Ludvig M Sollid

..We conclude that future development of novel therapies will be aided considerably by the identification of new, preferably noninvasive, surrogate markers for coeliac disease activity...

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..This insight gives clues for understanding the involvement of PTMs in other autoimmune diseases...

..In this work, we give an overview of these epitopes and suggest a comprehensive, new nomenclature...

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..Other possible treatments include cytokine therapy, and selective adhesion molecule inhibitors that interfere with inflammatory reactions, some of which are already showing promise in the clinic for other gastrointestinal diseases...

..Here we discuss how the new insight in the pathogenesis has lead to development of new diagnostics and nourished research into novel treatments...

..In light of this, the many autoimmune phenomena associated with celiac disease are thought-provoking, and they challenge us to rethink the boundaries between autoimmunity and immunopathology...

..The 33-mer is thus a potent T cell stimulator that does not require further processing within APC for T cell presentation and that binds to DQ2 with a pH profile that promotes extracellular binding...

..Peptides combining the DQ2 and DQ8 signatures could be presented by DQ2, DQ8, and trans-encoded DQ heterodimers. Our findings shed light on the basis for the HLA associations in celiac disease and type 1 diabetes...

..This was observed also for gliadin peptides introducing a novel route for the generation of deamidated T cell epitopes in celiac disease...

..This could result in preferential recruitment of plasma cells from naive IgD- and IgM-expressing B cells, thus possibly explaining why the antibody response to TG2 bears signs of a primary immune response despite the disease chronicity...

..Contrary to previous findings, our data do not show selective presentation of DQ2.5 over DQ2.2 for gluten epitopes that carry proline residues at the P3 position...

..In this study we aimed to identify the preferred peptide substrates of TG2 in a heterogeneous proteolytic digest of whole wheat gluten...

..In comparison, DQ8 exhibits different binding characteristics, which may explain the lesser risk for disease in association with this molecule...

..3 together with all other available DQ crystal structures and sequences led us to categorize DQA1 and DQB1 genes into two groups where any α-chain and β-chain belonging to the same group are expected to form a stable heterodimer...

..Thus, the rate of deamidation by TG2 appears to be a factor of importance for the T-cell response to gluten in celiac disease...

..The aim of this study was to identify the antigen-presenting cells that are responsible for the activation of gluten-reactive T cells in the celiac lesion...

..The results demonstrate that the gluten T-cell epitopes mainly bind to the DQ2 molecule...

..2 (phenylalanine) cannot. Our findings suggest that the kinetic stability of complexes of peptide and major histocompatibility complex (MHC) is of importance for the association of HLA with disease...

..This study demonstrates that the human small intestine harbors a population of nonproliferating plasma cells that are instructed by the microenvironment for prolonged survival and Ab secretion...

..Interestingly, TG2 is able to hydrolyze the peptide-histamine conjugates when the concentrations of substrates are lowered, thereby releasing deamidated gluten peptides that are stimulatory to T cells...

..The differential ability of DQ8 and DQ9 to harness a negatively charged anchor at P9 may result in fewer potential gluten epitopes in DQ9 patients. Our data further indicate that DQ9 is a susceptibility factor for celiac disease...

..Clinical follow-up of celiac disease patients eating oats is advisable...

..This is a unique feature of DQ2 and is likely a key parameter for preferential binding of proline-rich gluten peptides and development of celiac disease...

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..However, this finding may not exclude an effect of these autoantibodies on citrullination of protein substrates in RA...

..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...

..Most of the cells had a memory phenotype, but many other phenotypic markers showed a heterogeneous pattern. Tetramer staining of gluten-specific T cells has the potential to be used for diagnosis of celiac disease...

..We suggest that the unusual interaction of DQ2 with Ii and DM may provide a basis for the known disease associations of DQ2...

..Thus, single loops in C regions of recombinant antibodies seem versatile and may be used for delivery of lengthy, complex and multiple T cell epitopes to human APCs...

..Collective effects of multiple risk genes within the region, incomplete genetic coverage or effects related to copy number variation are possible explanations for our findings...

..The results are relevant to the understanding of how antibodies to TG2 are formed in celiac disease...

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..The findings have implications for understanding T cell responses to posttranslationally modified Ags...

..On the other hand, we were unable to reproduce our initial findings in the T1D case-control dataset (global p=0.6). Our results suggest that the tested FOXP3 markers do not have any major impact on susceptibility for these diseases...

