Role of collagen type II specific antibodies in arthritis

Estelle Bajtner

Role of collagen type II specific antibodies in arthritis

Estelle Bajtner

Research output: Thesis › Doctoral Thesis (compilation)

Abstract

Rheumatoid arthritis (RA) is a chronic inflammatory disease resulting in destruction of cartilage and bone. The role of the B cells in RA pathogenesis clearly involves autoantibodies. Collagen type II (CII)-specific antibodies have been identified in RA synovium and synovial fluid. The work in this thesis is focused on the role of CII specific antibodies in the initiation and pathogenesis of arthritis. Additionally, the importance of B cell tolerance in the development of autoimmune disease has been investigated. To study some of the pathogenic mechanisms involved in RA, we used the animal model collagen-induced arthritis (CIA), where the disease characteristics resembles RA in many ways. We investigated the epitope selection and V gene usage of CII specific monoclonal antibodies (mAbs) and demonstrated that the presence of a selective V gene repertoire could result in CII epitope binding capacity. Further, the antibody response and B cell epitope specificity was examined in chronic relapsing CIA models. We found that the B cell responses against CII in both mice and rats were directed against immunodominant epitopes that were conserved between the species, including humans. Here the development of chronic arthritis was related to an antibody response to defined epitopes on CII (C1, J1 and U1) and mAbs to these epitopes could induce relapses. A significant correlation between U1-specific antibodies and disease progression was found in CIA. We also detected U1-specific autoantibodies in RA, especially in association with early joint erosions. U1 specific antibodies bound cartilage in vivo and triggered the development of arthritis on its own. Therefore, antibodies directed to a specific epitope on CII could be related to arthritis progression and the epitope specificity of the mAb could determine its arthritogenicity. Finally, the importance of B cell tolerance in autoimmune arthritis development was investigated. By creating a gene replacement mouse with an inserted VDJ region coding for an anti-CII antibody, we could study some of the B cell tolerance mechanisms. Our findings suggested that B cells expressing autoantibodies directed against CII may escape negative selection events and could be present in the periphery with a maintained specificity. In conclusion, CII specific antibodies are essential for the induction and pathogenesis of arthritis.

Original language	English
Qualification	Doctor
Awarding Institution	Department of Experimental Medical Science
Supervisors/Advisors	Holmdahl, Rikard, Supervisor
Award date	2005 Sept 17
Publisher	Department of Experimental Medical Science, Lund Univeristy
ISBN (Print)	91-85439-73-8
Publication status	Published - 2005

Bibliographical note

Defence details

Date: 2005-09-17
Time: 09:00
Place: Rune Grubb salen BMC Sölvegatan 19 Lund

External reviewer(s)

Name: Wahren-Herlenius, Marie
Title: Docent
Affiliation: CMM, Karolinska Institutet, Stockholm

---

<div class="article_info">Patrik Wernhoff, Christine Unger, Estelle Bajtner, Harald Burkhardt and Rikard Holmdahl. <span class="article_issue_date">2001</span>. <span class="article_title">Identification of conformation-dependent epitopes and V gene selection in the B cell response to type II collagen in the DA rat.</span> <span class="journal_series_title">International Immunology</span>, <span class="journal_volume">vol 13</span> <span class="journal_pages">pp 909-919</span>.</div>
<div class="article_info">Estelle Bajtner, Kutty S Nandakumar, Åke Engström and Rikard Holmdahl. <span class="article_issue_date">2005</span>. <span class="article_title">Chronic development of collagen-induced arthritis is associated with arthritogenic antibodies against specific epitopes on type II collagen.</span> <span class="journal_series_title">Arthritis Research & Therapy</span>, <span class="journal_volume">vol 7</span> <span class="journal_pages">pp R1148-R1157</span>.</div>
<div class="article_info">Kutty Selva Nandakumar, Estelle Bajtner, Leigh Hill, Beate Böhm, Merrill J Rowley, Harald Burkhardt and Rikard Holmdahl. <span class="article_issue_date"></span>. <span class="article_title">A conserved triple helical epitope on type II collagen is involved in arthritis development.</span> <span class="journal_series_title">Journal of Clinical Investigation</span>, (submitted)</div>
<div class="article_info">Estelle Bajtner, Myassa Dartell, John A. Mo, Thomas Blom and Rikard Holmdahl. <span class="article_issue_date"></span>. <span class="article_title">B lymphocytes producing collagen type II specific autoantibodies; development and function in heavy chain replacement mice.</span> (manuscript)</div>

