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Autoantigens in Inflammatory Bowel Disease and Primary Sclerosing Cholangitis
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Inflammatory bowel disease (IBD) comprises diseases that are characterized by chronic or relapsing inflammation of the gastrointestinal tract. Primary sclerosing cholangitis (PSC) is an extraintestinal manifestation in IBD. Immunoreactivity against an autoantigen that is expressed both in the gastrointestinal tract and the biliary tract could be the link between these diseases. A possible source of such an antigen is goblet cells.

Immunostainings of normal human tissues using IBD patient sera showed goblet cell immunoreactivity against goblet cells in all parts of the gastrointestinal tract. The most frequent immunostaining was found against goblet cells in the appendix against which 84% (42/50) of IBD patients compared to 8% (4/50) of healthy blood donors showed immunoreactivity. To identify the corresponding antigen we used three different approaches, investigation of immunoreactivity to different candidate proteins compared to IBD sera, immunoscreening of an appendiceal cDNA library, and immunoprecipitation of protein lysates from mucin producing cells followed by SDS-PAGE and 2D gel electrophoresis. These approaches led to the identification of several candidate autoantigens of which complement C3 is the most promising.

A novel staining pattern with strong immunoreactivity to granules and the apical membrane of biliary epithelial cells was identified with 35% (12/34) of PSC sera compared to none of healthy controls (n=28). Screening of a cDNA library from normal human choledochus identified PDZ domain containing 1 (Pdzk1) and Glutathion S transferase theta 1 (GSTT1) as potential candidates. Pdzk1 is an interesting candidate which is expressed in the intestinal tract and bile ducts. GSTT1 antibodies were not specific for PSC and are thought to develop as an alloimmune response in patients with the GSTT1-null genotype.

In conclusion, we have identified specific immunoreactivity to goblet cells and biliary epithelial cells using sera from patients with IBD and PSC respectively. We have also identified several potential autoantigens.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2008. , p. 62
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 342
Keywords [en]
Molecular medicine, inflammatory bowel disease, primary sclerosing cholangitis, autoimmunity, autoantigen, goblet cell
Keywords [sv]
Molekylärmedicin
Identifiers
URN: urn:nbn:se:uu:diva-8677ISBN: 978-91-554-7180-4 (print)OAI: oai:DiVA.org:uu-8677DiVA, id: diva2:171942
Public defence
2008-05-15, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2008-04-24 Created: 2008-04-24 Last updated: 2010-05-07Bibliographically approved
List of papers
1. Immunoreactivity against goblet cells in patients with inflammatory bowel disease
Open this publication in new window or tab >>Immunoreactivity against goblet cells in patients with inflammatory bowel disease
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2008 (English)In: Inflammatory Bowel Diseases, ISSN 1078-0998, E-ISSN 1536-4844, Vol. 14, no 5, p. 652-661Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: A number of autoantibodies have been reported in inflammatory bowel disease (IBD). The aim of this study was to investigate to what extent sera from patients with IBD contain autoantibodies directed against normal human gastrointestinal mucosa. METHODS: Samples of sera from 50 patients with IBD and 50 healthy subjects were used for immunostaining of normal and affected human gastrointestinal tissues. RESULTS: Eighty-four percent of the sera from IBD patients showed immunoreactivity against goblet cells in the appendix compared with 8% of the sera from healthy subjects. Goblet cell reactivity of IBD patient sera varied between regions in the gastrointestinal tract. Sera from healthy subjects only reacted with goblet cells in the appendix. In the colon and the appendix, goblet cell reactivity of IBD sera was generally weak at the base of the crypts and gradually increased toward the lumen. Three IBD sera samples reacted with gastrin cells in the antrum. In colon biopsies from patients with ulcerative colitis, immunoreactivity against the remaining goblet cells showed an inverse correlation with inflammatory activity. CONCLUSIONS: These findings suggest that immunoreactivity against goblet cells may be of central importance in the pathogenesis of IBD. Identification of goblet cell antigens could lead to a better understanding of IBD and provide a new diagnostic tool.

