Post by kickingfrog on Dec 6, 2011 8:58:56 GMT
Gastroenterology. 2011 Nov 18. [Epub ahead of print]
T-Cell Response to Gluten in Patients with HLA-DQ2.2 Reveals Requirement of Peptide-MHC Stability in Celiac Disease.
Bodd M, Kim CY, Lundin KE, Sollid LM.
Source
Centre for Immune Regulation and Department of Immunology, Oslo University Hospital-Rikshospitalet, 0027 Oslo, Norway.
Abstract
BACKGROUND & AIMS:
Celiac disease is a diet-induced, T-cell mediated enteropathy.
The HLA variant DQ2.5 increases risk for the disease, and the homologous DQ2.2 confers a lower level of risk.
As many as 5% of patients with celiac disease carry DQ2.2 without any other risk alleles.
Epitopes commonly recognized by T cells of patients with HLA DQ2.5 bind stably to DQ2.5 but unstably to DQ2.2.
We investigated the response to gluten in patients with HLA DQ2.2.
METHODS:
We generated intestinal T-cell lines and clones from 7 patients with HLA DQ2.2 (but not DQ2.5), and characterized the cells' responses to gluten. The epitope off-rate was evaluated by gel filtration and T-cell based assays. Peptide binding to DQ2.2 was studied with peptide substitutes and DQ2 mutants.
RESULTS:
Patients with DQ2.2 and no other risk alleles had gluten-reactive T cells that did not respond to the common, DQ2.5-restricted, T-cell epitopes.
Instead, many of the T cells responded to a distinct epitope that was not recognized by those from patients with HLA DQ2.5.
This immunodominant epitope bound stably to DQ2.2. A serine residue at P3 was required for the stable binding.
The effect of this residue related to a polymorphism at DQá22 which was previously shown to determine stable binding of peptides to DQ2.5.
CONCLUSION:
High levels of kinetic stability of peptide-MHC complexes are required to generate T-cell responses to gluten in celiac disease; the lower risk from DQ2.2 relates to constraints imposed on gluten peptides to stably bind this HLA molecule.
These observations increase our understanding of the role of the MHC in determining T-cell responses in patients with celiac disease and are important for peptide-based vaccination strategies.
Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.
PMID:
22108197
[PubMed - as supplied by publisher]
****************
From Bob
What language is this? Have you got subtitles?
**************
From Charlotte
The study is looking for very precise information on the faulty reaction (T-cell response) to (harmless) wheat proteins (peptides) in coeliac disease, by comparing (in the lab) the responses of cells from patients with very similar but subtly different genes (the DQ2 haplotype).
DQ2.5 is what most (more than 90%) coeliacs have, (which BTW also includes the most typical gut symptoms and increases the risk of of non-responsive CD).
DQ2.2 is very similar but seems not to carry the same risks - only 5% of coeliacs have this (and they seem to be less typical).
This is all at a molecular level and complex stuff. This kind of research is hopefully leading towards a vaccine for CD (or preventative strategies in at-risk groups) but perhaps even more importantly is contributing to the understanding of other "inappropriate" (ie disease-causing) immune responses in other auto-immune diseaseas like Type 1 Diabetes and Rheumatoid Arthritis for which the 'triggers' are still unknown. It's only possible to do this kind of research on coeliac patients because the trigger (gluten) is known, although it is clearly very complex.
The naming of the haplotypes is almost as confusing especially as many have been re-named and they all sound the same. I think this also relates to the 'gene dose effect'.
Refs (often best just to read 'Discussion'):
From the immunologist Ludwig Sollid:
"A strong anti-gluten T cell response require high HLA binding stability of gluten peptides, and the disparate HLA association between two closely related HLA molecules, HLA-DQ2.5 and HLA-DQ2.2, seems to relate to this phenomenon...[Similar findings] highlight [the fact that] that coeliac disease offers unique opportunities for dissection of T cell and B cell responses that lead to an autoimmune disease."
Coeliac disease: the showcase of interaction between genes, environment and immunology in chronic tissue inflammation [ie auto-immune disorders]
Ludvig M Sollid Centre for Immune Regulation, Institute of Immunology, University of Oslo
and Oslo University Hospital, Oslo, Norway
Journal of Translational Medicine 2011, 9(Suppl 2):I1
www.pnas.org/content/100/21/12390.full
The HLA-DQ2 gene dose effect in celiac disease is directly related to the magnitude and breadth of gluten-specific T cell responses.
Willemijn Vader et al, Proc Natl Acad Sci U S A. 2003 Oct 14;100 (21):12390-5 14530392 Cit:89
In patients with celiac disease, inflammatory T cell responses to HLA-DQ2-bound gluten peptides are thought to cause disease. Two types of HLA-DQ2 molecules exist, termed HLA-DQ2.5 and HLA-DQ2.2. Whereas HLA-DQ2.5 predisposes to celiac disease, HLA-DQ2.2 does not. We now provide evidence that the disease-associated HLA-DQ2.5 molecule presents a large repertoire of gluten peptides, whereas the non-disease-associated HLA-DQ2.2 molecule can present only a subset of these....
...Discussion
....In conclusion, this study provides an explanation for the HLA-DQ2 gene dose effect in the development of CD. Similar mechanisms may form the basis for HLA-gene dose effects in other diseases, including type I diabetes, rheumatoid arthritis, and multiple sclerosis
More on this here:
immunology.ucsf.edu/immuno/courses/micro204/2010/HLA%20and%20Celiac%20Disease.pdf
DISCUSSION
Of the two highly homologous [genetically alike] HLA-DQ2 molecules DQ2.5 and DQ2.2, which have almost identical specificity for antigen peptide binding and can both present gluten peptides, only DQ2.5 is strongly associated with a predisposition to celiac disease. Why this is so has been an enigma
***************
T-Cell Response to Gluten in Patients with HLA-DQ2.2 Reveals Requirement of Peptide-MHC Stability in Celiac Disease.
