathy.
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Dannheim K, Ouahed J, Field M, Snapper S, Raphael BP, Glover SC, Bishop PR, Bhesania N, Kamin D, Thiagarajah J, and Goldsmith JD
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- Child, Humans, Infant, Intestinal Mucosa pathology, Intestines abnormalities, Retrospective Studies, Germ-Line Mutation, Intestinal Atresia genetics, Proteins genetics, Severe Combined Immunodeficiency genetics, Severe Combined Immunodeficiency pathology
- Abstract
Mutations in the tetratricopeptide repeat domain 7A (TTC7A) gene are a rare cause of congenital enteropathy that can result in significant morbidity. TTC7A deficiency leads to disruption of the intestinal epithelium. The histopathology of this condition has been partly described in case reports and clinical studies. This manuscript describes an in-depth investigation of the pediatric gastrointestinal pathology of the largest histologically examined cohort with confirmed TTC7A mutations reported to date and, for the first time, compared the findings to age-matched and sex-matched control patients with intestinal atresia not thought to be associated with TTC7A mutations. Hematoxylin and eosin-stained slides of endoscopically obtained mucosal biopsies and surgical resection specimens from 7 patients with known TTC7A mutations were examined retrospectively. The microscopic findings were found to be on a spectrum from atresia-predominant to those with predominantly epithelial abnormalities. Several unique histopathologic characteristics were observed when compared with controls. These included neutrophilic colitis and prominent lamina propria eosinophilia throughout the gastrointestinal tract. Striking architectural abnormalities of the epithelium were observed in 4 of the 7 patients. The 5 patients with intestinal atresia demonstrated hypertrophy and disorganization of the colonic muscularis mucosae accompanied by bland spindle cell nodules within the intestinal wall. The components of the latter were further elucidated using immunohistochemistry, and we subsequently hypothesize that they represent obliterated mucosa with remnants of the muscularis mucosae. Finally, atrophic gastritis was noted in 4 patients. In conclusion, the unique histopathologic characteristics of TTC7A mutation-associated enteropathy described herein more fully describe this novel disease entity in infants who present with congenital enteropathy or enterocolitis., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)
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- 2022
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45. An Integrated Taxonomy for Monogenic Inflammatory Bowel Disease.
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Bolton C, Smillie CS, Pandey S, Elmentaite R, Wei G, Argmann C, Aschenbrenner D, James KR, McGovern DPB, Macchi M, Cho J, Shouval DS, Kammermeier J, Koletzko S, Bagalopal K, Capitani M, Cavounidis A, Pires E, Weidinger C, McCullagh J, Arkwright PD, Haller W, Siegmund B, Peters L, Jostins L, Travis SPL, Anderson CA, Snapper S, Klein C, Schadt E, Zilbauer M, Xavier R, Teichmann S, Muise AM, Regev A, and Uhlig HH
- Subjects
- Age of Onset, Antiporters genetics, Cells, Cultured, Classification, Gene Expression Profiling, Genetic Association Studies, Genotype, Glucose-6-Phosphatase genetics, Glucose-6-Phosphate metabolism, Humans, Inflammatory Bowel Diseases metabolism, Macrophages, Metabolomics, Monosaccharide Transport Proteins genetics, Penetrance, Phenotype, Signal Transduction genetics, Inflammatory Bowel Diseases classification, Inflammatory Bowel Diseases genetics
- Abstract
Background & Aims: Monogenic forms of inflammatory bowel disease (IBD) illustrate the essential roles of individual genes in pathways and networks safeguarding immune tolerance and gut homeostasis., Methods: To build a taxonomy model, we assessed 165 disorders. Genes were prioritized based on penetrance of IBD and disease phenotypes were integrated with multi-omics datasets. Monogenic IBD genes were classified by (1) overlapping syndromic features, (2) response to hematopoietic stem cell transplantation, (3) bulk RNA-sequencing of 32 tissues, (4) single-cell RNA-sequencing of >50 cell subsets from the intestine of healthy individuals and patients with IBD (pediatric and adult), and (5) proteomes of 43 immune subsets. The model was validated by addition of newly identified monogenic IBD defects. As a proof-of-concept, we explore the intersection between immunometabolism and antimicrobial activity for a group of disorders (G6PC3/SLC37A4)., Results: Our quantitative integrated taxonomy defines the cellular landscape of monogenic IBD gene expression across 102 genes with high and moderate penetrance (81 in the model set and 21 genes in the validation set). We illustrate distinct cellular networks, highlight expression profiles across understudied cell types (e.g., CD8
