Skip to main content
Top
Published in: BMC Immunology 1/2014

Open Access 01-12-2014 | Research article

Evidence for non-neutralizing autoantibodies against IL-10 signalling components in patients with inflammatory bowel disease

Published in: BMC Immunology | Issue 1/2014

Login to get access

Abstract

Background

Inflammatory bowel disease constitutes a heterogeneous group of conditions, whose aetiology is only partly understood. The prevailing hypothesis on its pathogenesis is that IBD is the result of an inadequate immune response to the resident bacterial flora of the intestine. An autoimmune background, however, has been discussed since the 1950s. Lately, it has been shown that failures in interleukin-10 (IL-10) signalling due to IL-10- and IL-10 receptor (IL-10R) mutations result in IBD. Our study aimed at investigating the existence of inhibitory autoantibodies against IL-10 and IL-10R in IBD patients capable of down-modulating IL-10 signalling thereby mimicking IL-10 or IL-10R deficiency.

Results

Thirteen IBD patients had IgG autoantibodies against IL-10, IL-10RA and/or IL-10RB, and three patients had IgA autoantibodies against IL-10. However, the absolute OD values of the serum antibodies measured by ELISA were low, there was overall no significant difference between patients and controls, and positive sera had no neutralizing activity.

Conclusion

No evidence for an involvement of autoantibodies against IL-10 or IL-10R in the pathogenesis of inflammatory bowel disease could be established.
Appendix
Available only for authorised users
Literature
1.
go back to reference Baumgart DC, Sandborn WJ: Inflammatory bowel disease: clinical aspects and established and evolving therapies. Lancet. 2007, 369: 1641-1657. 10.1016/S0140-6736(07)60751-X.PubMedCrossRef Baumgart DC, Sandborn WJ: Inflammatory bowel disease: clinical aspects and established and evolving therapies. Lancet. 2007, 369: 1641-1657. 10.1016/S0140-6736(07)60751-X.PubMedCrossRef
2.
go back to reference Baumgart DC, Carding SR: Inflammatory bowel disease: cause and immunobiology. Lancet. 2007, 369: 1627-1640. 10.1016/S0140-6736(07)60750-8.PubMedCrossRef Baumgart DC, Carding SR: Inflammatory bowel disease: cause and immunobiology. Lancet. 2007, 369: 1627-1640. 10.1016/S0140-6736(07)60750-8.PubMedCrossRef
3.
go back to reference Hayee B, Rahman FZ, Sewell G, Smith AM, Segal AW: Crohn’s disease as an immunodeficiency. Expert Rev Clin Immunol. 2010, 6: 585-596. 10.1586/eci.10.32.PubMedPubMedCentralCrossRef Hayee B, Rahman FZ, Sewell G, Smith AM, Segal AW: Crohn’s disease as an immunodeficiency. Expert Rev Clin Immunol. 2010, 6: 585-596. 10.1586/eci.10.32.PubMedPubMedCentralCrossRef
4.
go back to reference Smith AM, Rahman FZ, Hayee B, Graham SJ, Marks DJ, Sewell GW, Palmer CD, Wilde J, Foxwell BM, Gloger IS, Sweeting T, Marsh M, Walker AP, Bloom SL, Segal AW: Disordered macrophage cytokine secretion underlies impaired acute inflammation and bacterial clearance in Crohn’s disease. J Exp Med. 2009, 206: 1883-1897. 10.1084/jem.20091233.PubMedPubMedCentralCrossRef Smith AM, Rahman FZ, Hayee B, Graham SJ, Marks DJ, Sewell GW, Palmer CD, Wilde J, Foxwell BM, Gloger IS, Sweeting T, Marsh M, Walker AP, Bloom SL, Segal AW: Disordered macrophage cytokine secretion underlies impaired acute inflammation and bacterial clearance in Crohn’s disease. J Exp Med. 2009, 206: 1883-1897. 10.1084/jem.20091233.PubMedPubMedCentralCrossRef
