The CARD8 p.C10X mutation associates with a low anti-glycans antibody response in patients with Crohn’s disease

BMC Medical Genetics

Thierry Jouault²  Daniel Poulain²  Jean-Frederic Colombel²  Annie Standaert-Vitse²  Aurore Sarazin¹  Corinne Gower-Rousseau²  Franck Broly²  Boualem Sendid²  Francis Vasseur² 

[1] Inserm U995, Team 2, Faculté de Médecine H. Warembourg, Pôle Recherche, Place Verdun, Lille, F-59000, France;CHRU Lille, Lille, 59000, France

关键词: Adaptive immunity;    Inflammasome;    ASCA/ALCA;    CARD8/TUCAN;    Anti-glycan antibodies;    Crohn's disease;   

Others  :  1177718
DOI  :  10.1186/1471-2350-14-35

 received in 2012-06-19, accepted in 2013-03-13,  发布年份 2013

【 摘 要 】

Background

Crohn’s disease (CD) is associated with elevated anti-glycans antibody response in 60% of CD patients, and 25% of healthy first-degree relatives (HFDRs), suggesting a genetic influence for this humoral response. In mice, anti-glucan antibody response depends on the NLRP3 inflammasome. Here, we explored the effect of mutated CARD8, a component of the inflammasome, on anti-glycans antibody response in human.

Methods

The association between p.C10X mutation (rs2043211) of the CARD8 gene and the levels of anti-glycans antibody response was examined in 39 CD families. The family-based QTDT association test was used to test for the genetic association between CARD8 p.C10X mutation and anti-glycan antibodies in the pedigrees. The difference in antibody responses determined by ELISA was tested in a subgroup of CD probands (one per family) and in a subgroup of HFDRs using the Wilcoxon Kruskal Wallis non-parametric test.

Results

The QTDT familial transmission tests showed that the p.C10X mutation of CARD8 was significantly associated with lower levels of antibody to mannans and glucans but not chitin (p=0.024, p=0.0028 and p=0.577, for ASCA, ALCA and ACCA, respectively). These associations were independent of NOD2 and NOD1 genetic backgrounds. The p.C10X mutation significantly associated or displayed a trend toward lower ASCA and ALCA levels (p=0.038 and p=0.08, respectively) only in the subgroup of CD probands. Such associations were not significant for ACCA levels in both subgroups of CD probands and of HFDRs.

Conclusion

Our results show that ASCA and ALCA but not ACCA levels are under the influence of CARD8 genotype. Alteration of CARD8, a component of inflammasome, is associated with lower levels of antibodies directed to mannans and glucans at least in CD patients.