+ T cells, neutrophils, epithelial subsets, and endothelial cells) and define genotype-phenotype associations (perianal disease and defective antimicrobial activity). We illustrate processes and pathways shared across cellular compartments and phenotypic groups and highlight cellular immunometabolism with mammalian target of rapamycin activation as one of the converging pathways. There is an overlap of genes and enriched cell-specific expression between monogenic and polygenic IBD., Conclusion: Our taxonomy integrates genetic, clinical and multi-omic data; providing a basis for genomic diagnostics and testable hypotheses for disease functions and treatment responses., (Copyright © 2022 AGA Institute. All rights reserved.)- Published
- 2022
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46. Therapeutic options for CTLA-4 insufficiency.
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Egg D, Rump IC, Mitsuiki N, Rojas-Restrepo J, Maccari ME, Schwab C, Gabrysch A, Warnatz K, Goldacker S, Patiño V, Wolff D, Okada S, Hayakawa S, Shikama Y, Kanda K, Imai K, Sotomatsu M, Kuwashima M, Kamiya T, Morio T, Matsumoto K, Mori T, Yoshimoto Y, Dybedal I, Kanariou M, Kucuk ZY, Chapdelaine H, Petruzelkova L, Lorenz HM, Sullivan KE, Heimall J, Moutschen M, Litzman J, Recher M, Albert MH, Hauck F, Seneviratne S, Pachlopnik Schmid J, Kolios A, Unglik G, Klemann C, Snapper S, Giulino-Roth L, Svaton M, Platt CD, Hambleton S, Neth O, Gosse G, Reinsch S, Holzinger D, Kim YJ, Bakhtiar S, Atschekzei F, Schmidt R, Sogkas G, Chandrakasan S, Rae W, Derfalvi B, Marquart HV, Ozen A, Kiykim A, Karakoc-Aydiner E, Králíčková P, de Bree G, Kiritsi D, Seidel MG, Kobbe R, Dantzer J, Alsina L, Armangue T, Lougaris V, Agyeman P, Nyström S, Buchbinder D, Arkwright PD, and Grimbacher B
- Subjects
- Adolescent, Adult, Agammaglobulinemia etiology, Aged, Autoimmune Diseases etiology, CTLA-4 Antigen deficiency, Child, Child, Preschool, Female, Genetic Association Studies, Hematopoietic Stem Cell Transplantation, Humans, Immunologic Deficiency Syndromes complications, Immunologic Deficiency Syndromes genetics, Infant, Lung Diseases, Interstitial etiology, Male, Middle Aged, Transplantation, Homologous, Young Adult, CTLA-4 Antigen genetics, Germ-Line Mutation, Immunologic Deficiency Syndromes therapy
- Abstract
Background: Heterozygous germline mutations in cytotoxic T lymphocyte-associated antigen-4 (CTLA4) impair the immunomodulatory function of regulatory T cells. Affected individuals are prone to life-threatening autoimmune and lymphoproliferative complications. A number of therapeutic options are currently being used with variable effectiveness., Objective: Our aim was to characterize the responsiveness of patients with CTLA-4 insufficiency to specific therapies and provide recommendations for the diagnostic workup and therapy at an organ-specific level., Methods: Clinical features, laboratory findings, and response to treatment were reviewed retrospectively in an international cohort of 173 carriers of CTLA4 mutation. Patients were followed between 2014 and 2020 for a total of 2624 months from diagnosis. Clinical manifestations were grouped on the basis of organ-specific involvement. Medication use and response were recorded and evaluated., Results: Among the 173 CTLA4 mutation carriers, 123 (71%) had been treated for immune complications. Abatacept, rituximab, sirolimus, and corticosteroids ameliorated disease severity, especially in cases of cytopenias and lymphocytic organ infiltration of the gut, lungs, and central nervous system. Immunoglobulin replacement was effective in prevention of infection. Only 4 of 16 patients (25%) with cytopenia who underwent splenectomy had a sustained clinical response. Cure was achieved with stem cell transplantation in 13 of 18 patients (72%). As a result of the aforementioned methods, organ-specific treatment pathways were developed., Conclusion: Systemic immunosuppressants and abatacept may provide partial control but require ongoing administration. Allogeneic hematopoietic stem cell transplantation offers a possible cure for patients with CTLA-4 insufficiency., (Copyright © 2021. Published by Elsevier Inc.)
