Asbjørn Otto Christophersen

• Risnes, Louise Fremgaard; Reims, Henrik Mikael; Doyle, Ronan Mathieu; Qiao, Shuo-Wang; Sollid, Ludvig Magne & Lundin, Knut [Vis alle 7 forfattere av denne artikkelen] (2024). Gluten-Free Diet Induces Rapid Changes in Phenotype and Survival Properties of Gluten-Specific T Cells in Celiac Disease. Gastroenterology. ISSN 0016-5085. 167(2), s. 250–263. doi: 10.1053/j.gastro.2024.03.027. Fulltekst i vitenarkiv Vis sammendrag

  Background & Aims The treatment of celiac disease (CeD) with gluten-free diet (GFD) normalizes gut inflammation and disease-specific antibodies. CeD patients have HLA-restricted, gluten-specific T cells persisting in the blood and gut even after decades of GFD, which are reactivated and disease driving upon gluten exposure. Our aim was to examine the transition of activated gluten-specific T cells into a pool of persisting memory T cells concurrent with normalization of clinically relevant biomarkers during the first year of treatment. Methods We followed 17 CeD patients during their initial GFD year, leading to disease remission. We assessed activation and frequency of gluten-specific CD4+ blood and gut T cells with HLA-DQ2.5:gluten tetramers and flow cytometry, disease-specific serology, histology, and symptom scores. We assessed gluten-specific blood T cells within the first 3 weeks of GFD in 6 patients and serology in an additional 9 patients. Results Gluten-specific CD4+ T cells peaked in blood at day 14 while up-regulating Bcl-2 and down-regulating Ki-67 and then decreased in frequency within 10 weeks of GFD. CD38, ICOS, HLA-DR, and Ki-67 decreased in gluten-specific cells within 3 days. PD-1, CD39, and OX40 expression persisted even after 12 months. IgA–transglutaminase 2 decreased significantly within 4 weeks. Conclusions GFD induces rapid changes in the phenotype and number of gluten-specific CD4+ blood T cells, including a peak of nonproliferating, nonapoptotic cells at day 14. Subsequent alterations in T-cell phenotype associate with the quiescent but chronic nature of treated CeD. The rapid changes affecting gluten-specific T cells and disease-specific antibodies offer opportunities for clinical trials aiming at developing nondietary treatments for patients with newly diagnosed CeD.

• Santos, António J. M.; Unen, Vincent van; Lin, Zhongqi; Chirieleison, Steven M.; Ha, Nhi & Batish, Arpit [Vis alle 31 forfattere av denne artikkelen] (2024). A human autoimmune organoid model reveals IL-7 function in coeliac disease. Nature. ISSN 0028-0836. 632(8024), s. 401–410. doi: 10.1038/s41586-024-07716-2. Fulltekst i vitenarkiv
• Lindeman, Ida; Høydahl, Lene Støkken; Christophersen, Asbjørn Otto; Risnes, Louise Fremgaard; Jahnsen, Jørgen & Lundin, Knut [Vis alle 8 forfattere av denne artikkelen] (2024). Generation of circulating autoreactive pre-plasma cells fueled by naive B cells in celiac disease. Cell reports. 43:114045(4), s. 1–23. doi: 10.1016/j.celrep.2024.114045. Fulltekst i vitenarkiv Vis sammendrag

  Autoantibodies against the enzyme transglutaminase 2 (TG2) are characteristic of celiac disease (CeD), and TG2-specific immunoglobulin (Ig) A plasma cells are abundant in gut biopsies of patients. Here, we describe the corresponding population of autoreactive B cells in blood. Circulating TG2-specific IgA cells are present in untreated patients on a gluten-containing diet but not in controls. They are clonally related to TG2-specific small intestinal plasma cells, and they express gut-homing molecules, indicating that they are plasma cell precursors. Unlike other IgA-switched cells, the TG2-specific cells are negative for CD27, placing them in the double-negative (IgD−CD27−) category. They have a plasmablast or activated memory B cell phenotype, and they harbor fewer variable region mutations than other IgA cells. Based on their similarity to naive B cells, we propose that autoreactive IgA cells in CeD are generated mainly through chronic recruitment of naive B cells via an extrafollicular response involving gluten-specific CD4+ T cells.