【 授权许可】

   
2013 Vasseur et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

【 参考文献 】

• [1]Alavi A, Axford JS: Sweet and sour: the impact of sugars on disease. Rheumatology (Oxford) 2008, 47(6):760-770.
• [2]Sendid B, Poirot JL, Tabouret M, Bonnin A, Caillot D, Camus D, Poulain D: Combined detection of mannanaemia and antimannan antibodies as a strategy for the diagnosis of systemic infection caused by pathogenic Candida species. J Med Microbiol 2002, 51(5):433-442.
• [3]Quinton JF, Sendid B, Reumaux D, Duthilleul P, Cortot A, Grandbastien B, Charrier G, Targan SR, Colombel JF, Poulain D: Anti-Saccharomyces cerevisiae mannan antibodies combined with antineutrophil cytoplasmic autoantibodies in inflammatory bowel disease: prevalence and diagnostic role. Gut 1998, 42(6):788-791.
• [4]Hedin CR, Stagg AJ, Whelan K, Lindsay JO: Family studies in Crohn's disease: new horizons in understanding disease pathogenesis, risk and prevention. Gut 2012, 61(2):311-318.
• [5]Poulain D, Sendid B, Fajardy I, Danze PM, Colombel JF: Mother to child transmission of anti-S cerevisiae mannan antibodies (ASCA) in non-IBD families. Gut 2000, 47(6):870-871.
• [6]Vermeire S, Joossens S, Peeters M, Monsuur F, Marien G, Bossuyt X, Groenen P, Vlietinck R, Rutgeerts P: Comparative study of ASCA (Anti-Saccharomyces cerevisiae Antibody) assays in inflammatory bowel disease. Gastroenterology 2001, 120(4):827-833.
• [7]Sendid B, Quinton JF, Charrier G, Goulet O, Cortot A, Grandbastien B, Poulain D, Colombel JF: Anti-Saccharomyces cerevisiae mannan antibodies in familial Crohn's disease. Am J Gastroenterol 1998, 93(8):1306-1310.
• [8]Standaert-Vitse A, Jouault T, Vandewalle P, Mille C, Seddik M, Sendid B, Mallet J-M, Colombel J-F, Poulain D: Candida albicans is an immunogen for anti-Saccharomyces cerevisiae antibody markers of Crohn's disease. Gastroenterology 2006, 130(6):1764-1775.
• [9]Dotan I, Fishman S, Dgani Y, Schwartz M, Karban A, Lerner A, Weishauss O, Spector L, Shtevi A, Altstock RT: Antibodies against laminaribioside and chitobioside are novel serologic markers in Crohn's disease. Gastroenterology 2006, 131(2):366-378.
• [10]Sendid B, Dotan N, Nseir S, Savaux C, Vandewalle P, Standaert A, Zerimech F, Guery BP, Dukler A, Colombel JF: Antibodies against glucan, chitin, and Saccharomyces cerevisiae mannan as new biomarkers of Candida albicans infection that complement tests based on C. albicans mannan. Clin Vaccine Immunol 2008, 15(12):1868-1877.
• [11]Franke A, McGovern DPB, Barrett JC, Wang K, Radford-Smith GL, Ahmad T, Lees CW, Balschun T, Lee J, Roberts R: Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. Nat Genet 2010, 42(12):1118-1125.
• [12]Hugot JP, Chamaillard M, Zouali H, Lesage S, Cézard JP, Belaiche J, Almer S, Tysk C, O'Morain CA, Gassull M: Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature 2001, 411(6837):599-603.
• [13]Bouchier-Hayes L, Conroy H, Egan H, Adrain C, Creagh EM, MacFarlane M, Martin SJ: CARDINAL, a novel caspase recruitment domain protein, is an inhibitor of multiple NF-kappa B activation pathways. J Biol Chem 2001, 276(47):44069-44077.
• [14]Agostini L, Martinon F, Burns K, McDermott MF, Hawkins PN, Tschopp J: NALP3 forms an IL-1beta-processing inflammasome with increased activity in Muckle-Wells autoinflammatory disorder. Immunity 2004, 20(3):319-325.
• [15]Martinon F, Tschopp J: Inflammatory caspases: linking an intracellular innate immune system to autoinflammatory diseases. Cell 2004, 117(5):561-574.
• [16]Hornung V, Bauernfeind F, Halle A, Samstad EO, Kono H, Rock KL, Fitzgerald KA, Latz E: Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nat Immunol 2008, 9(8):847-856.
• [17]Hise AG, Tomalka J, Ganesan S, Patel K, Hall BA, Brown GD, Fitzgerald KA: An essential role for the NLRP3 inflammasome in host defense against the human fungal pathogen Candida albicans. Cell Host Microbe 2009, 5(5):487-497.
• [18]Joly S, Ma N, Sadler JJ, Soll DR, Cassel SL, Sutterwala FS: Cutting edge: Candida albicans hyphae formation triggers activation of the Nlrp3 inflammasome. J Immunol 2009, 183(6):3578-3581.
• [19]Kumar H, Kumagai Y, Tsuchida T, Koenig PA, Satoh T, Guo Z, Jang MH, Saitoh T, Akira S, Kawai T: Involvement of the NLRP3 inflammasome in innate and humoral adaptive immune responses to fungal beta-glucan. J Immunol 2009, 183(12):8061-8067.