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- 2022
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47. The Development and Initial Findings of A Study of a Prospective Adult Research Cohort with Inflammatory Bowel Disease (SPARC IBD).
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Raffals LE, Saha S, Bewtra M, Norris C, Dobes A, Heller C, O'Charoen S, Fehlmann T, Sweeney S, Weaver A, Bishu S, Cross R, Dassopoulos T, Fischer M, Yarur A, Hudesman D, Parakkal D, Duerr R, Caldera F, Korzenik J, Pekow J, Wells K, Bohm M, Perera L, Kaur M, Ciorba M, Snapper S, Scoville EA, Dalal S, Wong U, and Lewis JD
- Subjects
- Adult, Cohort Studies, Humans, Osteonectin, Prospective Studies, Colitis, Ulcerative diagnosis, Crohn Disease diagnosis, Inflammatory Bowel Diseases diagnosis
- Abstract
Background: Clinical and molecular subcategories of inflammatory bowel disease (IBD) are needed to discover mechanisms of disease and predictors of response and disease relapse. We aimed to develop a study of a prospective adult research cohort with IBD (SPARC IBD) including longitudinal clinical and patient-reported data and biosamples., Methods: We established a cohort of adults with IBD from a geographically diverse sample of patients across the United States with standardized data and biosample collection methods and sample processing techniques. At enrollment and at time of lower endoscopy, patient-reported outcomes (PRO), clinical data, and endoscopy scoring indices are captured. Patient-reported outcomes are collected quarterly. The quality of clinical data entry after the first year of the study was assessed., Results: Through January 2020, 3029 patients were enrolled in SPARC, of whom 66.1% have Crohn's disease (CD), 32.2% have ulcerative colitis (UC), and 1.7% have IBD-unclassified. Among patients enrolled, 990 underwent colonoscopy. Remission rates were 63.9% in the CD group and 80.6% in the UC group. In the quality study of the cohort, there was 96% agreement on year of diagnosis and 97% agreement on IBD subtype. There was 91% overall agreement describing UC extent as left-sided vs extensive or pancolitis. The overall agreement for CD behavior was 83%., Conclusion: The SPARC IBD is an ongoing large prospective cohort with longitudinal standardized collection of clinical data, biosamples, and PROs representing a unique resource aimed to drive discovery of clinical and molecular markers that will meet the needs of precision medicine in IBD., (© 2021 Crohn’s & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
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- 2022
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48. Association of Baseline Luminal Narrowing With Ileal Microbial Shifts and Gene Expression Programs and Subsequent Transmural Healing in Pediatric Crohn Disease.
