Skip to main content

Lund University Publications

LUND UNIVERSITY LIBRARIES

Analysis of effector pathways in arthritis

Kutty Selva, Nandakumar (2006)
Abstract
Rheumatoid arthritis (RA) is a multifactorial, polygenic autoimmune disease. For effective treatment and control of RA, understanding of disease pathways and identification of genes involved are essential. Animal models are efficient tools to identify such pathogenic mechanisms and genes underlying the disease process. In the present study, collagen antibody induced arthritis (CAIA), a mouse model for RA, was established and characterized. Two monoclonal antibodies (mAbs) binding to collagen type II (CII) epitopes, J1 and C1I, were used to induce an acute disease in naïve mice. Injection of lipopolysaccharide from E.coli enhanced the incidence and severity of the antibody initiated disease. Subsequently, an improved CAIA was developed... (More)
Rheumatoid arthritis (RA) is a multifactorial, polygenic autoimmune disease. For effective treatment and control of RA, understanding of disease pathways and identification of genes involved are essential. Animal models are efficient tools to identify such pathogenic mechanisms and genes underlying the disease process. In the present study, collagen antibody induced arthritis (CAIA), a mouse model for RA, was established and characterized. Two monoclonal antibodies (mAbs) binding to collagen type II (CII) epitopes, J1 and C1I, were used to induce an acute disease in naïve mice. Injection of lipopolysaccharide from E.coli enhanced the incidence and severity of the antibody initiated disease. Subsequently, an improved CAIA was developed using four mAbs binding to J1, C1I, D3 and U1 epitopes. Interestingly, we found that a single anti-CII mAb is sufficient to induce the disease. CAIA is age, sex, FcgR, complement, IL-1, IL-4 and TNF-a but not B and T cells dependent. Majority of the infiltrating cells in the inflamed joints were neutrophils and macrophages. We also found that CII but not ova specific T cells prolonged the disease course, estrogen treatment ameliorated CAIA and epitope specificity of the mAb is critical for its arthritogenicity. CAIA shares many characteristics of collagen-induced arthritis (CIA), since antibodies play an important role in the inflammatory phase of CIA. Using both CIA and CAIA, we identified the biological significance of the genetic contamination present in the MHC (major histocompatibility) congenic mouse strains in the Cia8 locus on chromosome 10. Significantly, in a backcross experiment using BALB/c and B10.Q mice, we found that heterozygous interactions with the MHC but not the MHC per se could facilitate chronic inflammation. Thus, some of the effector pathways and the gene regions involved in arthritis pathogenesis were identified for future studies. The developed animal model, CAIA, can be used for not only studying inflammatory processes in arthritis and screening drug candidates controlling joint inflammatory phase but also as a model for studying common mechanisms involved in many antibody mediated diseases. (Less)
Please use this url to cite or link to this publication:
author
opponent
  • Professor Heyman, Birgitta, Institute for Genetics and Pathology, Rudbeck laboratory, Uppsala University, Sweden.
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Immunologi, transplantation, Genetik, cytogenetics, Arthritis, mice, monoclonal antibody, collagen type II, Histology, histochemistry, cytochemistry, Histologi, tissue culture, cytokemi, histokemi, Genetics, vävnadskultur, serologi, cytogenetik, Immunology, serology
pages
198 pages
publisher
Medical Inflammation Research, Department of Experimental Medicine, Faculty of Medicine, Lund University
defense location
Rune Grubb lecture hall, Biomedical Center, Lund University, Lund.
defense date
2006-01-27 09:00:00
ISBN
91-85481-30-0
language
English
LU publication?
yes
additional info
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)
id
19190683-c6ba-4096-a498-544d9ac1a4cc (old id 546033)
date added to LUP
2016-04-01 16:07:55
date last changed
2018-11-21 20:38:57
@phdthesis{19190683-c6ba-4096-a498-544d9ac1a4cc,
  abstract     = {Rheumatoid arthritis (RA) is a multifactorial, polygenic autoimmune disease. For effective treatment and control of RA, understanding of disease pathways and identification of genes involved are essential. Animal models are efficient tools to identify such pathogenic mechanisms and genes underlying the disease process. In the present study, collagen antibody induced arthritis (CAIA), a mouse model for RA, was established and characterized. Two monoclonal antibodies (mAbs) binding to collagen type II (CII) epitopes, J1 and C1I, were used to induce an acute disease in naïve mice. Injection of lipopolysaccharide from E.coli enhanced the incidence and severity of the antibody initiated disease. Subsequently, an improved CAIA was developed using four mAbs binding to J1, C1I, D3 and U1 epitopes. Interestingly, we found that a single anti-CII mAb is sufficient to induce the disease. CAIA is age, sex, FcgR, complement, IL-1, IL-4 and TNF-a but not B and T cells dependent. Majority of the infiltrating cells in the inflamed joints were neutrophils and macrophages. We also found that CII but not ova specific T cells prolonged the disease course, estrogen treatment ameliorated CAIA and epitope specificity of the mAb is critical for its arthritogenicity. CAIA shares many characteristics of collagen-induced arthritis (CIA), since antibodies play an important role in the inflammatory phase of CIA. Using both CIA and CAIA, we identified the biological significance of the genetic contamination present in the MHC (major histocompatibility) congenic mouse strains in the Cia8 locus on chromosome 10. Significantly, in a backcross experiment using BALB/c and B10.Q mice, we found that heterozygous interactions with the MHC but not the MHC per se could facilitate chronic inflammation. Thus, some of the effector pathways and the gene regions involved in arthritis pathogenesis were identified for future studies. The developed animal model, CAIA, can be used for not only studying inflammatory processes in arthritis and screening drug candidates controlling joint inflammatory phase but also as a model for studying common mechanisms involved in many antibody mediated diseases.},
  author       = {Kutty Selva, Nandakumar},
  isbn         = {91-85481-30-0},
  language     = {eng},
  publisher    = {Medical Inflammation Research, Department of Experimental Medicine, Faculty of Medicine, Lund University},
  school       = {Lund University},
  title        = {Analysis of effector pathways in arthritis},
  year         = {2006},
}