5.
go back to reference Cheng LE, Kanwar B, Tcheurekdjian H, Grenert JP, Muskat M, Heyman MB, McCune JM, Wara DW: Persistent systemic inflammation and atypical enterocolitis in patients with NEMO syndrome. Clin Immunol. 2009, 132: 124-131. 10.1016/j.clim.2009.03.514.PubMedPubMedCentralCrossRef Cheng LE, Kanwar B, Tcheurekdjian H, Grenert JP, Muskat M, Heyman MB, McCune JM, Wara DW: Persistent systemic inflammation and atypical enterocolitis in patients with NEMO syndrome. Clin Immunol. 2009, 132: 124-131. 10.1016/j.clim.2009.03.514.PubMedPubMedCentralCrossRef
6.
go back to reference Pachlopnik SJ, Canioni D, Moshous D, Touzot F, Mahlaoui N, Hauck F, Kanegane H, Lopez-Granados E, Mejstrikova E, Pellier I, Galicier L, Galambrun C, Barlogis V, Bordigoni P, Fourmaintraux A, Hamidou M, Dabadie A, Le DF, Haerynck F, Ouachee-Chardin M, Rohrlich P, Stephan JL, Lenoir C, Rigaud S, Lambert N, Milili M, Schiff C, Chapel H, Picard C, de Saint BG, Blanche S, Fischer A, Latour S: Clinical similarities and differences of patients with X-linked lymphoproliferative syndrome type 1 (XLP-1/SAP deficiency) versus type 2 (XLP-2/XIAP deficiency). Blood. 2011, 117: 1522-1529. 10.1182/blood-2010-07-298372.CrossRef Pachlopnik SJ, Canioni D, Moshous D, Touzot F, Mahlaoui N, Hauck F, Kanegane H, Lopez-Granados E, Mejstrikova E, Pellier I, Galicier L, Galambrun C, Barlogis V, Bordigoni P, Fourmaintraux A, Hamidou M, Dabadie A, Le DF, Haerynck F, Ouachee-Chardin M, Rohrlich P, Stephan JL, Lenoir C, Rigaud S, Lambert N, Milili M, Schiff C, Chapel H, Picard C, de Saint BG, Blanche S, Fischer A, Latour S: Clinical similarities and differences of patients with X-linked lymphoproliferative syndrome type 1 (XLP-1/SAP deficiency) versus type 2 (XLP-2/XIAP deficiency). Blood. 2011, 117: 1522-1529. 10.1182/blood-2010-07-298372.CrossRef
8.
go back to reference Begue B, Verdier J, Rieux-Laucat F, Goulet O, Morali A, Canioni D, Hugot JP, Daussy C, Verkarre V, Pigneur B, Fischer A, Klein C, Cerf-Bensussan N, Ruemmele FM: Defective IL-10 signaling defining a subgroup of patients with inflammatory bowel disease. Am J Gastroenterol. 2011, 106: 1544-1555. 10.1038/ajg.2011.112.PubMedCrossRef Begue B, Verdier J, Rieux-Laucat F, Goulet O, Morali A, Canioni D, Hugot JP, Daussy C, Verkarre V, Pigneur B, Fischer A, Klein C, Cerf-Bensussan N, Ruemmele FM: Defective IL-10 signaling defining a subgroup of patients with inflammatory bowel disease. Am J Gastroenterol. 2011, 106: 1544-1555. 10.1038/ajg.2011.112.PubMedCrossRef
9.
go back to reference Glocker EO, Kotlarz D, Boztug K, Gertz EM, Schaffer AA, Noyan F, Perro M, Diestelhorst J, Allroth A, Murugan D, Hatscher N, Pfeifer D, Sykora KW, Sauer M, Kreipe H, Lacher M, Nustede R, Woellner C, Baumann U, Salzer U, Koletzko S, Shah N, Segal AW, Sauerbrey A, Buderus S, Snapper SB, Grimbacher B, Klein C: Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. N Engl J Med. 2009, 361: 2033-2045. 10.1056/NEJMoa0907206.PubMedPubMedCentralCrossRef Glocker EO, Kotlarz D, Boztug K, Gertz EM, Schaffer AA, Noyan F, Perro M, Diestelhorst J, Allroth A, Murugan D, Hatscher N, Pfeifer D, Sykora KW, Sauer M, Kreipe H, Lacher M, Nustede R, Woellner C, Baumann U, Salzer U, Koletzko S, Shah N, Segal AW, Sauerbrey A, Buderus S, Snapper SB, Grimbacher B, Klein C: Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. N Engl J Med. 2009, 361: 2033-2045. 10.1056/NEJMoa0907206.PubMedPubMedCentralCrossRef