..Further mapping of this fragment of 54 residues identified a pentadecapeptide with high affinity for sDQ2 which may serve as a lead compound for the design of HLA-DQ2 blockers...

..This dissection of the pathogenic mechanisms of coeliac disease has uncovered principles that are relevant to other chronic inflammatory diseases...

..The response is characterized by a strong Th1/Th17 response, but the relative importance of the various bacteria is not known...

..In conclusion, we confirmed in this study, the largest of its kind, that additional CD risk factors independent of DQ2 alleles do exist on the DR3 haplotype...

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..Here we review recent developments in the understanding of the role of T cells, B cells, and antigen-presenting cells in the pathogenic immune response of this instructive disorder...

..Our findings suggest that oxidation is likely to influence the amount of active TG2 present in the extracellular environment...

..Our findings lend credence to the notion that TG3 and TG6 are involved in the gluten-induced autoimmune responses of DH and GA...

..5 peptide binding motif. This novel method, limited by library complexity and sensitivity of mass spectrometry, allows the analysis of several thousand synthetic sequences concomitantly in a simple water soluble format...

..Alternatively, it might be due to variable linkage disequilibria in distinct populations in the tested SNPs and a causative mutation yet to be identified or to false positive findings (type I error) in the Dutch study...

..Our approach represents a straightforward strategy for developing high-affinity binders to HLA class II molecules...

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..Finally, we observed that a methylated lysine residue flanking the targeted arginine influences PAD-4-mediated deimination, also suggesting that posttranslational modifications can affect substrate efficiency...

..Non-celiac gluten sensitivity (NCGS) is another form of gluten intolerance where the immune response is less characterized. The aim of our study was to explore and compare the early mucosal immunological events in CD and NCGS...

..In this issue of Immunity, two papers uncover mechanisms controlling the cytolytic potential of these cells and provide evidence that lymphocyte killing of enterocytes is an important part of the celiac disease pathogenesis...

..The experiences from coeliac disease should therefore help identify disease-relevant T-cell epitopes in rheumatoid arthritis...

..This likely reflects epitope selection at the levels of digestive and antigen-presenting cell processing, transglutaminase-mediated deamidation, and/or peptide binding to DQ2...

..This effect should be tested in large populations with significant representations of both B8-DR3 and non-B8 DR3 haplotypes...

..The results presented should facilitate the development of tags that can be used for the enrichment and subsequent detection of citrulline-containing protein fragments by mass spectrometry...

..The potential benefit of reducing the heterogeneity of clinically defined diseases by the careful phenotyping of patients, cells and lesions using advanced molecular biology and imaging techniques is highlighted...

..This suggests that the deamidation of gluten peptides by TG2 more likely takes place in slightly acidic environments...

..These results strongly argue that DC-SIGN-specific mAb are channeled into the MHC class II presentation pathway. Thus, DC-SIGN could be an efficient target for antibody-mediated delivery of T cell epitopes in vaccine development...

..Here we review the current knowledge of this B-cell response and how it is induced, and we discuss key questions to be addressed in future research...

..These results underline the primary importance of HLA-DQ alleles in susceptibility to celiac disease, and the extreme rarity of celiac patients carrying neither the DQ2 or DQ8 heterodimers nor one half of the DQ2 heterodimer alone...

..This region was suggested by several individual studies, but did not reach statistical values high enough to be conclusive when data sets were analysed separately...

..In recent years we have gained new knowledge of the molecular basis of this disorder; this paper gives an overview of the current understanding of the pathogenesis of coeliac disease...

..Finally, surface-exposed proline residues in the proteolytically resistant ligand were replaced with functionalized analogs, thereby providing a starting point for the design of orally active agents for blocking gluten-induced toxicity...

..The peptide could be detoxified in in vitro and in vivo assays by exposure to a bacterial prolyl endopeptidase, suggesting a strategy for oral peptidase supplement therapy for Celiac Sprue...

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..2 A resolution and provided atomic insights into the observed subsite specificity of the endoprotease. Our findings suggest that orally administered proEP-B2 may be especially well suited for treatment of celiac sprue...

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..Coeliac disease can also exist with a normal serology. The trend in many countries is to require less pronounced mucosal abnormalities than previously for the diagnosis...

..One dimeric peptide analogue with an intermediate linker length was found to be especially effective at inhibiting DQ2 mediated antigen presentation. The implications of these findings for the treatment of celiac disease are discussed...

..Together, these observations provide a unique explanation for the disease inducing capacity of gluten...

..This editorial discusses this possibility in relation to the current understanding of the molecular basis of this disorder...

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