• Chlubnova, Marketa; Christophersen, Asbjørn Otto; Sandve, Geir Kjetil Ferkingstad; Lundin, Knut Erik Aslaksen; Jahnsen, Jørgen & Dahal-Koirala, Shiva [Vis alle 7 forfattere av denne artikkelen] (2023). Identification of gluten T cell epitopes driving celiac disease. Science Advances. 9(4), s. 1–8. doi: 10.1126/sciadv.ade5800. Fulltekst i vitenarkiv Vis sammendrag

  CD4+ T cells specific for cereal gluten proteins are key players in celiac disease (CeD) pathogenesis. While several CeD-relevant gluten T cell epitopes have been identified, epitopes recognized by a substantial proportion of gluten-reactive T cells remain unknown. The identification of such CeD-driving gluten epitopes is important for the food industry and in clinical settings. Here, we have combined the knowledge of a distinct phenotype of gluten-reactive T cells and key features of known gluten epitopes for the discovery of unknown epitopes. We tested 42 wheat gluten–reactive T cell clones, isolated on the basis of their distinct phenotype and with no reactivity to known epitopes, against a panel of synthetic peptides bioinformatically identified from a wheat gluten protein database. We were able to assign reactivity to 10 T cell clones and identified a 9-nucleotide oligomer core region of five previously uncharacterized gliadin/glutenin epitopes. This work represents an advance in the effort to identify CeD-driving gluten epitopes.

• Christophersen, Asbjørn Otto; Dahal-Koirala, Shiva; Chlubnova, Marketa; Jahnsen, Jørgen; Lundin, Knut & Sollid, Ludvig Magne (2022). Phenotype-Based Isolation of Antigen-Specific CD4+ T Cells in Autoimmunity: A Study of Celiac Disease. Advanced Science. 9(10), s. 1–10. doi: 10.1002/advs.202104766. Fulltekst i vitenarkiv Vis sammendrag

  The pathogenic immune response in celiac disease (CeD) is orchestrated by phenotypically distinct CD4+ T cells that recognize gluten epitopes in the context of disease-associated HLA-DQ allotypes. Cells with the same distinct phenotype, but with elusive specificities, are increased across multiple autoimmune conditions. Here, whether sorting of T cells based on their distinct phenotype (Tphe cells) yields gluten-reactive cells in CeD is tested. The method′s efficiency is benchmarked by parallel isolation of gluten-reactive T cells (Ttet cells), using HLA-DQ:gluten peptide tetramers. From gut biopsies of 12 untreated HLA-DQ2.5+ CeD patients, Ttet+/Tphe+, Ttet−/Tphe+, and Ttet−/Tphe− cells are sorted for single-cell T-cell receptor (TCR)-sequencing (n = 8) and T-cell clone (TCC)-generation (n = 5). The generated TCCs are TCR sequenced and tested for their reactivity against deamidated gluten. Gluten-reactivity is observed in 91.2% of Ttet+/Tphe+ TCCs, 65.3% of Ttet−/Tphe+ TCCs and 0% of Ttet−/Tphe− TCCs. TCR sequencing reveals clonal expansion and sequence sharing across patients, features reflecting antigen-driven responses. The feasibility to isolate antigen-specific CD4+ T cells by the sole use of phenotypic markers in CeD outlines a potential avenue for characterizing disease-driving CD4+ T cells in autoimmune conditions.

• Li, Jing; Zaslavsky, Maxim; Su, Yapeng; Guo, Jing; Sikora, Michael J. & Unen, Vincent van [Vis alle 36 forfattere av denne artikkelen] (2022). KIR+CD8+ T cells suppress pathogenic T cells and are active in autoimmune diseases and COVID-19. Science. ISSN 0036-8075. 376:eabi9591(6590), s. 1–15. doi: 10.1126/science.abi9591. Fulltekst i vitenarkiv Vis sammendrag

  In this work, we find that CD8+ T cells expressing inhibitory killer cell immunoglobulin-like receptors (KIRs) are the human equivalent of Ly49+CD8+ regulatory T cells in mice and are increased in the blood and inflamed tissues of patients with a variety of autoimmune diseases. Moreover, these CD8+ T cells efficiently eliminated pathogenic gliadin-specific CD4+ T cells from the leukocytes of celiac disease patients in vitro. We also find elevated levels of KIR+CD8+ T cells, but not CD4+ regulatory T cells, in COVID-19 patients, correlating with disease severity and vasculitis. Selective ablation of Ly49+CD8+ T cells in virus-infected mice led to autoimmunity after infection. Our results indicate that in both species, these regulatory CD8+ T cells act specifically to suppress pathogenic T cells in autoimmune and infectious diseases.

