The Role of the Complement System in Chronic Intestinal Inflammation

المؤلفون

  • fatima mohamed sirte university

الكلمات المفتاحية:

Chronic inflammation; Complement; Intestinal; Intestinal Complement system.

الملخص

Complement is an important component of the innate immunity that can initiate or sustain inflammation but can modulate the developing adaptive immune response against invading foreign pathogens. Chronic inflammation is a characteristic of many long-term clinical disorders. An imbalance in the activation and regulation of the intestinal complement system hampers effective intestinal barrier function and hence contributes to severe intestinal inflammation as observed in inflammatory bowel diseases patients. Animal models have been instrumental in the evaluation of over-activation or impaired activation of the intestinal complement system in determining the extent of chronic intestinal inflammation. This review examines the role and possible therapeutic manipulation of complement system in chronic intestinal inflammation.

المراجع

Pouw RB, Ricklin D. (2021) Tipping the balance: intricate roles of the complement system in disease and therapy. Semin Immunopathol. 43(6): 757-771.

Markiewski, M.; Lambris, J. (2007) The role of complement in inflammatory diseases from behind the scenes into the spotlight. Am J Pathol. 171(3):715-27

Sahu SK, Kulkarni DH, Ozanturk AN, Ma L, Kulkarni HS. (2022) Emerging roles of the complement system in host-pathogen interactions. Trends Microbiol. 30(4): 390-402.

Medzhitov, R. (2010) Inflammation: new adventures of an old flame. Cell. 140:771–776.

Ferrero-Miliani, L.; Nielsen, O.; Andersen, P.; Girardin, S. (2007) Chronic inflammation: importance of NOD2 and NALP3 in interleukin-1β generation. Clin Exp Immunol. 147:227–235

Sugimoto, M.A.; Sousa, L.P.; Pinho, V.; Perretti, M.; Teixeira, M.M. (2016) Resolution of Inflammation: What Controls Its Onset?. Front Immuno. https://doi.org/10.3389/fimmu.2016.00.00160.

West EE, Kemper C. (2023) Complosome-the intracellular complement system. Nat Rev Nephrol. 19(7): 426-439.

King BC, Blom AM. (2023) Intracellular complement: evidence, definitions, controversies, and solutions. Immunol Rev. 313(1): 104-119

Xiao F, Guo J, Tomlinson S, Yuan G, He S.The role of the complosome in health and disease. Front Immunol. 2023; 14:1146167.

Kaplan GG, Windsor JW. (2021) The four epidemiological stages in the global evolution of inflammatory bowel disease. Nat Rev Gastroenterol Hepatol. 18(1): 56-66.

Dahlhamer, J.M.; Zammitti, EP.; Ward, B.W.; Wheaton, A.G.; Croft, J.B. (2016) Prevalence of inflammatory bowel disease among adults aged ≥18 years—United States, 2015. MMWR Morb Mortal Wkly Rep. 65(42):1166-1169.

Chang JT. (2020) Pathophysiology of inflammatory bowel diseases. N Engl J Med. 383(27): 2652-2664.

Saez A, Herrero-Fernandez B, Gomez-Bris R, Sanchez-Martinez H, Gonzalez-Granado JM. (2023) Pathophysiology of inflammatory bowel disease: innate immune system. Int J Mol Sci. 24(2): 1526.

Cosnes J, Gower-Rousseau C, Seksik P, Cortot A. (2011) Epidemiology and natural history of inflammatory bowel diseases. Gastroenterology. 140(6): 1785-1794.

de Souza HS, Fiocchi C. (2016) Immunopathogenesis of IBD: current state of the art. Nat Rev Gastroenterol Hepatol. 13(1): 13-27.

Park JH, Peyrin-Biroulet L, Eisenhut M, Shin JI. (2017) IBD immunopathogenesis: a comprehensive review of inflammatory molecules. Autoimmun Rev. 16(4): 416-426.

Mcguckin, M.A.; Eri, R.; Simms, L.A. Florin TH, Radford-Smith G. (2009) Intestinal barrier dysfunction in inflammatory bowel diseases. Inflamm Bowel Dis. 15:100–113

Strober, W.; Fuss, I.; Mannon P. (2007) The fundamental basis of inflammatory bowel disease. J Clin Invest. 117:514–521

Fukata, M.; Arditi, M. (2013) The role of pattern recognition receptors in intestinal inflammation. Mucosal Immunol. 6:451–463.