The information about affiliations in this record was updated in December 2015.
The record was previously connected to the following departments: Department of Experimental Medical Science (013210000), Medical Inflammation Research (013212019)

Subject classification (UKÄ)

Basic Medicine

Free keywords

serologi
transplantation
serology
Immunology
tolerance
collagen type II
CIA
B cell epitope
antibody
arthritis
Immunologi

Cite this

@phdthesis{41457253ace44969af07360cb412e3d3,

title = "Role of collagen type II specific antibodies in arthritis",

abstract = "Rheumatoid arthritis (RA) is a chronic inflammatory disease resulting in destruction of cartilage and bone. The role of the B cells in RA pathogenesis clearly involves autoantibodies. Collagen type II (CII)-specific antibodies have been identified in RA synovium and synovial fluid. The work in this thesis is focused on the role of CII specific antibodies in the initiation and pathogenesis of arthritis. Additionally, the importance of B cell tolerance in the development of autoimmune disease has been investigated. To study some of the pathogenic mechanisms involved in RA, we used the animal model collagen-induced arthritis (CIA), where the disease characteristics resembles RA in many ways. We investigated the epitope selection and V gene usage of CII specific monoclonal antibodies (mAbs) and demonstrated that the presence of a selective V gene repertoire could result in CII epitope binding capacity. Further, the antibody response and B cell epitope specificity was examined in chronic relapsing CIA models. We found that the B cell responses against CII in both mice and rats were directed against immunodominant epitopes that were conserved between the species, including humans. Here the development of chronic arthritis was related to an antibody response to defined epitopes on CII (C1, J1 and U1) and mAbs to these epitopes could induce relapses. A significant correlation between U1-specific antibodies and disease progression was found in CIA. We also detected U1-specific autoantibodies in RA, especially in association with early joint erosions. U1 specific antibodies bound cartilage in vivo and triggered the development of arthritis on its own. Therefore, antibodies directed to a specific epitope on CII could be related to arthritis progression and the epitope specificity of the mAb could determine its arthritogenicity. Finally, the importance of B cell tolerance in autoimmune arthritis development was investigated. By creating a gene replacement mouse with an inserted VDJ region coding for an anti-CII antibody, we could study some of the B cell tolerance mechanisms. Our findings suggested that B cells expressing autoantibodies directed against CII may escape negative selection events and could be present in the periphery with a maintained specificity. In conclusion, CII specific antibodies are essential for the induction and pathogenesis of arthritis.",

keywords = "serologi, transplantation, serology, Immunology, tolerance, collagen type II, CIA, B cell epitope, antibody, arthritis, Immunologi",