• Christophersen, Asbjørn Otto; Zühlke, Stephanie; Lund, Eivind Gard; Snir, Omri; Dahal-Koirala, Shiva & Risnes, Louise Fremgaard [Vis alle 9 forfattere av denne artikkelen] (2021). Pathogenic T cells in celiac disease change phenotype on gluten challenge: Implications for T-cell-directed therapies. Advanced Science. 8(21), s. 1–11. doi: 10.1002/advs.202102778. Fulltekst i vitenarkiv
• Risnes, Louise Fremgaard; Eggesbø, Linn Margrethe; Zühlke, Stephanie; Dahal-Koirala, Shiva; Neumann, Ralf Stefan & Lundin, Knut Erik Aslaksen [Vis alle 8 forfattere av denne artikkelen] (2021). Circulating CD103+ γδ and CD8+ T cells are clonally shared with tissue-resident intraepithelial lymphocytes in celiac disease. Mucosal Immunology. ISSN 1933-0219. 14(4), s. 842–851. doi: 10.1038/s41385-021-00385-8. Fulltekst i vitenarkiv Vis sammendrag

  Gut intraepithelial γδ and CD8+ αβ T lymphocytes have been connected to celiac disease (CeD) pathogenesis. Based on the previous observation that activated (CD38+), gut-homing (CD103+) γδ and CD8+ αβ T cells increase in blood upon oral gluten challenge, we wanted to shed light on the pathogenic involvement of these T cells by examining the clonal relationship between cells of blood and gut during gluten exposure. Of 20 gluten-challenged CeD patients, 8 and 10 had increase in (CD38+CD103+) γδ and CD8+ αβ T cells, respectively, while 16 had increase in gluten-specific CD4+ T cells. We obtained γδ and αβ TCR sequences of >2500 single cells from blood and gut of 5 patients, before and during challenge. We observed extensive sharing between blood and gut γδ and CD8+ αβ T-cell clonotypes even prior to gluten challenge. In subjects with challenge-induced surge of γδ and/or CD8+ αβ T cells, as larger populations of cells analyzed, we observed more expanded clonotypes and clonal sharing, yet no discernible TCR similarities between expanded and/or shared clonotypes. Thus, CD4+ T cells appear to drive expansion of clonally diverse γδ or CD8+ αβ T-cell clonotypes that may not be specific for the gluten antigen.

• Dahal-Koirala, Shiva; Risnes, Louise Fremgaard; Neumann, Ralf Stefan; Christophersen, Asbjørn; Lundin, Knut E. A. & Sandve, Geir Kjetil [Vis alle 8 forfattere av denne artikkelen] (2021). Comprehensive Analysis of CDR3 Sequences in Gluten-Specific T-Cell Receptors Reveals a Dominant R-Motif and Several New Minor Motifs. Frontiers in Immunology. 12:639672, s. 1–13. doi: 10.3389/fimmu.2021.639672. Fulltekst i vitenarkiv Vis sammendrag

  Gluten-specific CD4+ T cells are drivers of celiac disease (CeD). Previous studies of gluten-specific T-cell receptor (TCR) repertoires have found public TCRs shared across multiple individuals, biased usage of particular V-genes and conserved CDR3 motifs. The CDR3 motifs within the gluten-specific TCR repertoire, however, have not been systematically investigated. In the current study, we analyzed the largest TCR database of gluten-specific CD4+ T cells studied so far consisting of TCRs of 3122 clonotypes from 63 CeD patients. We established a TCR database from CD4+ T cells isolated with a mix of HLA-DQ2.5:gluten tetramers representing four immunodominant gluten epitopes. In an unbiased fashion we searched by hierarchical clustering for common CDR3 motifs among 2764 clonotypes. We identified multiple CDR3α, CDR3β, and paired CDR3α:CDR3β motif candidates. Among these, a previously known conserved CDR3β R-motif used by TRAV26-1/TRBV7-2 TCRs specific for the DQ2.5-glia-α2 epitope was the most prominent motif. Furthermore, we identified the epitope specificity of altogether 16 new CDR3α:CDR3β motifs by comparing with TCR sequences of 231 T-cell clones with known specificity and TCR sequences of cells sorted with single HLA-DQ2.5:gluten tetramers. We identified 325 public TCRα and TCRβ sequences of which 145, 102 and 78 belonged to TCRα, TCRβ and paired TCRαβ sequences, respectively. While the number of public sequences was depended on the number of clonotypes in each patient, we found that the proportion of public clonotypes from the gluten-specific TCR repertoire of given CeD patients appeared to be stable (median 37%). Taken together, we here demonstrate that the TCR repertoire of CD4+ T cells specific to immunodominant gluten epitopes in CeD is diverse, yet there is clearly biased V-gene usage, presence of public TCRs and existence of conserved motifs of which R-motif is the most prominent.