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Ta AD, Ollberding NJ, Karns R, Haberman Y, Alazraki AL, Hercules D, Baldassano R, Markowitz J, Heyman MB, Kim S, Kirschner B, Shapiro JM, Noe J, Oliva-Hemker M, Otley A, Pfefferkorn M, Kellermayer R, Snapper S, Rabizadeh S, Xavier R, Dubinsky M, Hyams J, Kugathasan S, Jegga AG, Dillman JR, and Denson LA
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- Child, Cohort Studies, Constriction, Pathologic, Humans, RNA, Ribosomal, 16S, Crohn Disease genetics, Gene Expression, Wound Healing
- Abstract
Background: Transmural healing (TH) is associated with better long-term outcomes in Crohn disease (CD), whereas pretreatment ileal gene signatures encoding myeloid inflammatory responses and extracellular matrix production are associated with stricturing. We aimed to develop a predictive model for ileal TH and to identify ileal genes and microbes associated with baseline luminal narrowing (LN), a precursor to strictures., Materials and Methods: Baseline small bowel imaging obtained in the RISK pediatric CD cohort study was graded for LN. Ileal gene expression was determined by RNASeq, and the ileal microbial community composition was characterized using 16S rRNA amplicon sequencing. Clinical, demographic, radiologic, and genomic variables were tested for association with baseline LN and future TH., Results: After controlling for ileal location, baseline ileal LN (odds ratio [OR], 0.3; 95% confidence interval [CI], 0.1-0.8), increasing serum albumin (OR, 4; 95% CI, 1.3-12.3), and anti-Saccharomyces cerevisiae antibodies IgG serology (OR, 0.97; 95% CI, 0.95-1) were associated with subsequent TH. A multivariable regression model including these factors had excellent discriminant power for TH (area under the curve, 0.86; positive predictive value, 80%; negative predictive value, 87%). Patients with baseline LN exhibited increased Enterobacteriaceae and inflammatory and extracellular matrix gene signatures, coupled with reduced levels of butyrate-producing commensals and a respiratory electron transport gene signature. Taxa including Lachnospiraceae and the genus Roseburia were associated with increased respiratory and decreased inflammatory gene signatures, and Aggregatibacter and Blautia bacteria were associated with reduced extracellular matrix gene expression., Conclusions: Pediatric patients with CD with LN at diagnosis are less likely to achieve TH. The association between specific microbiota, wound healing gene programs, and LN may suggest future therapeutic targets., (© 2021 Crohn’s & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2021
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49. Pulmonary Effects of Sustained Periods of High-G Acceleration Relevant to Suborbital Spaceflight.
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Pollock RD, Jolley CJ, Abid N, Couper JH, Estrada-Petrocelli L, Hodkinson PD, Leonhardt S, Magor-Elliott S, Menden T, Rafferty G, Richmond G, Robbins PA, Ritchie GAD, Segal MJ, Stevenson AT, Tank HD, and Smith TG
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- Acceleration, Centrifugation, Gravitation, Humans, Aerospace Medicine, Space Flight
- Abstract
Abstract BACKGROUND: Members of the public will soon be taking commercial suborbital spaceflights with significant G
x (chest-to-back) acceleration potentially reaching up to 6 Gx . Pulmonary physiology is gravity-dependent and is likely to be affected, which may have clinical implications for medically susceptible individuals. METHODS: During 2-min centrifuge exposures ranging up to 6 Gx , 11 healthy subjects were studied using advanced respiratory techniques. These sustained exposures were intended to allow characterization of the underlying pulmonary response and did not replicate actual suborbital G profiles. Regional distribution of ventilation in the lungs was determined using electrical impedance tomography. Neural respiratory drive (from diaphragm electromyography) and work of breathing (from transdiaphragmatic pressures) were obtained via nasoesophageal catheters. Arterial blood gases were measured in a subset of subjects. Measurements were conducted while breathing air and breathing 15 