Bodd M, Kim CY, Lundin KE, Sollid LM.
Source
Centre for Immune Regulation and Department of Immunology, Oslo University Hospital-Rikshospitalet, 0027 Oslo, Norway.
Abstract
BACKGROUND & AIMS:
Celiac disease is a diet-induced, T-cell mediated enteropathy.
The HLA variant DQ2.5 increases risk for the disease, and the homologous DQ2.2 confers a lower level of risk.
As many as 5% of patients with celiac disease carry DQ2.2 without any other risk alleles.
Epitopes commonly recognized by T cells of patients with HLA DQ2.5 bind stably to DQ2.5 but unstably to DQ2.2.
We investigated the response to gluten in patients with HLA DQ2.2.
METHODS:
We generated intestinal T-cell lines and clones from 7 patients with HLA DQ2.2 (but not DQ2.5), and characterized the cells' responses to gluten. The epitope off-rate was evaluated by gel filtration and T-cell based assays. Peptide binding to DQ2.2 was studied with peptide substitutes and DQ2 mutants.
RESULTS:
Patients with DQ2.2 and no other risk alleles had gluten-reactive T cells that did not respond to the common, DQ2.5-restricted, T-cell epitopes.
Instead, many of the T cells responded to a distinct epitope that was not recognized by those from patients with HLA DQ2.5.
This immunodominant epitope bound stably to DQ2.2. A serine residue at P3 was required for the stable binding.
The effect of this residue related to a polymorphism at DQá22 which was previously shown to determine stable binding of peptides to DQ2.5.
CONCLUSION:
High levels of kinetic stability of peptide-MHC complexes are required to generate T-cell responses to gluten in celiac disease; the lower risk from DQ2.2 relates to constraints imposed on gluten peptides to stably bind this HLA molecule.
These observations increase our understanding of the role of the MHC in determining T-cell responses in patients with celiac disease and are important for peptide-based vaccination strategies.
Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.
PMID:
22108197
[PubMed - as supplied by publisher]
****************
From Bob
What language is this? Have you got subtitles?
**************
From Charlotte
The study is looking for very precise information on the faulty reaction (T-cell response) to (harmless) wheat proteins (peptides) in coeliac disease, by comparing (in the lab) the responses of cells from patients with very similar but subtly different genes (the DQ2 haplotype).
DQ2.5 is what most (more than 90%) coeliacs have, (which BTW also includes the most typical gut symptoms and increases the risk of of non-responsive CD).
DQ2.2 is very similar but seems not to carry the same risks - only 5% of coeliacs have this (and they seem to be less typical).
This is all at a molecular level and complex stuff. This kind of research is hopefully leading towards a vaccine for CD (or preventative strategies in at-risk groups) but perhaps even more importantly is contributing to the understanding of other "inappropriate" (ie disease-causing) immune responses in other auto-immune diseaseas like Type 1 Diabetes and Rheumatoid Arthritis for which the 'triggers' are still unknown. It's only possible to do this kind of research on coeliac patients because the trigger (gluten) is known, although it is clearly very complex.
The naming of the haplotypes is almost as confusing especially as many have been re-named and they all sound the same. I think this also relates to the 'gene dose effect'.
Refs (often best just to read 'Discussion'):
From the immunologist Ludwig Sollid:
"A strong anti-gluten T cell response require high HLA binding stability of gluten peptides, and the disparate HLA association between two closely related HLA molecules, HLA-DQ2.5 and HLA-DQ2.2, seems to relate to this phenomenon...[Similar findings] highlight [the fact that] that coeliac disease offers unique opportunities for dissection of T cell and B cell responses that lead to an autoimmune disease."
Coeliac disease: the showcase of interaction between genes, environment and immunology in chronic tissue inflammation [ie auto-immune disorders]
Ludvig M Sollid Centre for Immune Regulation, Institute of Immunology, University of Oslo
and Oslo University Hospital, Oslo, Norway
Journal of Translational Medicine 2011, 9(Suppl 2):I1
www.pnas.org/content/100/21/12390.full
The HLA-DQ2 gene dose effect in celiac disease is directly related to the magnitude and breadth of gluten-specific T cell responses.
Willemijn Vader et al, Proc Natl Acad Sci U S A. 2003 Oct 14;100 (21):12390-5 14530392 Cit:89
In patients with celiac disease, inflammatory T cell responses to HLA-DQ2-bound gluten peptides are thought to cause disease. Two types of HLA-DQ2 molecules exist, termed HLA-DQ2.5 and HLA-DQ2.2. Whereas HLA-DQ2.5 predisposes to celiac disease, HLA-DQ2.2 does not. We now provide evidence that the disease-associated HLA-DQ2.5 molecule presents a large repertoire of gluten peptides, whereas the non-disease-associated HLA-DQ2.2 molecule can present only a subset of these....
...Discussion
....In conclusion, this study provides an explanation for the HLA-DQ2 gene dose effect in the development of CD. Similar mechanisms may form the basis for HLA-gene dose effects in other diseases, including type I diabetes, rheumatoid arthritis, and multiple sclerosis
immunology.ucsf.edu/immuno/courses/micro204/2010/HLA%20and%20Celiac%20Disease.pdf
DISCUSSION
Of the two highly homologous [genetically alike] HLA-DQ2 molecules DQ2.5 and DQ2.2, which have almost identical specificity for antigen peptide binding and can both present gluten peptides, only DQ2.5 is strongly associated with a predisposition to celiac disease. Why this is so has been an enigma
***************