• Christophersen, Asbjørn (2019). Peptide-MHC class I and class II tetramers: From flow to mass cytometry. HLA. ISSN 2059-2302. s. 169–178. doi: 10.1111/tan.13789. Fulltekst i vitenarkiv Vis sammendrag

  To develop better vaccines and more targeted treatments for cancer and autoimmune disorders, the disease‐specific T cells and their cognate antigens need to be better characterized. For more than two decades, peptide‐major histocompatibility complex (pMHC) tetramers and flow cytometry have been the gold standard for detection of CD8+ and CD4+ T cells specific to antigens in the context of MHC class I and class II, respectively. Nonetheless, more recent studies combining such reagents with mass cytometry, that is, cytometry by time of flight (CyTOF), have offered far more comprehensive profiling of antigen‐specific T‐cell responses. In addition, mass cytometry has enabled ex vivo screening of CD8+ T‐cell reactivities against hundreds of MHC class I restricted candidate epitopes. MHC class II molecules, on the other hand, have been challenging to combine with mass cytometry as they are more complex and bind with lower affinities to cognate T‐cell receptors than MHC class I molecules. In this review, I discuss how techniques originally developed to improve the staining capacity of pMHC tetramers in flow cytometry led to the successful combination of such reagents with mass cytometry. Especially, I will highlight very recent advances facilitating the combination with pMHC class II tetramers. Together, these mass cytometry‐based studies can help develop more targeted treatments for cancer and autoimmune disorders.

• Eggesbø, Linn Margrethe; Risnes, Louise Fremgaard; Neumann, Ralf Stefan; Lundin, Knut Erik Aslaksen; Christophersen, Asbjørn & Sollid, Ludvig Magne (2019). Single-cell TCR sequencing of gut intraepithelial γδ T cells reveals a vast and diverse repertoire in celiac disease. Mucosal Immunology. ISSN 1933-0219. s. 1–9. doi: 10.1038/s41385-019-0222-9. Fulltekst i vitenarkiv Vis sammendrag

  A hallmark of celiac disease (CeD), a chronic condition driven by cereal gluten exposure, is increase of gut intraepithelial γδ T cells. This may indicate pathogenic involvement of γδ T cells and existence of disease-specific γδ T-cell receptors (TCRs) recognizing defined antigen(s). We performed high-throughput and paired γδ TCR sequencing of single intraepithelial γδ T cells of untreated CeD patients (n = 8; 1821 cells), CeD patients treated with a gluten-free diet (n = 5; 436 cells) and controls (n = 7; 1068 cells). We found that CeD patients, both untreated and treated, had larger and more diverse γδ TCR repertoires, more frequent usage of TRDV1 and TRDV3 and different patterns of TCRγ/TCRδ-pairing compared with controls. Although we observed no public CDR3δ sequences, there were several public CDR3γ sequences—many of which were shared by not only the CeD patients, but also by the controls. These public CDR3s were characterized by few N/P nucleotide insertions with germline and near-germline configuration, hence being easy to generate. Previous findings of CeD-specific CDR3 motifs were not replicated. Thus, being unable to raise evidence for CeD-specific γδ TCRs in this first large, paired γδ TCR single-cell sequencing study, we project challenges for identification of CeD-relevant γδ TCR ligands.