• [20]Saïd-Sadier N, Padilla E, Langsley G, Ojcius DM: Aspergillus fumigatus stimulates the NLRP3 inflammasome through a pathway requiring ROS production and the Syk tyrosine kinase. PLoS One 2010, 5(4):e10008.
• [21]Bellocchio S, Montagnoli C, Bozza S, Gaziano R, Rossi G, Mambula SS, Vecchi A, Mantovani A, Levitz SM, Romani L: The contribution of the Toll-like/IL-1 receptor superfamily to innate and adaptive immunity to fungal pathogens in vivo. J Immunol 2004, 172(5):3059-3069.
• [22]Mencacci A, Bacci A, Cenci E, Montagnoli C, Fiorucci S, Casagrande A, Flavell RA, Bistoni F, Romani L: Interleukin 18 restores defective Th1 immunity to Candida albicans in caspase 1-deficient mice. Infect Immun 2000, 68(9):5126-5131.
• [23]Netea MG, Simon A, van de Veerdonk F, Kullberg B-J, van der Meer JWM, Joosten LAB: IL-1beta Processing in Host Defense: Beyond the Inflammasomes. PLoS Pathog 2010, 6(2):e1000661.
• [24]Stuyt RJL, Netea MG, Verschueren I, Fantuzzi G, Dinarello CA, van der Meer JWM, Kullberg BJ: Role of interleukin-18 in host defense against disseminated Candida albicans infection. Infect Immun 2002, 70(6):3284-3286.
• [25]Vonk AG, Netea MG, van Krieken JH, Iwakura Y, van der Meer JWM, Kullberg BJ: Endogenous interleukin (IL)-1 alpha and IL-1 beta are crucial for host defense against disseminated candidiasis. J Infect Dis 2006, 193(10):1419-1426.
• [26]Eisenbarth SC, Colegio OR, O'Connor W, Sutterwala FS, Flavell RA: Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants. Nature 2008, 453(7198):1122-1126.
• [27]Kool M, Pétrilli V, De Smedt T, Rolaz A, Hammad H, van Nimwegen M, Bergen IM, Castillo R, Lambrecht BN, Tschopp J: Cutting edge: alum adjuvant stimulates inflammatory dendritic cells through activation of the NALP3 inflammasome. J Immunol 2008, 181(6):3755-3759.
• [28]Kankkunen P, Teirilä L, Rintahaka J, Alenius H, Wolff H, Matikainen S: (1,3)-{beta}-Glucans Activate Both Dectin-1 and NLRP3 Inflammasome in Human Macrophages. J Immunol 2010, 184(11):6335-6342.
• [29]Petterson T, Jendholm J, Månsson A, Bjartell A, Riesbeck K, Cardell L-O: Effects of NOD-like receptors in human B lymphocytes and crosstalk between NOD1/NOD2 and Toll-like receptors. J Leukoc Biol 2010, 89(2):177-187.
• [30]Vasseur F, Sendid B, Jouault T, Standaert-Vitse A, Dubuquoy L, Francois N, Gower-Rousseau C, Desreumaux P, Broly F, Vermeire S: Variants of NOD1 and NOD2 genes display opposite associations with familial risk of Crohn's disease and anti-saccharomyces cerevisiae antibody levels. Inflamm Bowel Dis 2012, 18(3):430-438.
• [31]Dassopoulos T, Frangakis C, Cruz-Correa M, Talor MV, Burek CL, Datta L, Nouvet F, Bayless TM, Brant SR: Antibodies to saccharomyces cerevisiae in Crohn's disease: higher titers are associated with a greater frequency of mutant NOD2/CARD15 alleles and with a higher probability of complicated disease. Inflamm Bowel Dis 2007, 13(2):143-151.
• [32]Henckaerts L, Pierik M, Joossens M, Ferrante M, Rutgeerts P, Vermeire S: Mutations in pattern recognition receptor genes modulate seroreactivity to microbial antigens in patients with inflammatory bowel disease. Gut 2007, 56(11):1536-1542.
• [33]Kastbom A, Johansson M, Verma D, Soderkvist P, Rantapaa-Dahlqvist S: CARD8 p.C10X polymorphism is associated with inflammatory activity in early rheumatoid arthritis. Ann Rheum Dis 2010, 69(4):723-726.
• [34]McGovern DPB, Butler H, Ahmad T, Paolucci M, van Heel DA, Negoro K, Hysi P, Ragoussis J, Travis SPL, Cardon LR: TUCAN (CARD8) genetic variants and inflammatory bowel disease. Gastroenterology 2006, 131(4):1190-1196.
• [35]Roberts RL, Topless RK, Phipps-Green AJ, Gearry RB, Barclay ML, Merriman TR: Evidence of interaction of CARD8 rs2043211 with NALP3 rs35829419 in Crohn's disease. Genes Immun 2010, 11(4):351-356.
• [36]Schoultz I, Verma D, Halfvarsson J, Törkvist L, Fredrikson M, Sjöqvist U, Lördal M, Tysk C, Lerm M, Söderkvist P: Combined polymorphisms in genes encoding the inflammasome components NALP3 and CARD8 confer susceptibility to Crohn's disease in Swedish men. Am J Gastroenterol 2009, 104(5):1180-1188.
