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IGHV3-21 stereotyped subset-2 chronic lymphocytic leukemia cells make autoantibodies that bind to an 11.5kDa gastric mucosal antigen
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Background: The immunoglobulin heavy chain variable region (IGHV) gene mutational status is an important prognostic factor in chronic lymphocytic leukemia (CLL). Patients with mutated IGHV genes show significantly longer survival than unmutated cases. CLL patients with mutated IGHV3-21 genes, however, have a shorter survival compared to other mutated CLL cases. Recently, we showed that CLL cells react with oxidized epitopes exposed on apoptotic cells and bacteria. The gastric mucosal reactivity was of special interest to further characterize in detail.

Methods: We collected corpus biopsies from seven Helicobacter pylori (H.p.)+ study subjects withnon-atrophic gastritis, six subjects with H.p.- atrophic gastritis, eight subjects with H.p.+ atrophicgastric and from eight controls without gastritis. The binding pattern of CLL subset-2 IGHV3-21antibodies was analyzed by immunohistochemistry and the antigen was biochemically purified byaffinity chromatography.

Results: The subset-2 IGHV3-21 Abs bound to mucosal glands in 18 of 29 cases regardless of H.p.status or diagnosis. It also showed staining of connective tissue in all of the biopsies. The antigen waspurified and a protein of 11.5 kDa MW was isolated.

Conclusion: The results from this study indicate that IGHV3-21 subset-2 CLL Abs bind an 11.5kDaprotein present in gastric mucosal glands or connective tissue. This autoantigen has no associationwith H.p. since it is present in normal, non-atrophic H.p.+ and atrophic H.p.+/H.p.- gastric mucosafrom corpus. The exact nature of the 11.5 kDa protein is currently under detailed structure massspectrometry analysis in order to reveal whether bacterial mimicry is the mechanism behind theinduction of this particular autoantibody.

National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-53279OAI: oai:DiVA.org:liu-53279DiVA: diva2:288128
Available from: 2010-01-20 Created: 2010-01-20 Last updated: 2010-01-20Bibliographically approved
In thesis
1. Antigen interaction with B cells in two proliferative disorders: CLL and MGUS
Open this publication in new window or tab >>Antigen interaction with B cells in two proliferative disorders: CLL and MGUS
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The aim of the work presented in this thesis was to elucidate B cell interaction with antigen in the two B cell proliferative disorders chronic lymphocytic leukemia (CLL) and monoclonal gammopathy of undetermined significance (MGUS). In the first part we investigated the antigen specificity of CLL cells and characterized Epstein-Barr virus (EBV)-transformed CLL cell lines with regard to phenotype and genotype. The second part consists of studies on the antigen presenting capacity of myelin protein zero (P0) specific MGUS B cells and their relation to T cells and development of polyneuropathy.

The aim of the work presented in this thesis was to elucidate B cell interaction with antigen in the two B cell proliferative disorders chronic lymphocytic leukemia (CLL) and monoclonal gammopathy of undetermined significance (MGUS). In the first part we investigated the antigen specificity of CLL cells and characterized Epstein-Barr virus (EBV)-transformed CLL cell lines with regard to phenotype and genotype. The second part consists of studies on the antigen presenting capacity of myelin protein zero (P0) specific MGUS B cells and their relation to T cells and development of polyneuropathy.

CLL cells are considered antigen experienced and different patient-derived CLL cells expressing B cell receptors (BCR) with highly homologous antigen binding sites are believed to have been selected by a common antigen at some point during the leukemogenesis. In paper I we investigated the antigen specificity of CLL-cell derived antibodies (Abs) with various IGHV gene usage and stereotyped BCR subset belonging. Identified CLL antigens included vimentin, filamin B, cofilin-1, proline rich acidic protein-1, cardiolipin, oxidized low density lipoprotein and Streptococcus pneumoniae capsular polysaccharides. Many of the CLL Abs studied displayed an oligo- or polyreactive antigen binding pattern and the identified antigens were either associated with apoptotic cells or microbial infection. This is similar to what has been described for innate natural antibodies, possibly indicating that CLL cells are derived from a natural-antibody- producing B cell population. Further characterization of CLL homology subset-2 antigen specificity showed binding to glands in human gastric mucosa corpus tissue sections for a CLL homology subset-2 Ab with HCDR3 motif-1, suggesting that this CLL subset recognize an autoantigen much like the CLL Abs tested in Paper I.

Characterization of EBV-transformed CLL and normal lymphoblastoid cell lines (LCLs) in paper II showed that eight of the CLL cell lines were verified to be of authentic neoplastic origin. Indication for a biclonal CLL was found in two of the cell lines and two of the presumably normal LCLs turned out to represent the malignant CLL clone. For three cell lines no conclusive evidence for CLL origin could be found emphasizing the importance of verifying the identity of cell lines used in research.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2010. 59 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1158
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-53281 (URN)978-91-7393-475-6 (ISBN)
Public defence
2010-01-15, Aulan, Katastrofmedicinskt Centrum, Campus US, Linköpings universitet, Linköping, 09:00 (English)
Opponent
Supervisors
Available from: 2010-01-20 Created: 2010-01-20 Last updated: 2017-09-22Bibliographically approved

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Hellqvist, EvaMorad, VivianBorch, Kurt

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