10.
go back to reference Glocker EO, Frede N, Perro M, Sebire N, Elawad M, Shah N, Grimbacher B: Infant colitis–it’s in the genes. Lancet. 2010, 376: 1272-10.1016/S0140-6736(10)61008-2.PubMedCrossRef Glocker EO, Frede N, Perro M, Sebire N, Elawad M, Shah N, Grimbacher B: Infant colitis–it’s in the genes. Lancet. 2010, 376: 1272-10.1016/S0140-6736(10)61008-2.PubMedCrossRef
11.
go back to reference de Waal MR, Abrams J, Bennett B, Figdor CG, de Vries JE: Interleukin 10 (IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes. J Exp Med. 1991, 174: 1209-1220. 10.1084/jem.174.5.1209.CrossRef de Waal MR, Abrams J, Bennett B, Figdor CG, de Vries JE: Interleukin 10 (IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes. J Exp Med. 1991, 174: 1209-1220. 10.1084/jem.174.5.1209.CrossRef
12.
go back to reference Moore KW, de Waal MR, Coffman RL, O’Garra A: Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol. 2001, 19: 683-765. 10.1146/annurev.immunol.19.1.683.PubMedCrossRef Moore KW, de Waal MR, Coffman RL, O’Garra A: Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol. 2001, 19: 683-765. 10.1146/annurev.immunol.19.1.683.PubMedCrossRef
13.
go back to reference Williams LM, Ricchetti G, Sarma U, Smallie T, Foxwell BM: Interleukin-10 suppression of myeloid cell activation–a continuing puzzle. Immunology. 2004, 113: 281-292. 10.1111/j.1365-2567.2004.01988.x.PubMedPubMedCentralCrossRef Williams LM, Ricchetti G, Sarma U, Smallie T, Foxwell BM: Interleukin-10 suppression of myeloid cell activation–a continuing puzzle. Immunology. 2004, 113: 281-292. 10.1111/j.1365-2567.2004.01988.x.PubMedPubMedCentralCrossRef
15.
go back to reference Das KM, Dasgupta A, Mandal A, Geng X: Autoimmunity to cytoskeletal protein tropomyosin. A clue to the pathogenetic mechanism for ulcerative colitis. J Immunol. 1993, 150: 2487-2493.PubMed Das KM, Dasgupta A, Mandal A, Geng X: Autoimmunity to cytoskeletal protein tropomyosin. A clue to the pathogenetic mechanism for ulcerative colitis. J Immunol. 1993, 150: 2487-2493.PubMed
16.
go back to reference Lundgren BA, Rorsman F, Portela-Gomes GM, Grimelius L, Ekdahl KN, Nilsson B, Ekwall O: Identification of complement C3 as an autoantigen in inflammatory bowel disease. Eur J Gastroenterol Hepatol. 2010, 22: 429-436. 10.1097/MEG.0b013e32833283b1.PubMedCrossRef Lundgren BA, Rorsman F, Portela-Gomes GM, Grimelius L, Ekdahl KN, Nilsson B, Ekwall O: Identification of complement C3 as an autoantigen in inflammatory bowel disease. Eur J Gastroenterol Hepatol. 2010, 22: 429-436. 10.1097/MEG.0b013e32833283b1.PubMedCrossRef
17.
go back to reference Rahbar A, Bostrom L, Soderberg-Naucler C: Detection of cytotoxic CD13-specific autoantibodies in sera from patients with ulcerative colitis and Crohn’s disease. J Autoimmun. 2006, 26: 155-164. 10.1016/j.jaut.2006.02.003.PubMedCrossRef Rahbar A, Bostrom L, Soderberg-Naucler C: Detection of cytotoxic CD13-specific autoantibodies in sera from patients with ulcerative colitis and Crohn’s disease. J Autoimmun. 2006, 26: 155-164. 10.1016/j.jaut.2006.02.003.PubMedCrossRef