Grehan, J; Levay-Young, B; Fogelson, J; François-Bongarçon, V; Benson, B; Dalmasso, A. (2005) IL-4 and IL-13 Induce Protection of Porcine Endothelial Cells from Killing by Human Complement and from Apoptosis through Activation of a Phosphatidylinositide 3-Kinase/Akt Pathway. J Immunol.;175 (3)1903-1910; DOI: https://doi.org/10.4049/jimmunol.175.3.1903

Liu, J; Lin, F; Strainic, M; An, F; Miller, R; Altuntas, C; Heeger, P; Tuohy, V; Medof, M. (2008) IFN-γ and IL-17 production in Experimental Autoimmune Encephalomyelitis depends on local APC•T cell complement production. J Immunol.1; 180(9): 5882–5889. doi: 10.4049/jimmunol.180.9.5882.

Fang, C; Zhang, X; Miwa, T; Song, W. (2009) Complement promotes the development of inflammatory T-helper 17 cells through synergistic interaction with Toll-like receptor signaling and interleukin-6 production. Blood. 114 (5): 1005–1015. https://doi.org/10.1182/blood-2009-01-198283.

Bosmann, M., Sarma, J. V., Atefi, G., Zetoune, F., Ward, P. (2012) Evidence for anti-inflammatory effects of C5a on the innate IL-17A/IL-23 axis. FASEB J, 26(4): 1640–1651. doi: 10.1096/fj.11-199216

Halstensen, T.; Mollnes, T.; Garred, P.; Fausa, O.; Brandtzaeg, P. (1992) Surface epithelium related activation of complement differs in Crohn's disease and ulcerative colitis. Gut, 33,902-908

Ahrenstedt, O.; Knutson, L.; Nilsson, B.; Nilsson-Ekdahl, K.; Odlind, B.; Hällgren, R. (1990) Enhanced local production of complement components in the small intestines of patients with Crohn’s disease. N Engl J Med. 322:1345–1349.

Elmgreen, J.; Both, H.; Binder, V. (1985) Familial occurrence of complement dysfunction in Crohn’s disease: correlation with intestinal symptoms and hypercatabolism of complement. Gut. 26:151–157.

Preisker, S.; Brethack, A.; Bokemeyer, A.; Bettenworth, D.; Sina, C.; Derer, S. (2019) Crohn’s Disease Patients in Remission Display an Enhanced Intestinal IgM+ B Cell Count in Concert with a Strong. Cells. 21;8(1):78. doi: 10.3390/cells8010078.

Sina, C.; Kemper, C.; Derer, S. (2018) The intestinal complement system in inflammatory bowel disease: Shaping intestinal barrier function. Semin Immunol. 37:66-73. doi: 10.1016/j.smim.2018.02.008.

Nagao-Kitamoto H, Kitamoto S, Kamada N. (2022) Inflammatory bowel disease and carcinogenesis. Cancer Metastasis Rev. 41(2): 301-316.

Popivanova, B.K.; Kitamura, K.; Wu, Yu.; Kondo, T.; Kagaya, T.; Kaneko, S.; Oshima, M.; Fujii, C.; Mukaida, N. (2008) Blocking TNF-alpha in mice reduces colorectal carcinogenesis associated with chronic colitis. J. Clin. Invest. 118, 560–570.

Matsumoto, S.; Hara, T.; Mitsuyama, K.; Yamamoto, M.; Tsuruta, O.; Sata, M.; Scheller, J.; Rose-John, S.; Kado, S.; Takada, T. (2010) Essential roles of IL-6 trans-signaling in colonic epithelial cells, induced by the IL-6/soluble-IL-6 receptor derived from lamina propria macrophages, on the development of colitis-associated premalignant cancer in a murine model. J. Immunol. 184, 1543–1551.

Hyun, Y.S.; Han, D.S.; Lee, A.R.; EUN, C.S.; Youn, J.; Kim, H.Y. (2012) Role of IL-17A in the development of colitis-associated cancer. Carcinogenesis. 33, 931–936.

Biesiada, G.; Czepiel, J.; Ptak-Belowska, A.; Targosz, A.; Krzysiek-Maczka, G.; Strzalka, M.; Konturek, S.J.; Brzozowski, T.; Mach, T. (2012) Expression and release of leptin and proinflammatory cytokines in patients with ulcerative colitis and infectious diarrhea. J Physiol Pharmacol. 63:471–481.