• [37]Molinié F, Gower-Rousseau C, Yzet T, Merle V, Grandbastien B, Marti R, Lerebours E, Dupas J-L, Colombel J-F, Salomez J-L: Opposite evolution in incidence of Crohn's disease and ulcerative colitis in Northern France (1988–1999). Gut 2004, 53(6):843-848.
• [38]Satsangi J, Silverberg MS, Vermeire S, Colombel J-F: The Montreal classification of inflammatory bowel disease: controversies, consensus, and implications. Gut 2006, 55(6):749-753.
• [39]Barrett JC, Fry B, Maller J, Daly MJ: Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005, 21(2):263-265.
• [40]Abecasis GR, Cardon LR, Cookson WO: A general test of association for quantitative traits in nuclear families. Am J Hum Genet 2000, 66(1):279-292.
• [41]Sham PC, Curtis D: Monte Carlo tests for associations between disease and alleles at highly polymorphic loci. Ann Hum Genet 1995, 59(Pt 1):97-105.
• [42]Li X, Conklin L, Alex P: New serological biomarkers of inflammatory bowel disease. World J Gastroenterol 2008, 14(33):5115-5124.
• [43]Standaert-Vitse A, Sendid B, Joossens M, François N, Vandewalle-El Khoury P, Branche J, Van Kruiningen H, Jouault T, Rutgeerts P, Gower-Rousseau C: Candida albicans Colonization and ASCA in Familial Crohn's Disease. Am J Gastroenterol 2009, 104(7):1745-1753.
• [44]Fisher SA, Mirza MM, Onnie CM, Soars D, Lewis CM, Prescott NJ, Mathew CG, Sanderson J, Forbes A, Todhunter C: Combined evidence from three large British Association studies rejects TUCAN/CARD8 as an IBD susceptibility gene. Gastroenterology 2007, 132(5):2078-2080.
• [45]Yang S-K, Kim H, Hong M, Lim J, Choi E, Ye BD, Park S-K, Song K: Association of CARD8 with inflammatory bowel disease in Koreans. J Hum Genet 2011, 56(3):217-223.
• [46]Takedatsu H, Taylor KD, Mei L, Mcgovern DPB, Landers CJ, Gonsky R, Cong Y, Vasiliauskas EA, Ippoliti A, Elson CO: Linkage of Crohn's disease-related serological phenotypes: NFKB1 haplotypes are associated with anti-CBir1 and ASCA, and show reduced NF-kappaB activation. Gut 2009, 58(1):60-67.
• [47]von Kampen O, Lipinski S, Till A, Martin SJ, Nietfeld W, Lehrach H, Schreiber S, Rosenstiel P: Caspase recruitment domain-containing protein 8 (CARD8) negatively regulates NOD2-mediated signaling. J Biol Chem 2010, 285(26):19921-19926.
• [48]Dinarello CA: IL-1: Discoveries, controversies and future directions. Eur J Immunol 2010, 40(3):599-606.
• [49]Nambu A, Nakae S, Iwakura Y: IL-1beta, but not IL-1alpha, is required for antigen-specific T cell activation and the induction of local inflammation in the delayed-type hypersensitivity responses. Int Immunol 2006, 18(5):701-712.
• [50]Harnack U, Kellermann U, Pecher G: Yeast-derived Beta-(1–3), (1–6)-D-glucan Induces Up-regulation of CD86 on Dectin-1-positive Human B-Lymphoma Cell Lines. Anticancer Res 2011, 31(12):4195-4199.
• [51]Puga I, Cols M, Barra CM, He B, Cassis L, Gentile M, Comerma L, Chorny A, Shan M, Xu W: B cell–helper neutrophils stimulate the diversification and production of immunoglobulin in the marginal zone of the spleen. Nat Immunol 2011, 13(2):170-180.
• [52]Bordon Y: Antibody responses: Neutrophils zone in to help B cells. Nat Rev Immunol 2012, 12(2):73.
• [53]Dharancy S, Body-Malapel M, Louvet A, Berrebi D, Gantier E, Gosset P, Viala J, Hollebecque A, Moreno C, Philpott DJ: Neutrophil migration during liver injury is under nucleotide-binding oligomerization domain 1 control. Gastroenterology 2010, 138(4):1546-1556. 1556 e1541-1545
• [54]Russell RK, Ip B, Aldhous MC, MacDougall M, Drummond HE, Arnott IDR, Gillett PM, McGrogan P, Weaver LT, Bisset WM: Anti-Saccharomyces cerevisiae antibodies status is associated with oral involvement and disease severity in Crohn disease. J Pediatr Gastroenterol Nutr 2009, 48(2):161-167.
• [55]Walker LJ, Aldhous MC, Drummond HE, Smith BRK, Nimmo ER, Arnott IDR, Satsangi J: Anti-Saccharomyces cerevisiae antibodies (ASCA) in Crohn's disease are associated with disease severity but not NOD2/CARD15 mutations. Clin Exp Immunol 2004, 135(3):490-496.
• [56]Dinarello CA: Immunological and inflammatory functions of the interleukin-1 family. Annu Rev Immunol 2009, 27:519-550.
• [57]Rehaume LM, Jouault T, Chamaillard M: Lessons from the inflammasome: a molecular sentry linking Candida and Crohn's disease. Trends Immunol 2010, 31(5):171-175.