18.
go back to reference Roggenbuck D, Hausdorf G, Martinez-Gamboa L, Reinhold D, Buttner T, Jungblut PR, Porstmann T, Laass MW, Henker J, Buning C, Feist E, Conrad K: Identification of GP2, the major zymogen granule membrane glycoprotein, as the autoantigen of pancreatic antibodies in Crohn’s disease. Gut. 2009, 58: 1620-1628. 10.1136/gut.2008.162495.PubMedCrossRef Roggenbuck D, Hausdorf G, Martinez-Gamboa L, Reinhold D, Buttner T, Jungblut PR, Porstmann T, Laass MW, Henker J, Buning C, Feist E, Conrad K: Identification of GP2, the major zymogen granule membrane glycoprotein, as the autoantigen of pancreatic antibodies in Crohn’s disease. Gut. 2009, 58: 1620-1628. 10.1136/gut.2008.162495.PubMedCrossRef
19.
go back to reference Ebert EC, Panja A, Das KM, Praveen R, Geng X, Rezac C, Bajpai M: Patients with inflammatory bowel disease may have a transforming growth factor-beta-, interleukin (IL)-2- or IL-10-deficient state induced by intrinsic neutralizing antibodies. Clin Exp Immunol. 2009, 155: 65-71. 10.1111/j.1365-2249.2008.03802.x.PubMedPubMedCentralCrossRef Ebert EC, Panja A, Das KM, Praveen R, Geng X, Rezac C, Bajpai M: Patients with inflammatory bowel disease may have a transforming growth factor-beta-, interleukin (IL)-2- or IL-10-deficient state induced by intrinsic neutralizing antibodies. Clin Exp Immunol. 2009, 155: 65-71. 10.1111/j.1365-2249.2008.03802.x.PubMedPubMedCentralCrossRef
20.
go back to reference de Lemos RC, Galle P, Svenson M, Pedersen BK, Hansen MB: Preparation and validation of radio iodinated recombinant human IL-10 for the measurement of natural human antibodies against IL-10. J Immunol Methods. 2009, 350: 46-53. 10.1016/j.jim.2009.07.005.CrossRef de Lemos RC, Galle P, Svenson M, Pedersen BK, Hansen MB: Preparation and validation of radio iodinated recombinant human IL-10 for the measurement of natural human antibodies against IL-10. J Immunol Methods. 2009, 350: 46-53. 10.1016/j.jim.2009.07.005.CrossRef
21.
go back to reference de Lemos RC, Galle P, Pedersen BK, Hansen MB: A state of acquired IL-10 deficiency in 0.4% of Danish blood donors. Cytokine. 2010, 51: 286-293. 10.1016/j.cyto.2010.06.009.CrossRef de Lemos RC, Galle P, Pedersen BK, Hansen MB: A state of acquired IL-10 deficiency in 0.4% of Danish blood donors. Cytokine. 2010, 51: 286-293. 10.1016/j.cyto.2010.06.009.CrossRef
22.
go back to reference Watanabe M, Uchida K, Nakagaki K, Kanazawa H, Trapnell BC, Hoshino Y, Kagamu H, Yoshizawa H, Keicho N, Goto H, Nakata K: Anti-cytokine autoantibodies are ubiquitous in healthy individuals. FEBS Lett. 2007, 581: 2017-2021. 10.1016/j.febslet.2007.04.029.PubMedCrossRef Watanabe M, Uchida K, Nakagaki K, Kanazawa H, Trapnell BC, Hoshino Y, Kagamu H, Yoshizawa H, Keicho N, Goto H, Nakata K: Anti-cytokine autoantibodies are ubiquitous in healthy individuals. FEBS Lett. 2007, 581: 2017-2021. 10.1016/j.febslet.2007.04.029.PubMedCrossRef
23.