• Zühlke, Stephanie; Risnes, Louise Fremgaard; Dahal-Koirala, Shiva; Christophersen, Asbjørn; Sollid, Ludvig Magne & Lundin, Knut Erik Aslaksen (2019). CD38 expression on gluten-specific T cells is a robust marker of gluten re-exposure in coeliac disease. United European Gastroenterology Journal (UEG Journal). ISSN 2050-6406. 7(10), s. 1337–1344. doi: 10.1177/2050640619874183. Fulltekst i vitenarkiv
• Christophersen, Asbjørn; Risnes, Louise Fremgaard; Dahal-Koirala, Shiva & Sollid, Ludvig Magne (2019). Therapeutic and diagnostic implications of T cell scarring in celiac disease and beyond. Trends in Molecular Medicine. ISSN 1471-4914. 25(10), s. 836–852. doi: 10.1016/j.molmed.2019.05.009. Fulltekst i vitenarkiv Vis sammendrag

  Few therapeutic and diagnostic tools specifically aim at T cells in autoimmune disorders, but are T cells a narrow target in these diseases? Lessons may be learned from celiac disease (CeD), one of the few autoimmune disorders where the T cell driving antigens are known, i.e. dietary gluten proteins. T cell clonotypes specific to gluten are expanded, persist for decades and express a distinct phenotype in CeD patients. Cells with this phenotype are increased also in other autoimmune conditions. Accordingly, disease-specific CD4+ T cells form an immunological scar in CeD and probably other autoimmune disorders. We discuss approaches how such T cells may be targeted for better treatment and diagnosis via their antigen specificity or via their expression of characteristic phenotypic markers.

• Christophersen, Asbjørn; Lund, Eivind Gard; Snir, Omri; Solà, Elsa; Kanduri, Srinivasa Kalyana Chakravarthi & Dahal-Koirala, Shiva [Vis alle 15 forfattere av denne artikkelen] (2019). Distinct phenotype of CD4+ T cells driving celiac disease identified in multiple autoimmune conditions. Nature Medicine. ISSN 1078-8956. 25(5), s. 734–737. doi: 10.1038/s41591-019-0403-9. Fulltekst i vitenarkiv Vis sammendrag

  Combining HLA-DQ–gluten tetramers with mass cytometry and RNA sequencing analysis, we find that gluten-specific CD4+ T cells in the blood and intestines of patients with celiac disease display a surprisingly rare phenotype. Cells with this phenotype are also elevated in patients with systemic sclerosis and systemic lupus erythematosus, suggesting a way to characterize CD4+ T cells specific for disease-driving antigens in multiple autoimmune conditions.

• Dahal-Koirala, Shiva; Ciacchi, Laura; Petersen, Jan; Risnes, Louise Fremgaard; Neumann, Ralf Stefan & Christophersen, Asbjørn [Vis alle 11 forfattere av denne artikkelen] (2018). Discriminative T-cell receptor recognition of highly homologous HLA-DQ2-bound gluten epitopes. Journal of Biological Chemistry. ISSN 0021-9258. 294(3), s. 941–952. doi: 10.1074/jbc.RA118.005736. Fulltekst i vitenarkiv Vis sammendrag

  Celiac disease (CeD) provides an opportunity to study the specificity underlying human T-cell responses to an array of similar epitopes presented by the same human leukocyte antigen II (HLA-II) molecule. Here, we investigated T-cell responses to the two immunodominant and highly homologous HLA-DQ2.5–restricted gluten epitopes, DQ2.5-glia-α1a (PFPQPELPY) and DQ2.5-glia-ω1 (PFPQPEQPF). Using HLA-DQ2.5–DQ2.5-glia-α1a and HLA-DQ2.5–DQ2.5-glia-ω1 tetramers and single-cell αβ T-cell receptor (TCR) sequencing, we observed that despite similarity in biased variable-gene usage in the TCR repertoire responding to these nearly identical peptide–HLA-II complexes, most of the T cells are specific for either of the two epitopes. To understand the molecular basis of this exquisite fine specificity, we undertook Ala substitution assays revealing that the p7 residue (Leu/Gln) is critical for specific epitope recognition by both DQ2.5-glia-α1a– and DQ2.5-glia-ω1–reactive T-cell clones. We determined high-resolution binary crystal structures of HLA-DQ2.5 bound to DQ2.5-glia-α1a (2.0 Å) and DQ2.5-glia-ω1 (2.6 Å). These structures disclosed that differences around the p7 residue subtly alter the neighboring substructure and electrostatic properties of the HLA-DQ2.5–peptide complex, providing the fine specificity underlying the responses against these two highly homologous gluten epitopes. This study underscores the ability of TCRs to recognize subtle differences in the peptide–HLA-II landscape in a human disease setting.