Ohman, L.; Dahle´n, R.; Isaksson, S.; Sjo¨ ling, A.; Wick, M.J.; Sjövall, H.; Van, O.; Simrén, M., Hans, S. (2013) Serum IL-17A in newly diagnosed treatment-naı¨ve patients with ulcerative colitis reflects clinical disease severity and predicts the course of disease. Inflamm Bowel Dis. 19:2433–2439.

Ning, C.; Li, Y.Y.; Wang, Y.; Han, G.C.; Wang, R-X.; Xiao, H.; Li, X.Y.; Hou, C.M.; Ma, Y-F.; Sheng, D.S.; Shen, B.F.; Feng, J.N.; Guo, R.F.; Li, Y.; Chen, G.J. (2015) Complement activation promotes colitis-associated carcinogenesis through activating intestinal IL-1b/IL-17A axis. Mucosal Immunology. 8:1275–1284

Zimmer, J.; Hobkirk, J.; Mohamed, F.; Browning, M.; Stover, C. (2015) On the functional overlap between complement and anti-microbial peptides. Front. Immunol. 5.689. https://doi.org/10.3389/fimmu.2014.00689.

Peterson LW, Artis D. (2014) Intestinal epithelial cells: regulators of barrier function and immune homeostasis. Nat Rev Immunol. 14:141–52.10.1038/nri3608

Fahlgren A, Hammarström S, Danielsson Å, Hammarström M-L. Beta-defensin-3 and -4 in intestinal epithelial cells display increased mRNA expression in ulcerative colitis. Clin Exp Immunol (2004) 137:379–85.10.1111/j.1365-2249.2004.02543

O’Neil DA, Porter EM, Elewaut D, Anderson GM, Eckmann L, Ganz T, et al. (1999) Expression and regulation of the human β-defensins hBD-1 and hBD-2 in intestinal epithelium. J Immunol. 163:6718–24.

Chu H, Mazmanian SK. (2013) Innate immune recognition of the microbiota promotes host-microbial symbiosis. Nat Immunol.14:668–75.10.1038/ni.2635

Ostaff MJ, Stange EF, Wehkamp J. Antimicrobial peptides and gut microbiota in homeostasis and pathology. EMBO Mol Med (2013) 5:1465–83.10.1002/emmm.201201773

Fahlgren A, Hammarström S, Danielsson Å, Hammarström M-L. (2003) Increased expression of antimicrobial peptides and lysozyme in colonic cells of patients with ulcerative colitis. Clin Exp Immunol. 131:90–101.10.1046/j.1365-2249.2003.02035.

Natividad JMM, Hayes CL, Motta J-P, Jury J, Galipeau HJ, Philip V, et al. (2013) Differential induction of antimicrobial REGIII by the intestinal microbiota and Bifidobacterium breve NCC2950. Appl Environ Microbiol. 79:7745–54.10.1128/AEM.02470-13

Hase K, Eckmann L, Leopard JD, Varki N, Kagnoff MF. (2002) Cell differentiation is a key determinant of cathelicidin LL-37/human cationic antimicrobial protein 18 expression by human colon epithelium. Infect Immun. 70:953–63.10.1128/IAI.70.2.953-963.2002

Schauber J, Svanholm C, Termén S, Iffland K, Menzel T, Scheppach W, et al. (2003) Expression of the cathelicidin LL-37 is modulated by short chain fatty acids in colonocytes: relevance of signalling pathways. Gut. 52:735–41.10.1136/gut.52.5.735

Cash HL, Whitham CV, Behrendt CL, Hooper LV. (2006) Symbiotic bacteria direct expression of an intestinal bactericidal lectin. Science. 313:1126–30.10.1126/science.1127119

Shi J. (2007) Defensins and Paneth cells in inflammatory bowel disease. Inflamm Bowel Dis. 13:1284–92.10.1002/ibd.20197

Cunliffe RN, Mahida YR. Expression and regulation of antimicrobial peptides in the gastrointestinal tract. (2004) J Leukoc Biol. 75:49–58.10.1189/jlb.0503249

Mohamed M F, Febry T, Stover C. (2019) The Roles of Epithelial Cells in Gut Immunity. The Journal of Medical Research. 5(5):198-203

Haapamäki MM, Grönroos JM, Nurmi H, Alanen K, Kallajoki M, Nevalainen TJ. (1997) Gene expression of group II phospholipase A2 in intestine in ulcerative colitis. Gut. 40:95–101.10.1136/gut.40.1.95

Kopp, Z.; Jain, U.; Limbergen, J.V.; Stadnyk, A.W. (2015) Do Antimicrobial Peptides and Complement Collaborate in the Intestinal Mucosa?. Front Immunol. 6: 17. doi: 10.3389/fimmu.2015.00017

Zhang, L; Gallo, R.L. (2016)nAntimicrobial peptides. Current Biology. 11; 26(1): R14-9. doi: 10.1016/j.cub.2015.11.017.

