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Myelin protein zero is naturally processed in IgM MGUS B cells: Aberrant triggering of patient T cells
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology. 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, Neurology. Linköping University, Faculty of Health Sciences.
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2010 (English)In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 95, no 4, 627-636 p.Article in journal (Refereed) Published
Abstract [en]

Background and Objectives: Monoclonal gammopathy of undetermined significance (MGUS) of IgM isotype is a condition with clonally expanded B cells, recently suggested having an infectious origin. MGUS is frequently associated with polyneuropathy and antibodies against myelin protein zero (P0), whereas the role of the T cells remains largely unknown. Here we have analyzed P0-specific B cells, as antigen-presenting cells, and their capacity to activate T helper cells.

Design and Methods: We used a well-characterized MGUS-derived B cell line, TJ2, expressing anti-P0 IgM. The ability of TJ2 cells to bind, endocytose, process, and present P0 was investigated by receptor-clustering and immunofluorescence. The activation of P0-specific autologous T cells was studied by measuring IL2 and IFNγ with flow cytometry, immunobeads, and ELISPOT.

Results: Surface-receptor clustering and endocytosis of receptor-ligand (IgM/P0) complexes were pronounced after P0 exposure. Naturally processed or synthetic P0 peptide (194-208)-pulsed TJ2 cells significantly induced IL2 secretion from autologous T cells compared to control antigen pulsed cells (p<0 .001). The numbers of IFNγ producing T helper cells, including CD4+/CD8+ cells, were also significantly increased (p=0.0152). Affinity-isolated naturally processed myelin peptides were potent IFNγ stimulators for autologous PBMCs, but not for control PBMCs.

Interpretation and conclusions: We show for the first time that myelin P0 is naturally processed in IgM MGUS B cells, acting as aberrant antigen-presenting cells in activation of patients T helper cells. Our findings cast new light on the important role of autoreactive P0-specific B cells in he induction of the pathogenic T cell responses found in nerve lesions of MGUS patients with peripheral neuropathy.

Place, publisher, year, edition, pages
2010. Vol. 95, no 4, 627-636 p.
Keyword [en]
Monoclonal gammopathy of undetermined significance, myelin P0, peripheral neuropathy, CD5+B cells
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-53280DOI: 10.3324/haematol.2009.015123ISI: 000277144800017OAI: oai:DiVA.org:liu-53280DiVA: diva2:288133
Available from: 2010-01-20 Created: 2010-01-20 Last updated: 2017-12-12
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)
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Available from: 2010-01-20 Created: 2010-01-20 Last updated: 2017-09-22Bibliographically approved

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Hellqvist, EvaKvarnström, MariaSöderberg, AnitaErnerudh, JanRosén, Anders

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Haematologica
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