go back to reference Doffinger R, Helbert MR, Barcenas-Morales G, Yang K, Dupuis S, Ceron-Gutierrez L, Espitia-Pinzon C, Barnes N, Bothamley G, Casanova JL, Longhurst HJ, Kumararatne DS: Autoantibodies to interferon-gamma in a patient with selective susceptibility to mycobacterial infection and organ-specific autoimmunity. Clin Infect Dis. 2004, 38: e10-e14. 10.1086/380453.PubMedCrossRef Doffinger R, Helbert MR, Barcenas-Morales G, Yang K, Dupuis S, Ceron-Gutierrez L, Espitia-Pinzon C, Barnes N, Bothamley G, Casanova JL, Longhurst HJ, Kumararatne DS: Autoantibodies to interferon-gamma in a patient with selective susceptibility to mycobacterial infection and organ-specific autoimmunity. Clin Infect Dis. 2004, 38: e10-e14. 10.1086/380453.PubMedCrossRef
24.
go back to reference Kisand K, Boe Wolff AS, Podkrajsek KT, Tserel L, Link M, Kisand KV, Ersvaer E, Perheentupa J, Erichsen MM, Bratanic N, Meloni A, Cetani F, Perniola R, Ergun-Longmire B, Maclaren N, Krohn KJ, Pura M, Schalke B, Strobel P, Leite MI, Battelino T, Husebye ES, Peterson P, Willcox N, Meager A: Chronic mucocutaneous candidiasis in APECED or thymoma patients correlates with autoimmunity to Th17-associated cytokines. J Exp Med. 2010, 207: 299-308. 10.1084/jem.20091669.PubMedPubMedCentralCrossRef Kisand K, Boe Wolff AS, Podkrajsek KT, Tserel L, Link M, Kisand KV, Ersvaer E, Perheentupa J, Erichsen MM, Bratanic N, Meloni A, Cetani F, Perniola R, Ergun-Longmire B, Maclaren N, Krohn KJ, Pura M, Schalke B, Strobel P, Leite MI, Battelino T, Husebye ES, Peterson P, Willcox N, Meager A: Chronic mucocutaneous candidiasis in APECED or thymoma patients correlates with autoimmunity to Th17-associated cytokines. J Exp Med. 2010, 207: 299-308. 10.1084/jem.20091669.PubMedPubMedCentralCrossRef
25.
go back to reference Holdstock G, Ershler WB, Krawitt EL: Defective lymphocyte IgA production in inflammatory bowel disease. Clin Immunol Immunopathol. 1982, 24: 47-54. 10.1016/0090-1229(82)90087-3.PubMedCrossRef Holdstock G, Ershler WB, Krawitt EL: Defective lymphocyte IgA production in inflammatory bowel disease. Clin Immunol Immunopathol. 1982, 24: 47-54. 10.1016/0090-1229(82)90087-3.PubMedCrossRef
26.
go back to reference Anderson CA, Boucher G, Lees CW, Franke A, D'Amato M, Taylor KD, Lee JC, Goyette P, Imielinski M, Latiano A, Lagace C, Scott R, Amininejad L, Bumpstead S, Baidoo L, Baldassano RN, Barclay M, Bayless TM, Brand S, Buning C, Colombel JF, Denson LA, De Vos M, Dubinsky M, Edwards C, Ellinghaus D, Fehrmann RS, Floyd JA, Florin T, Franchimont D:Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. Nat Genet. 2011, 43: 246-252. 10.1038/ng.764.PubMedPubMedCentralCrossRef Anderson CA, Boucher G, Lees CW, Franke A, D'Amato M, Taylor KD, Lee JC, Goyette P, Imielinski M, Latiano A, Lagace C, Scott R, Amininejad L, Bumpstead S, Baidoo L, Baldassano RN, Barclay M, Bayless TM, Brand S, Buning C, Colombel JF, Denson LA, De Vos M, Dubinsky M, Edwards C, Ellinghaus D, Fehrmann RS, Floyd JA, Florin T, Franchimont D:Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. Nat Genet. 2011, 43: 246-252. 10.1038/ng.764.PubMedPubMedCentralCrossRef
27.
go back to reference Van Limbergen J, Wilson DC, Satsangi J: The genetics of Crohn’s disease. Annu Rev Genomics Hum Genet. 2009, 10: 89-116. 10.1146/annurev-genom-082908-150013.PubMedCrossRef Van Limbergen J, Wilson DC, Satsangi J: The genetics of Crohn’s disease. Annu Rev Genomics Hum Genet. 2009, 10: 89-116. 10.1146/annurev-genom-082908-150013.PubMedCrossRef