Rivas-Santiago B, Serrano, C; Enciso-Moreno J.A. (2009) Susceptibility to Infectious Diseases Based on Antimicrobial Peptide Production. Infect Immun. 77(11):4690-5. doi: 10.1128/IAI.01515-08

Pazmandi, J.; Kalinichenko, A.; Chandra Ardy, R.; Boztug, K. (2019) Early-onset inflammatory bowel disease as a model disease to identify key regulators of immune homeostasis mechanisms. Immunological Reviews. 287:162–185

Jain, U.; Otley, A.; Van Limbergen, J.; Stadnyk, A.W. (2014) The Complement System in Inflammatory Bowel Disease. Inflammatory Bowel Diseases. 20 (9), 1628-1637

Berstad, A.; Brandtzaeg, P. (1998) Expression of cell membrane complement regulatory glycoproteins along the normal and diseased human gastrointestinal tract, Gut. 42 (4) 522–529.

Stengaard-Pedersen K, Thiel S, Gadjeva M, et al. (2003) Inherited deficiency of mannan-binding lectin–associated serine protease 2. N Engl J Med. 349:554‐560.

Schauer, I.G.; Zhang, J.; Xing, Z.; Guo, X.; Mercado-Uribe, I.; Sood, A.K.; Huang, P.; Liu, J. (2013) Interleukin-1beta promotes ovarian tumorigenesis through a p53/NF-kappaB-mediated inflammatory response in stromal fibroblasts. Neoplasia. 15:409–420.

Huang, Q. Lan, F.; Wang, X.; Yu, Y.; et al. (2014) IL-1beta-induced activation of p38 promotes metastasis in gastric adenocarcinoma via upregulation of AP-1/c-fos, MMP2 and MMP9. Mol. Cancer. 13, 18.

Coccia, M.; Harrison, O.J.; Schiering, C.; Asquith,M.J.; Becher, B.; Powrie, F.; Maloy, K. (2012) IL-1beta mediates chronic intestinal inflammation by promoting the accumulation of IL-17A secreting innate lymphoid cells and CD4(þ) Th17 cells. J. Exp. Med. 209, 1595–1609.

Shaw, M.H., Kamada, N., Kim, Y.G.; Nunez, G. (2012) Microbiota-induced IL-1beta, but not IL-6, is critical for the development of steady-state TH17 cells in the intestine. J. Exp. Med. 209, 251–258.

Wehkamp J, Fellermann K, Herrlinger KR, Baxmann S, Schmidt K, Schwind B, Duchrow M, Wohlschlager C, Feller AC, Stange EF. (2002) Human beta-defensin 2 but not beta-defensin 1 is expressed preferentially in colonic mucosa of inflammatory bowel disease. Eur J Gastroenterol Hepatol. 14:745–52.

Yamaguchi N, Isomoto H, Mukae H, Ishimoto H, Ohnita K, Shikuwa S, Mizuta Y, Nakazato M, Kohno S. (2009) Concentrations of alpha- and beta-defensins in plasma of patients with inflammatory bowel disease. Inflamm Res. 58:192–7

Sakurai T, Kashida H, Watanabe T, Hagiwara S, Mizushima T, Iijima H. (2014) Stress Response Protein Cirp Links Inflammation and Tumorigenesis in Colitis-Associated Cancer. Cancer Res.74:6119–28.

Sakurai T, Higashitsuji H, Kashida H, Watanabe T, Komeda Y, Nagai T, et al. (2017) The oncoprotein gankyrin promotes the development of colitis-associated cancer through activation of STAT3. Oncotarget.8:24762–76.

Ho, S; Pothoulakis, C; Koon, H.W. (2013) Antimicrobial Peptides and Colitis. Curr Pharm Des. 19(1): 40–47.