author = "Estelle Bajtner",

note = "Defence details Date: 2005-09-17 Time: 09:00 Place: Rune Grubb salen BMC S{\"o}lvegatan 19 Lund External reviewer(s) Name: Wahren-Herlenius, Marie Title: Docent Affiliation: CMM, Karolinska Institutet, Stockholm --- <div class={"}article\_info{"}>Patrik Wernhoff, Christine Unger, Estelle Bajtner, Harald Burkhardt and Rikard Holmdahl. <span class={"}article\_issue\_date{"}>2001</span>. <span class={"}article\_title{"}>Identification of conformation-dependent epitopes and V gene selection in the B cell response to type II collagen in the DA rat.</span> <span class={"}journal\_series\_title{"}>International Immunology</span>, <span class={"}journal\_volume{"}>vol 13</span> <span class={"}journal\_pages{"}>pp 909-919</span>.</div> <div class={"}article\_info{"}>Estelle Bajtner, Kutty S Nandakumar, {\AA}ke Engstr{\"o}m and Rikard Holmdahl. <span class={"}article\_issue\_date{"}>2005</span>. <span class={"}article\_title{"}>Chronic development of collagen-induced arthritis is associated with arthritogenic antibodies against specific epitopes on type II collagen.</span> <span class={"}journal\_series\_title{"}>Arthritis Research \& Therapy</span>, <span class={"}journal\_volume{"}>vol 7</span> <span class={"}journal\_pages{"}>pp R1148-R1157</span>.</div> <div class={"}article\_info{"}>Kutty Selva Nandakumar, Estelle Bajtner, Leigh Hill, Beate B{\"o}hm, Merrill J Rowley, Harald Burkhardt and Rikard Holmdahl. <span class={"}article\_issue\_date{"}></span>. <span class={"}article\_title{"}>A conserved triple helical epitope on type II collagen is involved in arthritis development.</span> <span class={"}journal\_series\_title{"}>Journal of Clinical Investigation</span>, (submitted)</div> <div class={"}article\_info{"}>Estelle Bajtner, Myassa Dartell, John A. Mo, Thomas Blom and Rikard Holmdahl. <span class={"}article\_issue\_date{"}></span>. <span class={"}article\_title{"}>B lymphocytes producing collagen type II specific autoantibodies; development and function in heavy chain replacement mice.</span> (manuscript)</div> The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Department of Experimental Medical Science (013210000), Medical Inflammation Research (013212019)",

year = "2005",

language = "English",

isbn = "91-85439-73-8",

publisher = "Department of Experimental Medical Science, Lund Univeristy",

type = "Doctoral Thesis (compilation)",

school = "Department of Experimental Medical Science",

}

TY - THES

T1 - Role of collagen type II specific antibodies in arthritis

AU - Bajtner, Estelle

N1 - Defence details Date: 2005-09-17 Time: 09:00 Place: Rune Grubb salen BMC Sölvegatan 19 Lund External reviewer(s) Name: Wahren-Herlenius, Marie Title: Docent Affiliation: CMM, Karolinska Institutet, Stockholm --- <div class="article_info">Patrik Wernhoff, Christine Unger, Estelle Bajtner, Harald Burkhardt and Rikard Holmdahl. <span class="article_issue_date">2001</span>. <span class="article_title">Identification of conformation-dependent epitopes and V gene selection in the B cell response to type II collagen in the DA rat.</span> <span class="journal_series_title">International Immunology</span>, <span class="journal_volume">vol 13</span> <span class="journal_pages">pp 909-919</span>.</div> <div class="article_info">Estelle Bajtner, Kutty S Nandakumar, Åke Engström and Rikard Holmdahl. <span class="article_issue_date">2005</span>. <span class="article_title">Chronic development of collagen-induced arthritis is associated with arthritogenic antibodies against specific epitopes on type II collagen.</span> <span class="journal_series_title">Arthritis Research & Therapy</span>, <span class="journal_volume">vol 7</span> <span class="journal_pages">pp R1148-R1157</span>.</div> <div class="article_info">Kutty Selva Nandakumar, Estelle Bajtner, Leigh Hill, Beate Böhm, Merrill J Rowley, Harald Burkhardt and Rikard Holmdahl. <span class="article_issue_date"></span>. <span class="article_title">A conserved triple helical epitope on type II collagen is involved in arthritis development.</span> <span class="journal_series_title">Journal of Clinical Investigation</span>, (submitted)</div> <div class="article_info">Estelle Bajtner, Myassa Dartell, John A. Mo, Thomas Blom and Rikard Holmdahl. <span class="article_issue_date"></span>. <span class="article_title">B lymphocytes producing collagen type II specific autoantibodies; development and function in heavy chain replacement mice.</span> (manuscript)</div> The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Department of Experimental Medical Science (013210000), Medical Inflammation Research (013212019)