oxygen to simulate anticipated cabin pressurization conditions. RESULTS: Acceleration caused hypoxemia that worsened with increasing magnitude and duration of Gx . Minimum arterial oxygen saturation at 6 Gx was 86 1 breathing air and 79 1 breathing 15 oxygen. With increasing Gx the alveolar-arterial (A-a) oxygen gradient widened progressively and the relative distribution of ventilation reversed from posterior to anterior lung regions with substantial gas-trapping anteriorly. Severe breathlessness accompanied large progressive increases in work of breathing and neural respiratory drive. DISCUSSION: Sustained high-G acceleration at magnitudes relevant to suborbital flight profoundly affects respiratory physiology. These effects may become clinically important in the most medically susceptible passengers, in whom the potential role of centrifuge-based preflight evaluation requires further investigation. Pollock RD, Jolley CJ, Abid N, Couper JH, Estrada-Petrocelli L, Hodkinson PD, Leonhardt S, Mago-Elliott S, Menden T, Rafferty G, Richmond G, Robbins PA, Ritchie GAD, Segal MJ, Stevenson AT, Tank HD, Smith TG. Pulmonary effects of sustained periods of high-G acceleration relevant to suborbital spaceflight . Aerosp Med Hum Perform. 2021; 92(7):633641.- Published
- 2021
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50. Natural History of Very Early Onset Inflammatory Bowel Disease in North America: A Retrospective Cohort Study.
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Kerur B, Benchimol EI, Fiedler K, Stahl M, Hyams J, Stephens M, Lu Y, Pfefferkorn M, Alkhouri R, Strople J, Kelsen J, Siebold L, Goyal A, Rosh JR, LeLeiko N, Van Limbergen J, Guerrerio AL, Maltz R, Karam L, Crowley E, Griffiths A, Heyman MB, Deneau M, Benkov K, Noe J, Mouton D, Pappa H, Galanko JA, Snapper S, Muise AM, and Kappelman MD
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- Child, Child, Preschool, Chronic Disease, Colectomy, Constriction, Pathologic, Humans, North America epidemiology, Retrospective Studies, Colitis, Ulcerative epidemiology, Crohn Disease epidemiology
- Abstract
Background: The incidence of very early onset inflammatory bowel disease (VEOIBD) is increasing, yet the phenotype and natural history of VEOIBD are not well described., Methods: We performed a retrospective cohort study of patients diagnosed with VEOIBD (6 years of age and younger) between 2008 and 2013 at 25 North American centers. Eligible patients at each center were randomly selected for chart review. We abstracted data at diagnosis and at 1, 3, and 5 years after diagnosis. We compared the clinical features and outcomes with VEOIBD diagnosed younger than 3 years of age with children diagnosed with VEOIBD at age 3 to 6 years., Results: The study population included 269 children (105 [39%] Crohn's disease, 106 [39%] ulcerative colitis, and 58 [22%] IBD unclassified). The median age of diagnosis was 4.2 years (interquartile range 2.9-5.2). Most (94%) Crohn's disease patients had inflammatory disease behavior (B1). Isolated colitis (L2) was the most common disease location (70% of children diagnosed younger than 3 years vs 43% of children diagnosed 3 years and older; P = 0.10). By the end of follow-up, stricturing/penetrating occurred in 7 (6.6%) children. The risk of any bowel surgery in Crohn's disease was 3% by 1 year, 12% by 3 years, and 15% by 5 years and did not differ by age at diagnosis. Most ulcerative colitis patients had pancolitis (57% of children diagnosed younger than 3 years vs 45% of children diagnosed 3 years and older; P = 0.18). The risk of colectomy in ulcerative colitis/IBD unclassified was 0% by 1 year, 3% by 3 years, and 14% by 5 years and did not differ by age of diagnosis., Conclusions: Very early onset inflammatory bowel disease has a distinct phenotype with predominantly colonic involvement and infrequent stricturing/penetrating disease. The cumulative risk of bowel surgery in children with VEOIBD was approximately 14%-15% by 5 years. These data can be used to provide anticipatory guidance in this emerging patient population., (© 2020 Crohn’s & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2021
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