Sakurai, T; Nishiyama, H; Tomoyuki Nagai, T; Goto, S; Ogata, H; Kudo, M. (2020) Deficiency of Gankyrin in the small intestine is associated with augmented colitis accompanied by altered bacterial composition of intestinal microbiota. BMC Gastroenterology. 20:12 https://doi.org/10.1186/s12876-019-1156-0

Okayasu, I.; Hatakeyama, S.; Yamada, M.; Ohkusa, T.; Inagaki, Y.; Nakaya, R. (1990) A novel method in the induction of reliable experimental acute and chronic ulcerative colitis in mice. Gastroenterology. 98:694–702.

Elvington, M.; Schepp-Berglind, J.; Tomlinson, S. (2014) Regulation of the alternative pathway of complement modulates injury and immunity in a chronic model of dextran sulphate sodium-induced colitis. Clinical and Experimental Immunology. 179: 500–5018

Wang Y, You K, You Y, et al. (2022) Paeoniflorin prevents aberrant proliferation and differentiation of intestinal stem cells by controlling C1q release from macrophages in chronic colitis. Pharmacol Res. 182:106309.

Gunji N, Katakura K, Abe K, et al. (2021) Upregulation of complement C1q reflects mucosal regeneration in a mouse model of colitis. Med Mol Morphol. 54(2): 87-94

Johswich, K.; Martin, M.; Bleich, A.; Kracht, M.; Dittrich-Breiholz, O.; Gessner, J.E.; Suerbaum, S.; Wende, E.; Rheinheimer, C.; Klos, A. (2009) Role of the C5a receptor (C5aR) in acute and chronic dextran sulfate-induced models of inflammatory bowel disease. Inflamm. Bowel Dis. 15, 1812–1823

Rieder F, Brenmoehl J, Leeb S, Scholmerich J, Rogler G. (2007) Wound healing and fibrosis in intestinal disease. Gut. 56:130–9.

Costello, C.; Mah, N.; Ha¨ sler, R.; Rosenstiel, P.; Waetzig, G.; Hahn, A.; Lu, T.; Gurbuz, Y.; Nikolaus, S.; Albrecht, M.; Hampe, J.; Lucius, R.; Klo¨ppel, G.; Eickhoff, H.; Lehrach, H.; Lengauer, T.; Schreiber, S. (2005) Dissection of the Inflammatory Bowel Disease Transcriptome Using Genome-Wide cDNA Microarrays. PLoS Med. 2(8): e199. doi: 10.1371/journal.pmed.0020199.

Dobre, M; Milanesi, E; Mănuc, T.E; Arsene, D.E; Ţieranu, C.G; Maj, C; Becheanu, G; Mănuc, M. (2018) Differential Intestinal Mucosa Transcriptomic Biomarkers for Crohn’s Disease and Ulcerative Colitis. Journal of Immunology Research. Article ID 9208274, 10 pages https://doi.org/10.1155/2018/9208274.

Hsu, Y.M; Zhang, Y; You, Y; Wang, D; Li, H; Duramad, O; Qin, X; Dong, C; Lin, X. The adaptor protein CARD9 is required for innate immune responses to intracellular pathogens. Nat. Immunol. 2007. 8, 198–205.

Dorhoi, A; Desel, C; Yeremeev, V; Pradl, L; Brinkmann, V; Mollenkopf, H.J; Hanke, K; Gross, O; Ruland, J; Kaufmann, S. (2010) The adaptor molecule CARD9 is essential for tuberculosis control. J. Exp. Med. 207, 777–792.

Hara, H. & Saito, T. (2009) CARD9 versus CARMA1 in innate and adaptive immunity.Trends Immunol. 30, 234–242.

Sokol, H. et al. Card9 mediates intestinal epithelial cell restitution, T-helper 17 responses, and control of bacterial infection in mice. Gastroenterology, 2013,145, 591–601.

Lamas, B., Richard, M. L. & Sokol, H. (2016) CARD9 is involved in the recovery of colitis by promoting the production of AhR ligands by the intestinal microbiota. Med. Sci. 32, 933–936.

Zhong, X; Chen, B; Yang, L; Yang, Z. (2018) Molecular and physiological roles of the adaptor protein CARD9 in immunity. Cell Death and Disease. 9:52 DOI 10.1038/s41419-017-0084-6

Longhi, M.P.; Harris, C.L.; Morgan, B.P.; Gallimore, A. (2006) Holding T cells in check – a new role for complement regulators? Trends Immunol. 27:102–8.