• Risnes, Louise Fremgaard; Christophersen, Asbjørn; Dahal-Koirala, Shiva; Neumann, Ralf Stefan; Sandve, Geir Kjetil & Sarna, Vikas Kumar [Vis alle 9 forfattere av denne artikkelen] (2018). Disease-driving CD4+ T cell clonotypes persist for decades in celiac disease. Journal of Clinical Investigation. ISSN 0021-9738. 128(6), s. 2642–2650. doi: 10.1172/JCI98819. Fulltekst i vitenarkiv Vis sammendrag

  Little is known about the repertoire dynamics and persistence of pathogenic T cells in HLA-associated disorders. In celiac disease, a disorder with a strong association with certain HLA-DQ allotypes, presumed pathogenic T cells can be visualized and isolated with HLA-DQ:gluten tetramers, thereby enabling further characterization. Single and bulk populations of HLA-DQ:gluten tetramer–sorted CD4+ T cells were analyzed by high-throughput DNA sequencing of rearranged TCR-α and -β genes. Blood and gut biopsy samples from 21 celiac disease patients, taken at various stages of disease and in intervals of weeks to decades apart, were examined. Persistence of the same clonotypes was seen in both compartments over decades, with up to 53% overlap between samples obtained 16 to 28 years apart. Further, we observed that the recall response following oral gluten challenge was dominated by preexisting CD4+ T cell clonotypes. Public features were frequent among gluten-specific T cells, as 10% of TCR-α, TCR-β, or paired TCR-αβ amino acid sequences of total 1813 TCRs generated from 17 patients were observed in 2 or more patients. In established celiac disease, the T cell clonotypes that recognize gluten are persistent for decades, making up fixed repertoires that prevalently exhibit public features. These T cells represent an attractive therapeutic target.

• Tutturen, Astrid Elisabeth Voorham; Dørum, Siri; Clancy, Trevor; Reims, Henrik Mikael; Christophersen, Asbjørn & Lundin, Knut Erik Aslaksen [Vis alle 9 forfattere av denne artikkelen] (2018). Characterization of the Small Intestinal Lesion in Celiac Disease by Label-Free Quantitative Mass Spectrometry. American Journal of Pathology. ISSN 0002-9440. 188(7), s. 1563–1579. doi: 10.1016/j.ajpath.2018.03.017. Fulltekst i vitenarkiv Vis sammendrag

  Global characterization of tissue proteomes from small amounts of biopsy material has become feasible because of advances in mass spectrometry and bioinformatics tools. In celiac disease (CD), dietary gluten induces an immune response that is accompanied by pronounced remodeling of the small intestine. Removal of gluten from the diet abrogates the immune response, and the tissue architecture normalizes. In this study, differences in global protein expression of small intestinal biopsy specimens from CD patients were quantified by analyzing formalin-fixed, paraffin-embedded material using liquid chromatography–mass spectrometry and label-free protein quantitation. Protein expression was compared in biopsy specimens collected from the same patients before and after 1-year treatment with gluten-free diet (n = 10) or before and after 3-day gluten provocation (n = 4). Differential expression of proteins in particular from mature enterocytes, neutrophils, and plasma cells could distinguish untreated from treated CD mucosa, and Ig variable region IGHV5-51 expression was found to serve as a CD-specific marker of ongoing immune activation. In patients who had undergone gluten challenge, coordinated up-regulation of wound response proteins, including the CD autoantigen transglutaminase 2, was observed. Our study provides a global and unbiased assessment of antigen-driven changes in protein expression in the celiac intestinal mucosa.

• Sarna, Vikas Kumar; Lundin, Knut Erik Aslaksen; Mørkrid, Lars; Qiao, Shuo Wang; Sollid, Ludvig Magne & Christophersen, Asbjørn (2017). HLA-DQ-gluten tetramer blood test accurately identifies patients with and without celiac disease in absence of gluten consumption. Gastroenterology. ISSN 0016-5085. 154(4), s. 886–896.e6. doi: 10.1053/j.gastro.2017.11.006. Fulltekst i vitenarkiv Vis sammendrag

