| 1. |
- Andersson, Ida E., 1982-, et al.
(author)
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(E)-Alkene and Ethylene Isosteres Substantially Alter the Hydrogen-Bonding Network in Class II MHC Aq/Glycopeptide Complexes and Affect T-Cell Recognition
- 2011
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In: Journal of the American Chemical Society. - : American Chemical Society. - 0002-7863 .- 1520-5126. ; 133:36, s. 14368-14378
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Journal article (peer-reviewed)abstract
- The structural basis for antigen presentation by class II major histocompatibility complex (MHC) proteins to CD4(+) T-cells is important for understanding and possibly treating autoimmune diseases. In the work described in this paper, (E)-alkene and ethylene amide-bond isosteres were used to investigate the effect of removing hydrogen-bonding possibilities from the CII259-270 glycopeptide, which is bound by the arthritis-associated murine A(q) class II MHC protein. The isostere-modified glycopeptides showed varying and unexpectedly large losses of A(q) binding that could be linked to the dynamics of the system. Molecular dynamics (MD) simulations revealed that the backbone of CII259-270 and the A(q) protein are able to form up to 11 hydrogen bonds, but fewer than this number are present at any one time. Most of the strong hydrogen-bond interactions were formed by the N-terminal part of the glycopeptide, i.e., in the region where the isosteric replacements were made. The structural dynamics also revealed that hydrogen bonds were strongly coupled to each other; the loss of one hydrogen-bond interaction had a profound effect on the entire hydrogen-bonding network. The A(q) binding data revealed that an ethylene isostere glycopeptide unexpectedly bound more strongly to A(q) than the corresponding (E)-alkene, which is in contrast to the trend observed for the other isosteres. Analysis of the MD trajectories revealed that the complex conformation of this ethylene isostere was structurally different and had an altered molecular interaction pattern compared to the other A(q)/glycopeptide complexes. The introduced amide-bond isosteres also affected the interactions of the glycopeptide/A(q) complexes with T-cell receptors. The dynamic variation of the patterns and strengths of the hydrogen-bond interactions in the class II MHC system is of critical importance for the class II MHC/peptide/TCR signaling system.
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| 2. |
- Haag, Sabrina, et al.
(author)
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Positional Identification of RT1-B (HLA-DQ) as Susceptibility Locus for Autoimmune Arthritis
- 2015
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In: Journal of Immunology. - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 194:6, s. 2539-2550
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Journal article (peer-reviewed)abstract
- Rheumatoid arthritis (RA) is associated with amino acid variants in multiple MHC molecules. The association to MHC class II (MHC-II) has been studied in several animal models of RA. In most cases these models depend on T cells restricted to a single immunodominant peptide of the immunizing Ag, which does not resemble the autoreactive T cells in RA. An exception is pristane-induced arthritis (PIA) in the rat where polyclonal T cells induce chronic arthritis after being primed against endogenous Ags. In this study, we used a mixed genetic and functional approach to show that RT1-Ba and RT1-Bb (RT1-B locus), the rat orthologs of HLA-DQA and HLA-DQB, determine the onset and severity of PIA. We isolated a 0.2-Mb interval within the MHC-II locus of three MHC-congenic strains, of which two were protected from severe PIA. Comparison of sequence and expression variation, as well as in vivo blocking of RT1-B and RT1-D (HLA-DR), showed that arthritis in these strains is regulated by coding polymorphisms in the RT1-B genes. Motif prediction based on MHC-II eluted peptides and structural homology modeling suggested that variants in the RT1-B P1 pocket, which likely affect the editing capacity by RT1-DM, are important for the development of PIA.