Carroll M.C. The complement system in regulation of adaptive immunity. Nat Immunol. 2004;5:981–6

Denson, L.A. (2013) The Role of the Innate and Adaptive Immune System in Pediatric Inflammatory Bowel Disease. Inflamm Bowel Dis. 19(9): 2011–2020. doi: 10.1097/MIB.0b013e318281f590.

Holleran, G; Lopetuso, L; Petito, V; Graziani, C; Ianiro, G; McNamara, D; Antonio Gasbarrini, A; Scaldaferri, F. The Innate and Adaptive Immune System as Targets for Biologic Therapies in Inflammatory Bowel Disease. Int J Mol Sci. 2017. 18(10): 2020. doi: 10.3390/ijms18102020.

Dasgupta S, Erturk-Hasdemir D, Ochoa-Reparaz J, Reinecker HC, Kasper DL. (2014) Plasmacytoid dendritic cells mediate anti-inflammatory responses to a gut commensal molecule via both innate and adaptive mechanisms. Cell Host Microbe. 15:413–23. 10.1016/j.chom.2014.03.006

Round JL, Mazmanian SK. (2010) Inducible Foxp3+ regulatory T-cell development by a commensal bacterium of the intestinal microbiota. Proc Natl Acad Sci USA.107:12204–9. 10.1073/pnas.0909122107

Telesford KM, Yan W, Ochoa-Reparaz J, Pant A, Kircher C, Christy MA, et al. A commensal symbiotic factor derived from Bacteroides fragilis promotes human CD39(+)Foxp3(+) T cells and Treg function. Gut Microbes. 2015, 6:234–42. 10.1080/19490976.2015.1056973

Sorbara MT, Foerster EG, Tsalikis J, Abdel-Nour M, Mangiapane J, Sirluck-Schroeder I, et al. (2018) Complement C3 Drives Autophagy-Dependent Restriction of Cyto-invasive Bacteria. Cell Host Microbe. 23(5):644–52 e5.

pathophysiology of inflammatory bowel disease?. Mol Immunol. 90:227–38.

Moriel DG, Rosini R, Seib KL, Serino L, Pizza M, Rappuoli R. Escherichia coli: great diversity around a common core. mBio. 2012, 3(3).

Lee JG, Han DS, Jo SV, Lee AR, Park CH, Eun CS, et al. (2019) Characteristics and pathogenic role of adherent-invasive Escherichia coli in inflammatory bowel disease: Potential impact on clinical outcomes. PLoS One. 14(4):e0216165.

Palmela C, Chevarin C, Xu Z, Torres J, Sevrin G, Hirten R, et al. (2018) Adherent-invasive Escherichia coli in inflammatory bowel disease. Gut. 67(3):574–87.

Liu TC, Stappenbeck TS. (2016) Genetics and Pathogenesis of Inflammatory Bowel Disease. Annu Rev Pathol. 11:127–48.

Castellanos JG, Woo V, Viladomiu M, Putzel G, Lima S, Diehl GE, et al. (2018) Microbiota-Induced TNF-like Ligand 1A Drives Group 3 Innate Lymphoid Cell-Mediated Barrier Protection and Intestinal T Cell Activation during Colitis. Immunity. 49(6):1077–89 e5.

Geremia A, Arancibia-Carcamo CV, Fleming MP, Rust N, Singh B, Mortensen NJ, et al. (2011) IL-23-responsive innate lymphoid cells are increased in inflammatory bowel disease. J Exp Med. 208(6):1127–33.

Nissilä, E.; Korpela, K.; Lokki, A .; Paakkanen, R .; Jokiranta, S.; de Vos M.W.; Lokki, M.; Kolho, K.; Meri, S. C4B gene influences intestinal microbiota through complement activation in patients with paediatric-onset inflammatory bowel disease. Clin Exp Immunol. 2017. 190(3):394-405. doi: 10.1111/cei.13040.

التنزيلات

منشور

2024-08-11

كيفية الاقتباس

mohamed, fatima (2024) "The Role of the Complement System in Chronic Intestinal Inflammation", المجلة الليبية للعلوم, 27(2). موجود في: http://uot.edu.ly/journals/index.php/ljs/article/view/885 (تاريخ الوصول: 17 أغسطس 2024).

إصدار

القسم

Zoology

الفئات

#