  Background & Aims: Celiac disease is characterized by HLA-DQ2/8-restricted responses of CD4+ T cells to cereal gluten proteins. A diagnosis of celiac disease based on serologic and histologic evidence requires patients to be on gluten-containing diets. The growing number of individuals adhering to a gluten-free diet (GFD) without exclusion of celiac disease complicates its detection. HLA-DQ–gluten tetramers can be used to detect gluten-specific T cells in blood of patients with celiac disease, even if they are on a GFD. We investigated whether an HLA-DQ–gluten tetramer-based assay accurately identifies patients with celiac disease. Methods: We produced HLA-DQ–gluten tetramers and added them to peripheral blood mononuclear cells isolated from 143 HLA-DQ2.5+ subjects (62 subjects with celiac disease on a GFD, 19 subjects without celiac disease on a GFD [due to self-reported gluten sensitivity], 10 subjects with celiac disease on a gluten-containing diet, and 52 presumed healthy individuals [controls]). T cells that bound HLA-DQ–gluten tetramers were quantified by flow cytometry. Laboratory tests and flow cytometry gating analyses were performed by researchers blinded to sample type, except for samples from subjects with celiac disease on a gluten-containing diet. Test precision analyses were performed using samples from 10 subjects. Results: For the HLA-DQ–gluten tetramer-based assay, we combined flow-cytometry variables in a multiple regression model that identified individuals with celiac disease on a GFD with an area under the receiver operating characteristic curve value of 0.96 (95% confidence interval [CI] 0.89–1.00) vs subjects without celiac disease on a GFD. The assay detected individuals with celiac disease on a gluten-containing diet vs controls with an area under the receiver operating characteristic curve value of 0.95 (95% CI 0.90–1.00). Optimized cutoff values identified subjects with celiac disease on a GFD with 97% sensitivity (95% CI 0.92–1.00) and 95% specificity (95% CI 0.84–1.00) vs subjects without celiac disease on a GFD. The values identified subjects with celiac disease on a gluten-containing diet with 100% sensitivity (95% CI 1.00–1.00]) and 90% specificity (95% CI 0.83–0.98) vs controls. In an analysis of 4 controls with positive results from the HLA-DQ–gluten tetramer test, 2 had unrecognized celiac disease and the remaining 2 had T cells that proliferated in response to gluten antigen in vitro. Conclusions: An HLA-DQ–gluten tetramer-based assays that detects gluten-reactive T cells identifies patients with and without celiac disease with a high level of accuracy, regardless of whether the individuals are on a GFD. This test would allow individuals with suspected celiac disease to avoid gluten challenge and duodenal biopsy, but requires validation in a larger study. Clinicaltrials.gov no: NCT02442219.

• Christophersen, Asbjørn; Risnes, Louise Fremgaard; Bergseng, Elin; Lundin, Knut Erik Aslaksen; Sollid, Ludvig Magne & Qiao, Shuo Wang (2016). Healthy HLA-DQ2.5<sup>+</sup> subjects lack regulatory and memory T cells specific for immunodominant gluten epitopes of celiac disease. Journal of Immunology. ISSN 0022-1767. 196(6), s. 2819–2826. doi: 10.4049/jimmunol.1501152. Fulltekst i vitenarkiv
• Christophersen, Asbjørn (2016). Ny blodprøve kan forenkle diagnostikk av cøliaki. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 136(6), s. 555–555. doi: 10.4045/tidsskr.16.0106. Fulltekst i vitenarkiv
• Dahal-Koirala, Shiva; Risnes, Louise Fremgaard; Christophersen, Asbjørn; Sarna, Vikas Kumar; Lundin, Knut Erik Aslaksen & Sollid, Ludvig Magne [Vis alle 7 forfattere av denne artikkelen] (2016). TCR sequencing of single cells reactive to DQ2.5-glia-α2 and DQ2.5-glia-ω2 reveals clonal expansion and epitope-specific V-gene usage. Mucosal Immunology. ISSN 1933-0219. 9(3), s. 587–596. doi: 10.1038/mi.2015.147. Fulltekst i vitenarkiv Vis sammendrag

  CD4+ T cells recognizing dietary gluten epitopes in the context of disease-associated human leukocyte antigen (HLA)-DQ2 or HLA-DQ8 molecules are the key players in celiac disease pathogenesis. Here, we conducted a large-scale single-cell paired T-cell receptor (TCR) sequencing study to characterize the TCR repertoire for two homologous immunodominant gluten epitopes, DQ2.5-glia-α2 and DQ2.5-glia-ω2, in blood of celiac disease patients after oral gluten challenge. Despite sequence similarity of the epitopes, the TCR repertoires are unique but shared several overall features. We demonstrate that clonally expanded T cells dominate the T-cell responses to both epitopes. Moreover, we find V-gene bias of TRAV26, TRAV4, and TRBV7 in DQ2.5-glia-α2 reactive TCRs, while DQ2.5-glia-ω2 TCRs displayed significant bias toward TRAV4 and TRBV4. The knowledge that antigen-specific TCR repertoire in chronic inflammatory diseases tends to be dominated by a few expanded clones that use the same TCR V-gene segments across patients is important information for HLA-associated diseases where the antigen is unknown.