PY - 2005

Y1 - 2005

N2 - Rheumatoid arthritis (RA) is a chronic inflammatory disease resulting in destruction of cartilage and bone. The role of the B cells in RA pathogenesis clearly involves autoantibodies. Collagen type II (CII)-specific antibodies have been identified in RA synovium and synovial fluid. The work in this thesis is focused on the role of CII specific antibodies in the initiation and pathogenesis of arthritis. Additionally, the importance of B cell tolerance in the development of autoimmune disease has been investigated. To study some of the pathogenic mechanisms involved in RA, we used the animal model collagen-induced arthritis (CIA), where the disease characteristics resembles RA in many ways. We investigated the epitope selection and V gene usage of CII specific monoclonal antibodies (mAbs) and demonstrated that the presence of a selective V gene repertoire could result in CII epitope binding capacity. Further, the antibody response and B cell epitope specificity was examined in chronic relapsing CIA models. We found that the B cell responses against CII in both mice and rats were directed against immunodominant epitopes that were conserved between the species, including humans. Here the development of chronic arthritis was related to an antibody response to defined epitopes on CII (C1, J1 and U1) and mAbs to these epitopes could induce relapses. A significant correlation between U1-specific antibodies and disease progression was found in CIA. We also detected U1-specific autoantibodies in RA, especially in association with early joint erosions. U1 specific antibodies bound cartilage in vivo and triggered the development of arthritis on its own. Therefore, antibodies directed to a specific epitope on CII could be related to arthritis progression and the epitope specificity of the mAb could determine its arthritogenicity. Finally, the importance of B cell tolerance in autoimmune arthritis development was investigated. By creating a gene replacement mouse with an inserted VDJ region coding for an anti-CII antibody, we could study some of the B cell tolerance mechanisms. Our findings suggested that B cells expressing autoantibodies directed against CII may escape negative selection events and could be present in the periphery with a maintained specificity. In conclusion, CII specific antibodies are essential for the induction and pathogenesis of arthritis.

AB - Rheumatoid arthritis (RA) is a chronic inflammatory disease resulting in destruction of cartilage and bone. The role of the B cells in RA pathogenesis clearly involves autoantibodies. Collagen type II (CII)-specific antibodies have been identified in RA synovium and synovial fluid. The work in this thesis is focused on the role of CII specific antibodies in the initiation and pathogenesis of arthritis. Additionally, the importance of B cell tolerance in the development of autoimmune disease has been investigated. To study some of the pathogenic mechanisms involved in RA, we used the animal model collagen-induced arthritis (CIA), where the disease characteristics resembles RA in many ways. We investigated the epitope selection and V gene usage of CII specific monoclonal antibodies (mAbs) and demonstrated that the presence of a selective V gene repertoire could result in CII epitope binding capacity. Further, the antibody response and B cell epitope specificity was examined in chronic relapsing CIA models. We found that the B cell responses against CII in both mice and rats were directed against immunodominant epitopes that were conserved between the species, including humans. Here the development of chronic arthritis was related to an antibody response to defined epitopes on CII (C1, J1 and U1) and mAbs to these epitopes could induce relapses. A significant correlation between U1-specific antibodies and disease progression was found in CIA. We also detected U1-specific autoantibodies in RA, especially in association with early joint erosions. U1 specific antibodies bound cartilage in vivo and triggered the development of arthritis on its own. Therefore, antibodies directed to a specific epitope on CII could be related to arthritis progression and the epitope specificity of the mAb could determine its arthritogenicity. Finally, the importance of B cell tolerance in autoimmune arthritis development was investigated. By creating a gene replacement mouse with an inserted VDJ region coding for an anti-CII antibody, we could study some of the B cell tolerance mechanisms. Our findings suggested that B cells expressing autoantibodies directed against CII may escape negative selection events and could be present in the periphery with a maintained specificity. In conclusion, CII specific antibodies are essential for the induction and pathogenesis of arthritis.

KW - serologi

KW - transplantation

KW - serology

KW - Immunology

KW - tolerance

KW - collagen type II

KW - CIA

KW - B cell epitope

KW - antibody

KW - arthritis

KW - Immunologi

M3 - Doctoral Thesis (compilation)

SN - 91-85439-73-8

PB - Department of Experimental Medical Science, Lund Univeristy

ER -

Role of collagen type II specific antibodies in arthritis

Abstract

Bibliographical note

Subject classification (UKÄ)

Free keywords

Fingerprint

Cite this