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| 3. |
- Haag, Sabrina
(author)
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The MHC and the recognition of self and altered self in experimental and rheumatoid arthritis
- 2014
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Doctoral thesis (other academic/artistic)abstract
- The Major histocompatibility complex (MHC) is a highly polymorphic and gene-dense region on chromosome 6 in humans and 20 in the rat. Genes in the MHC are the major risk factor for the development of autoimmunity. Rheumatoid arthritis (RA) is a common autoimmune disease with a strong association to a specific subset of HLA-DRB1 alleles, which encode a shared amino acid motif in the HLA-DRβ chain. This shared epitope (SE) contributes to the formation of the P4 pocket in the peptide-binding groove of the HLA-DR complex. Recently, two weaker associations to the MHC class I gene HLA-B and to a second MHC class II gene, HLA-DPB1, have been identified. Whereas the dissection of the genetic association between autoimmunity and the MHC has progressed rapidly in the last decade, the functional role of the MHC genes in the development of autoimmunity has not yet been resolved to the same extent. The work presented in this thesis represents some of our efforts to contribute to this understanding. Paper I describes our attempts to induce arthritis with α-enolase and citrullinated α-enolase in HLA-DR4 transgenic mice. Based on the strong genetic association between antibodies to citrullinated α-enolase peptide 1 (CEP-1) and HLA-DRB1 SE alleles, we aimed to identify if anti-CEP-1 antibodies can be induced in mice transgenic for a human HLA-DRB1 SE allele, and if this would depend on a citrullinated HLA-DRB1*0401 restricted T cell epitope. We could neither prove that native or citrullinated α-enolase induced arthritis nor did we observe a citrulline specific B or T cell response. In Paper II we investigated the relevance and the extent of joint-directed anti-citrulline immunity in RA. We identified two citrullinated antibody epitopes on type II collagen (CII) present in 17% and 21% of RA patients. Anti-citrullinated CII reactivity partly overlapped with the reactivity towards CEP-1, however only antibodies directed to citrullinated CII bound to RA cartilage specimens. This suggests that antibodies directed to citrullinated CII may contribute to the inflammatory process in the joints. Paper III-V summarizes our work concerning the influence of allelic variation in the rat MHC on T cell selection, MHC expression and susceptibility to autoimmune arthritis. Paper III introduces our panel of intra-MHC congenic strains and demonstrates that an interaction between the RT1-A genes in the MHC class I and Tap2 in the MHC class II region regulates the negative selection of CD8 T cells. The RT1-A genes are part of a haplotype designated T cell selection QTL-1 (Tcs1), whereas Tap2 is in linkage disequilibrium with the MHC class II genes, in the locus designated T cell selection QTL-2 (Tcs2). In Paper IV we evaluated the impact of these two QTL on the regulation of Pristane-induced arthritis (PIA). Allelic variation in Tcs1 did not influence PIA, whereas Tcs2 regulated the onset and the severity of PIA. A comparison of the amino acid polymorphisms between the haplotypes as well as functional studies suggested a major contribution of the HLA-DQ homolog RT1-B to the development of PIA. It has earlier been demonstrated that pristane-primed CD4 T cells transfer arthritis in naive recipients. To investigate how the MHC-II haplotype affects T cell priming and the subsequent PIA development, we characterized the T cell compartment after pristane administration. The frequency of Th1 cells correlated with an early onset of PIA and reduced arthritis severity in one haplotype was associatedwith a high ratio of T regulatory to T effector cells. These results are presented in Paper V.
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| 4. |
- Lindgren, Cecilia, et al.
(author)
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Hydroxyethylene isosteres introduced in type II collagen fragments substantially alter the structure and dynamics of class II MHC A(q)/glycopeptide complexes
- 2015
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In: Organic and biomolecular chemistry. - : Royal Society of Chemistry (RSC). - 1477-0520 .- 1477-0539. ; 13:22, s. 6203-6216
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Journal article (peer-reviewed)abstract
- Class II major histocompatibility complex (MHC) proteins are involved in initiation of immune responses to foreign antigens via presentation of peptides to receptors of CD4(+) T-cells. An analogous presentation of self-peptides may lead to autoimmune diseases, such as rheumatoid arthritis (RA). The glycopeptide fragment CII259-273, derived from type II collagen, is presented by A(q) MHCII molecules in the mouse and has a key role in development of collagen induced arthritis (CIA), a validated model for RA. We have introduced hydroxyethylene amide bond isosteres at the Ala(261)-Gly(262) position of CII259-273. Biological evaluation showed that A(q) binding and T cell recognition were dramatically reduced for the modified glycopeptides, although static models predicted similar binding modes as the native type II collagen fragment. Molecular dynamics (MD) simulations demonstrated that introduction of the hydroxyethylene isosteres disturbed the entire hydrogen bond network between the glycopeptides and A(q). As a consequence the hydroxyethylene isosteric glycopeptides were prone to dissociation from A(q) and unfolding of the beta(1)-helix. Thus, the isostere induced adjustment of the hydrogen bond network altered the structure and dynamics of A(q)/glycopeptide complexes leading to the loss of A(q) affinity and subsequent T cell response.
