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Molecular mechanisms and complete antigen formation in allergic contact dermatitis

Ahlfors, Stefan LU (2008) In Lund University, Faculty of Medicine Doctoral Dissertation Series 2008:105.
Abstract
Allergic contact dermatitis (ACD) is a common T cell mediated skin disease. Small reactive organic molecules called haptens induce ACD. Haptens are not recognized by themselves, but need to bond to endogenous proteins in the skin, and processed further into complete antigens. Antigen specific T cells then recognize the resulting antigen. Although the haptens are well known, the chemical reactions of haptens inducing ACD is not well known. Neither are the chemical structures of the complete antigens associated with ACD in humans.

This study is composed of three parts. Reactivity study of strong sensitizers like 2,4-dinitrofluorobenzene (DNFB), 1,4-benzoquinone (BQ), 4-t-butyl-1,2-benzoquinone (tBuBQ) and... (More)
Allergic contact dermatitis (ACD) is a common T cell mediated skin disease. Small reactive organic molecules called haptens induce ACD. Haptens are not recognized by themselves, but need to bond to endogenous proteins in the skin, and processed further into complete antigens. Antigen specific T cells then recognize the resulting antigen. Although the haptens are well known, the chemical reactions of haptens inducing ACD is not well known. Neither are the chemical structures of the complete antigens associated with ACD in humans.

This study is composed of three parts. Reactivity study of strong sensitizers like 2,4-dinitrofluorobenzene (DNFB), 1,4-benzoquinone (BQ), 4-t-butyl-1,2-benzoquinone (tBuBQ) and cis-1,2-hexahydrophthalic-anhydride (HHPA) under physiologic conditions with nucleophilic amino acids and peptides by analytical methods (HPLC, LC/MS/MS). The new reaction products were isolated and their structures were determined by NMR and MS. We found that most haptens reacted predominantly with cystein and cystein containing peptides.

We then synthesized an array of 2,4-dinitrophenyl- (Dnp) modified collagen II peptides, as complete antigens, by solid phase peptide synthesis (SPPS). In a MHC class II (H2-Aq) restricted T cell model of ACD, we evaluated the responses of these antigens. The length of the amino acid side chain bonding the Dnp-group determined the T cell response. Substitution of lysine for ornithine gave a complete loss of T cell recognition.

We finally used homology modeling to construct a model of the H2-Aq/antigen/TCR complex, a part of the ”immunological synapse”. Our new model could explain the experimental T cell responses in terms of a defined structure of the MHC/antigen, and how this structure is displayed for the TCR. This study may contribute to better diagnosis, and possibly a cure of ACD in the future. (Less)
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author
supervisor
opponent
  • Professor Ann-Therese, Karlberg, Avdelningen för dermatokemi och hudallergi, Institutionen för kemi, Göteborgs Universitet
organization
publishing date
type
Thesis
publication status
published
subject
keywords
hypersensitivity, adduct, immune response., Allergy, hapten
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
volume
2008:105
pages
110 pages
publisher
Department of Clinical Sciences, Lund University
defense location
föreläsningssalen, Hudkliniken, Lasarettsgatan 15, Lund
defense date
2008-11-21 13:15
ISSN
1652-8220
ISBN
978-91-86059-58-3
language
English
LU publication?
yes
id
0d3fc213-58f7-4de6-9a9b-868d86f710fd (old id 1261451)
date added to LUP
2008-11-04 11:13:42
date last changed
2016-09-19 08:44:46
@phdthesis{0d3fc213-58f7-4de6-9a9b-868d86f710fd,
  abstract     = {Allergic contact dermatitis (ACD) is a common T cell mediated skin disease. Small reactive organic molecules called haptens induce ACD. Haptens are not recognized by themselves, but need to bond to endogenous proteins in the skin, and processed further into complete antigens. Antigen specific T cells then recognize the resulting antigen. Although the haptens are well known, the chemical reactions of haptens inducing ACD is not well known. Neither are the chemical structures of the complete antigens associated with ACD in humans.<br/><br>
This study is composed of three parts. Reactivity study of strong sensitizers like 2,4-dinitrofluorobenzene (DNFB), 1,4-benzoquinone (BQ), 4-t-butyl-1,2-benzoquinone (tBuBQ) and cis-1,2-hexahydrophthalic-anhydride (HHPA) under physiologic conditions with nucleophilic amino acids and peptides by analytical methods (HPLC, LC/MS/MS). The new reaction products were isolated and their structures were determined by NMR and MS. We found that most haptens reacted predominantly with cystein and cystein containing peptides.<br/><br>
We then synthesized an array of 2,4-dinitrophenyl- (Dnp) modified collagen II peptides, as complete antigens, by solid phase peptide synthesis (SPPS). In a MHC class II (H2-Aq) restricted T cell model of ACD, we evaluated the responses of these antigens. The length of the amino acid side chain bonding the Dnp-group determined the T cell response. Substitution of lysine for ornithine gave a complete loss of T cell recognition. <br/><br>
We finally used homology modeling to construct a model of the H2-Aq/antigen/TCR complex, a part of the ”immunological synapse”. Our new model could explain the experimental T cell responses in terms of a defined structure of the MHC/antigen, and how this structure is displayed for the TCR. This study may contribute to better diagnosis, and possibly a cure of ACD in the future.},
  author       = {Ahlfors, Stefan},
  isbn         = {978-91-86059-58-3},
  issn         = {1652-8220},
  keyword      = {hypersensitivity,adduct,immune response.,Allergy,hapten},
  language     = {eng},
  pages        = {110},
  publisher    = {Department of Clinical Sciences, Lund University},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation Series},
  title        = {Molecular mechanisms and complete antigen formation in allergic contact dermatitis},
  volume       = {2008:105},
  year         = {2008},
}