28.
go back to reference Stange EF, Travis SP, Vermeire S, Reinisch W, Geboes K, Barakauskiene A, Feakins R, Flejou JF, Herfarth H, Hommes DW, Kupcinskas L, Lakatos PL, Mantzaris GJ, Schreiber S, Villanacci V, Warren BF: European evidence-based Consensus on the diagnosis and management of ulcerative colitis: definitions and diagnosis. J Crohns Colitis. 2008, 2: 1-23. 10.1016/j.crohns.2007.11.001.PubMedCrossRef Stange EF, Travis SP, Vermeire S, Reinisch W, Geboes K, Barakauskiene A, Feakins R, Flejou JF, Herfarth H, Hommes DW, Kupcinskas L, Lakatos PL, Mantzaris GJ, Schreiber S, Villanacci V, Warren BF: European evidence-based Consensus on the diagnosis and management of ulcerative colitis: definitions and diagnosis. J Crohns Colitis. 2008, 2: 1-23. 10.1016/j.crohns.2007.11.001.PubMedCrossRef
29.
go back to reference Van Assche G, Dignass A, Panes J, Beaugerie L, Karagiannis J, Allez M, Ochsenkuhn T, Orchard T, Rogler G, Louis E, Kupcinskas L, Mantzaris G, Travis S, Stange E: The second European evidence-based Consensus on the diagnosis and management of Crohn’s disease: definitions and diagnosis. J Crohns Colitis. 2010, 4: 7-27. 10.1016/j.crohns.2009.12.003.PubMedCrossRef Van Assche G, Dignass A, Panes J, Beaugerie L, Karagiannis J, Allez M, Ochsenkuhn T, Orchard T, Rogler G, Louis E, Kupcinskas L, Mantzaris G, Travis S, Stange E: The second European evidence-based Consensus on the diagnosis and management of Crohn’s disease: definitions and diagnosis. J Crohns Colitis. 2010, 4: 7-27. 10.1016/j.crohns.2009.12.003.PubMedCrossRef
30.
go back to reference Working IBD: Group of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition. Inflammatory bowel disease in children and adolescents: recommendations for diagnosis–the Porto criteria. J Pediatr Gastroenterol Nutr. 2005, 41: 1-7. 10.1097/01.MPG.0000163736.30261.82.CrossRef Working IBD: Group of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition. Inflammatory bowel disease in children and adolescents: recommendations for diagnosis–the Porto criteria. J Pediatr Gastroenterol Nutr. 2005, 41: 1-7. 10.1097/01.MPG.0000163736.30261.82.CrossRef
31.
go back to reference Levine A, Griffiths A, Markowitz J, Wilson DC, Turner D, Russell RK, Fell J, Ruemmele FM, Walters T, Sherlock M, Dubinsky M, Hyams JS: Pediatric modification of the Montreal classification for inflammatory bowel disease: the Paris classification. Inflamm Bowel Dis. 2011, 17: 1314-1321. 10.1002/ibd.21493.PubMedCrossRef Levine A, Griffiths A, Markowitz J, Wilson DC, Turner D, Russell RK, Fell J, Ruemmele FM, Walters T, Sherlock M, Dubinsky M, Hyams JS: Pediatric modification of the Montreal classification for inflammatory bowel disease: the Paris classification. Inflamm Bowel Dis. 2011, 17: 1314-1321. 10.1002/ibd.21493.PubMedCrossRef
Metadata
Title
Evidence for non-neutralizing autoantibodies against IL-10 signalling components in patients with inflammatory bowel disease
Publication date
01-12-2014
Published in
BMC Immunology / Issue 1/2014
Electronic ISSN: 1471-2172
DOI
https://doi.org/10.1186/1471-2172-15-10

Other articles of this Issue 1/2014

BMC Immunology 1/2014 Go to the issue

Reviewer acknowledgement

Reviewer acknowledgement 2013