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Structural and Functional Studies on Posttranslational Modifications of Collagen type II in Rheumatoid Arthritis.

Uysal, Hüseyin LU (2008)
Abstract
The molecular mechanisms behind the development and progression of rheumatoid

arthritis are not known in fine details. Both humoral and cellular responses against

collagen type II in joint cartilage seems to be important for the disease development.

Especially posttranslational modifications on collagen type II are important in regulation

of molecular mechanisms implicated in the disease. In this thesis we tried to identify

molecular principles of anti-collagen immunity and its relation with pathogenicity by

mainly X-ray crystallography. The crystal structure of anti-collagen antibody CIIC1

showed that it not only binds to collagen type II but also cross reacts with... (More)
The molecular mechanisms behind the development and progression of rheumatoid

arthritis are not known in fine details. Both humoral and cellular responses against

collagen type II in joint cartilage seems to be important for the disease development.

Especially posttranslational modifications on collagen type II are important in regulation

of molecular mechanisms implicated in the disease. In this thesis we tried to identify

molecular principles of anti-collagen immunity and its relation with pathogenicity by

mainly X-ray crystallography. The crystal structure of anti-collagen antibody CIIC1

showed that it not only binds to collagen type II but also cross reacts with other

immunoglobulins which is the typical behavior of rheumatoid factors. The arthritogenic

and collagen specific antibody CIIC1 with this dual behavior suggests that RFs specific

for joint proteins may form large immune complexes in the joints and simultaneously

trigger inflammation and create a vicious cycle that produces new RFs in the way to a

complete RA. The second article from the thesis describes the recognition of a

citrullinated peptide from collagen type II by the arthritis enhancing antibody ACC4. The

structure provides important clues explaining the higher antigenicity of the citrullinated

peptide therefore the high titer of the ACPA antibodies in RA. In addition, we also

showed that the citrullinated CII epitopes recognized by ACC4 and other ACC antibodies

exist on the inflamed cartilage and in the synovial fluid which suggests that ACPA

antibodies play a role in a vicious cycle that keeps inflammation continuing.

Inflammation causes the formation of citrullinated antigenic epitopes or peptides which

drives the formation of new ACPA antibodies eventually paves the way to a chronic

inflammation and RA. The last two papers describe our experimental design to

understand the role of cellular response against collagen type II and against another

posttranslational modification which is glycosylation on collagen type II. In this context,

we reported, in paper III, the experimental procedure that resulted in successful

crystallization of MHC class II Aq presenting immunodominant CII peptide. In paper IV,

experimental design for efficient production of Aq restricted collagen specific T cell

receptors HCQ3 and HCR2 in insect cells by fusing to leucine zippers were described. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Dr. Stura, Enrico, Institute of Biology and Technology, Saclay, France
organization
publishing date
type
Thesis
publication status
published
subject
pages
142 pages
publisher
Department of Molecular Biophysics, Lund University
defense location
Seminerrum E, Kemicentrum, Getingevägen 60, Lund
defense date
2008-05-20 10:00
ISBN
978-91-7422-195-4
language
English
LU publication?
yes
id
53a36616-ce7f-4122-8084-e7c13dc6a8da (old id 1144982)
date added to LUP
2008-04-25 09:35:11
date last changed
2016-09-19 08:45:07
@misc{53a36616-ce7f-4122-8084-e7c13dc6a8da,
  abstract     = {The molecular mechanisms behind the development and progression of rheumatoid<br/><br>
arthritis are not known in fine details. Both humoral and cellular responses against<br/><br>
collagen type II in joint cartilage seems to be important for the disease development.<br/><br>
Especially posttranslational modifications on collagen type II are important in regulation<br/><br>
of molecular mechanisms implicated in the disease. In this thesis we tried to identify<br/><br>
molecular principles of anti-collagen immunity and its relation with pathogenicity by<br/><br>
mainly X-ray crystallography. The crystal structure of anti-collagen antibody CIIC1<br/><br>
showed that it not only binds to collagen type II but also cross reacts with other<br/><br>
immunoglobulins which is the typical behavior of rheumatoid factors. The arthritogenic<br/><br>
and collagen specific antibody CIIC1 with this dual behavior suggests that RFs specific<br/><br>
for joint proteins may form large immune complexes in the joints and simultaneously<br/><br>
trigger inflammation and create a vicious cycle that produces new RFs in the way to a<br/><br>
complete RA. The second article from the thesis describes the recognition of a<br/><br>
citrullinated peptide from collagen type II by the arthritis enhancing antibody ACC4. The<br/><br>
structure provides important clues explaining the higher antigenicity of the citrullinated<br/><br>
peptide therefore the high titer of the ACPA antibodies in RA. In addition, we also<br/><br>
showed that the citrullinated CII epitopes recognized by ACC4 and other ACC antibodies<br/><br>
exist on the inflamed cartilage and in the synovial fluid which suggests that ACPA<br/><br>
antibodies play a role in a vicious cycle that keeps inflammation continuing.<br/><br>
Inflammation causes the formation of citrullinated antigenic epitopes or peptides which<br/><br>
drives the formation of new ACPA antibodies eventually paves the way to a chronic<br/><br>
inflammation and RA. The last two papers describe our experimental design to<br/><br>
understand the role of cellular response against collagen type II and against another<br/><br>
posttranslational modification which is glycosylation on collagen type II. In this context,<br/><br>
we reported, in paper III, the experimental procedure that resulted in successful<br/><br>
crystallization of MHC class II Aq presenting immunodominant CII peptide. In paper IV,<br/><br>
experimental design for efficient production of Aq restricted collagen specific T cell<br/><br>
receptors HCQ3 and HCR2 in insect cells by fusing to leucine zippers were described.},
  author       = {Uysal, Hüseyin},
  isbn         = {978-91-7422-195-4},
  language     = {eng},
  pages        = {142},
  publisher    = {ARRAY(0x9c50b68)},
  title        = {Structural and Functional Studies on Posttranslational Modifications of Collagen type II in Rheumatoid Arthritis.},
  year         = {2008},
}