Keywords
inflammatory bowel disease, goblet cells, autoimmunity, autoantibodies
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-97134 (URN)10.1002/ibd.20370 (DOI)000255581500009 ()18213698 (PubMedID)
Available from: 2008-04-24 Created: 2008-04-24 Last updated: 2022-01-28Bibliographically approved
2. Investigation of goblet cell autoantigens in patients with inflammatory bowel disease.
Open this publication in new window or tab >>Investigation of goblet cell autoantigens in patients with inflammatory bowel disease.
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(English)Manuscript (Other academic)
Identifiers
urn:nbn:se:uu:diva-97135 (URN)
Available from: 2008-04-24 Created: 2008-04-24 Last updated: 2010-05-07Bibliographically approved
3. Autoantibodies to Glutathione S-transferase theta 1 in patients with primary sclerosing cholangitis and other autoimmune diseases
Open this publication in new window or tab >>Autoantibodies to Glutathione S-transferase theta 1 in patients with primary sclerosing cholangitis and other autoimmune diseases
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2008 (English)In: Journal of Autoimmunity, ISSN 0896-8411, E-ISSN 1095-9157, Vol. 30, no 4, p. 273-282Article in journal (Refereed) Published
Abstract [en]

Primary sclerosing cholangitis (PSC) is an enigmatic disorder with a suggested autoimmune basis. A variety of autoantigens have been suggested but no specific or highly directed epitope has been identified. To address this issue, we constructed a cDNA library from normal human choledochus and screened expressing clones with serum from a patient with PSC and inflammatory bowel disease (IBD). Based on this screening, glutathione S-transferase theta 1 (GSTT1) was identified as a potential autoantigenic target. To study the specificity of GSTT1, we determined immunoreactivity using a panel of 58 patients with PSC, with and without IBD, 57 patients with IBD, 31 patients with Hashimoto's thyroiditis, 30 patients with primary biliary cirrhosis (PBC), 20 patients with insulin dependent diabetes mellitus, 22 patients with autoimmune polyendocrine syndrome type 1, 10 patients with systemic lupus erythematosus (SLE), 20 patients with Sjogren's syndrome, 12 patients with autoimmune pancreatitis, 28 patients with Addison's disease, 27 patients with Grave's disease, 17 with myasthenia gravis, and 118 healthy controls. Reactivity against GSTT1 was found with PSC and IBD as well as some patients with other autoimmune pathology, indicating that this population of antibodies is neither specific nor a sensitive serologic marker for PSC, but the frequency was clearly higher in autoimmune patients than controls. GSTT1-antibodies have been described in persons with GSTT1-null genotype and are suggested to develop as an alloimmune response to blood transfusions from GSTT1-positive donors or pregnancies with GSTT1-positive children. Therefore, two IBD patients with and 15 PSC patients without GSTT1-antibodies were genotyped for GSTT1 to investigate if the presence of GSTT1-antibodies was associated with the GSTT1-null genotype and possibly caused by an alloimmune response. Both IBD patients and three of the PSC patients were of the GSTT1-null genotype. We note that the frequency of GSTT1-antibodies in this study is more than 100-fold higher than the frequency described earlier in patients with autoimmune diseases. We also observe an increased frequency of GSTT1-antibodies in patients with autoimmune diseases compared to healthy controls. This increased frequency can be explained by an autoimmune phenotype which increases susceptibility to such autoantibodies, or by a high frequency of the GSTT1-null genotype in autoimmune disease.

Keywords
autoantibodies, copy number variation, glutathione S-transferase theta 1, PCR product based array-CGH, primary sclerosing cholangitis
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-97136 (URN)10.1016/j.jaut.2007.11.008 (DOI)000255834500010 ()18242955 (PubMedID)
Available from: 2008-04-24 Created: 2008-04-24 Last updated: 2022-01-28Bibliographically approved
4. Immunoreactivity against bile duct epithelial cells and identification of PDZ domain containing 1 as a novel autoantigen in Primary sclerosing cholangitis.
Open this publication in new window or tab >>Immunoreactivity against bile duct epithelial cells and identification of PDZ domain containing 1 as a novel autoantigen in Primary sclerosing cholangitis.
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(English)Manuscript (Other academic)
Identifiers
urn:nbn:se:uu:diva-97137 (URN)
Available from: 2008-04-24 Created: 2008-04-24 Last updated: 2020-11-04Bibliographically approved

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