• Sollid, Ludvig Magne; Iversen, Rasmus; Steinsbø, Øyvind; Qiao, Shuo Wang; Bergseng, Elin & Dørum, Siri [Vis alle 14 forfattere av denne artikkelen] (2015). Small bowel, celiac disease and adaptive immunity. Digestive Diseases. ISSN 0257-2753. 33(2), s. 115–121. doi: 10.1159/000369512. Fulltekst i vitenarkiv
• Christophersen, Asbjørn; Raki, Melinda; Bergseng, Elin; Lundin, Knut E A; Jahnsen, Jørgen & Sollid, Ludvig Magne [Vis alle 7 forfattere av denne artikkelen] (2014). Tetramer-visualized gluten-specific CD4+ T cells in blood as a potential diagnostic marker for coeliac disease without oral gluten challenge. United European Gastroenterology Journal (UEG Journal). ISSN 2050-6406. 2(4), s. 268–278. doi: 10.1177/2050640614540154. Fulltekst i vitenarkiv
• Dørum, Siri; Bodd, Michael; Fallang, Lars-Egil; Bergseng, Elin; Christophersen, Asbjørn & Johansen, Marie Kongshaug [Vis alle 10 forfattere av denne artikkelen] (2014). HLA-DQ molecules as affinity matrix for identification of gluten T cell epitopes. Journal of Immunology. ISSN 0022-1767. 193(9), s. 4497–4506. doi: 10.4049/jimmunol.1301466. Fulltekst i vitenarkiv
• Qiao, Shuo Wang; Christophersen, Asbjørn; Lundin, Knut E A & Sollid, Ludvig Magne (2014). Biased usage and preferred pairing of α-and β-chains of TCRs specific for an immunodominant gluten epitope in coeliac disease. International Immunology. ISSN 0953-8178. 26(1), s. 13–19. doi: 10.1093/intimm/dxt037. Fulltekst i vitenarkiv

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• Risnes, Louise Fremgaard; Dahal-Koirala, Shiva; Hjort, Rebecka Louise; Bolstad, Nils; Christophersen, Asbjørn Otto & Sarna, Vikas Kumar [Vis alle 9 forfattere av denne artikkelen] (2024). Påvisning av glutenspesifikke CD4+ T-celler med tetramertest blant anti-transglutaminase seropositive deltakere i HUNT4-studien. Fulltekst i vitenarkiv
• Vikse, Jens; Christophersen, Asbjørn; Goll, Guro Løvik & Molberg, Øyvind (2024). Immunologi: en oversikt. I Vikse, Jens; Haavardsholm, Espen A. & Molberg, Øyvind (Red.), Revmatologi. Universitetsforlaget. ISSN 9788215068589. Fulltekst i vitenarkiv
• Risnes, Louise Fremgaard; Eggesbø, Linn Margrethe; Christophersen, Asbjørn Otto & Sollid, Ludvig Magne (2021). Response to: “Some considerations about γδ and CD8+ T-cell responses in blood after gluten challenge in treated celiac disease”. Mucosal Immunology. ISSN 1933-0219. 14(5), s. 1216–1217. doi: 10.1038/s41385-021-00422-6. Fulltekst i vitenarkiv
• Eggesbø, Linn Margrethe; Risnes, Louise Fremgaard; Neumann, Ralf Stefan; Lundin, Knut E. A.; Christophersen, Asbjørn Otto & Sollid, Ludvig Magne (2021). Single-cell TCR repertoire analysis reveals highly polyclonal composition of human intraepithelial CD8⁺ αβ T lymphocytes in untreated celiac disease. European Journal of Immunology. ISSN 0014-2980. 51(6), s. 1542–1545. doi: 10.1002/eji.202048974. Fulltekst i vitenarkiv

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