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Autoantibodies to Glutathione S-transferase theta 1 in patients with primary sclerosing cholangitis and other autoimmune diseases
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. (Autoimmuna sjukdomar (Kämpe))
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. (magtarm)
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2008 (English)In: Journal of Autoimmunity, ISSN 0896-8411, E-ISSN 1095-9157, Vol. 30, no 4, 273-282 p.Article 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.

Place, publisher, year, edition, pages
2008. Vol. 30, no 4, 273-282 p.
Keyword [en]
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: urn:nbn:se:uu:diva-97136DOI: 10.1016/j.jaut.2007.11.008ISI: 000255834500010PubMedID: 18242955OAI: oai:DiVA.org:uu-97136DiVA: diva2:171940
Available from: 2008-04-24 Created: 2008-04-24 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Autoantigens in Inflammatory Bowel Disease and Primary Sclerosing Cholangitis
Open this publication in new window or tab >>Autoantigens in Inflammatory Bowel Disease and Primary Sclerosing Cholangitis
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. 62 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 342
Keyword
Molecular medicine, inflammatory bowel disease, primary sclerosing cholangitis, autoimmunity, autoantigen, goblet cell, Molekylärmedicin
Identifiers
urn:nbn:se:uu:diva-8677 (URN)978-91-554-7180-4 (ISBN)
Public defence
2008-05-15, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 09:15 (English)
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Available from: 2008-04-24 Created: 2008-04-24 Last updated: 2010-05-07Bibliographically approved

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Ardesjö, BritaKämpe, Olle

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