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| 5. |
- Tuncel, Jonatan, et al.
(author)
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Self-reactive T cells induce and perpetuate chronic relapsing arthritis
- 2020
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In: Arthritis Research and Therapy. - : Springer Science and Business Media LLC. - 1478-6354 .- 1478-6362. ; 22:1
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Journal article (peer-reviewed)abstract
- Background: CD4+ T cells play a central role during the early stages of rheumatoid arthritis (RA), but to which extent they are required for the perpetuation of the disease is still not fully understood. The aim of the current study was to obtain conclusive evidence that T cells drive chronic relapsing arthritis. Methods: We used the rat pristane-induced arthritis model, which accurately portrays the chronic relapsing-remitting disease course of RA, to examine the contribution of T cells to chronic arthritis. Results: Rats subjected to whole-body irradiation and injected with CD4+ T cells from lymph nodes of pristane-injected donors developed chronic arthritis that lasted for more than 4 months, whereas T cells from the spleen only induced acute disease. Thymectomy in combination with irradiation enhanced the severity of arthritis, suggesting that sustained lymphopenia promotes T cell-driven chronic inflammation in this model. The ability of T cells to induce chronic arthritis correlated with their expression of Th17-associated transcripts, and while depletion of T cells in rats with chronic PIA led to transient, albeit significant, reduction in disease, neutralization of IL-17 resulted in almost complete and sustained remission. Conclusion: These findings show that, once activated, self-reactive T cells can sustain inflammatory responses for extended periods of time and suggest that such responses are promoted in the presence of IL-17.
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| 6. |
- Uysal, Hüseyin, et al.
(author)
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Antibodies to citrullinated proteins : molecular interactions and arthritogenicity
- 2010
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In: Immunological Reviews. - Hoboken, NJ : Wiley-Blackwell Publishing Inc.. - 0105-2896 .- 1600-065X. ; 233:1, s. 9-33
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Journal article (peer-reviewed)abstract
- The discovery of antibodies specific for citrullinated protein epitopes [anti-citrullinated protein antibodies (ACPAs)] is a hallmark for the diagnosis and prognosis of rheumatoid arthritis (RA) and will also be a useful tool for understanding the fundamental pathologic processes. There are several essential questions pertaining to ACPA that remain to be explored, such as understanding the early specificity of the underlying T-cell recognition, whether the production of ACPA is a primary or secondary process, and in the event of such antibodies being arthritogenic, whether they could possibly regulate the disease development. To answer these questions, animal models are needed, but unfortunately ACPA is not a prominent feature of any of the classical animal models of RA. However, we showed recently that ACPA can be isolated from animals susceptible to collagen-induced arthritis that are specific for citrullinated type II collagen (CII). The citrulline specificity could be visualized, and the specificity is determined primarily by a direct interaction with citrulline. We also demonstrated that these antibodies are specific for the citrullinated epitopes and are pathogenic in vivo. A new hypothesis to explain how inflammation in RA can be directed to cartilaginous joints and be self-perpetuating is suggested, which involves recognition of post-translational modifications (glycosylation and citrullination) on CII by T and B cells that can have both arthritogenic and regulatory consequences. © 2009 John Wiley & Sons A/S.
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