Jorunn Stamnæs

• Gildenblat, Jacob; Stamnæs, Jorunn & Pahnke, Jens (2025). Mass-spectrometry imaging-based explainable machine learning can be used to reveal biochemical landscapes of the brain. BioaRxiv. doi: 10.1101/2025.09.12.675752. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Recent computational advances in mass-spectrometry imaging (MSI) now enable unprecedented insight into organ-wide molecular composition and functional architecture. Here, we present a first example of a high-resolution, molecular-computational atlas of specific mouse brain lipids - acquired using a NEDC matrix and negative mode MSI - covering 123 anatomically defined regions with 191 polygonal annotations derived solely from the MSI data — no auxiliary imaging required. To overcome annotation ambiguity and MSI complexity, we introduced the Computational Brain Lipid Atlas (CBLA), a graph-based visual-explainability framework that generates virtual landscape visualizations (VLV) of specific lipids’ distributions across the brain substructures. The CBLA integrates dimensionality reduction and ensembles of supervised models to (i) refine annotations, (ii) elucidate interregional relationships, (iii) interpret model behavior, and (iv) formulate biologically testable hypotheses. The CBLA revealed novel lipid distribution patterns, functional integrations, anatomical connections - ’the brain’s telephone cables’, and region-specific disease signatures - disease networks in the basal ganglia. A new algorithm decomposes annotated regions into precise m/z features and resolves full-precision m/z values from MSI data, producing a comprehensive high-resolution brain map. It can be used for any MS measurements: metabolites, lipids, and peptides. This resource underpins downstream studies, exemplified here by characterizing the lipid molecular composition of A β plaques, their spatial arrangement, and their connections with the surrounding tissue. Highlights Mass Spectrometry Imaging (MSI) data were used to generate truthful visualizations for annotating brain regions with high resolution without the need for other modalities. MSI data were used to generate a computational atlas representation of the annotated brain regions. Pathological structures reveal their origin and their effects on specific brain networks. Anatomical regions and functional networks show specific lipid patterns. Brain stem nuclei and the white matter have a unique composition of lipids revealing their involvement in pathological networks. The atlas’ Virtual Landscape Visualizations (VLV) enable visualizing region-specific differences between different mouse models.

• Stamnæs, Jorunn; Stray, Daniel; Pré, Marie Fleur du; Risnes, Louise Fremgaard; Dewan, Alisa & Shaik, Jakeer [Vis alle 9 forfattere av denne artikkelen] (2025). IFN-gamma is a direct driver of crypt hyperplasia in celiac disease. Journal of Clinical Investigation. ISSN 0021-9738. 135(20). doi: 10.1172/JCI194858. Fulltekst i vitenarkiv Vis sammendrag

  Crypt hyperplasia is a key feature of celiac disease (CeD) and several other small intestinal inflammatory conditions. Analysis of the gut epithelial crypt zone by mass spectrometry–based tissue proteomics revealed a strong IFN-γ signal in active CeD. This signal, hallmarked by increased expression of MHC molecules, was paralleled by diminished expression of proteins associated with fatty acid metabolism. Crypt hyperplasia and the same proteomic changes were observed in WT mice administered IFN-γ. In mice with conditional KO of the IFN-γ receptor in gut epithelial cells, these signature morphological and proteomic changes were not induced with IFN-γ administration. IFN-γ was thus a driver of crypt hyperplasia in CeD by acting directly on crypt epithelial cells. The results are relevant to other enteropathies with involvement of IFN-γ.

• Johansen, Anette; Sandve, Geir Kjetil Ferkingstad; Maxwell, Joseph R.; Smithson, Glennda; Sollid, Ludvig Magne & Stamnæs, Jorunn (2024). Biopsy Proteome Score Performs Well as an Effect Measure in a Gluten Challenge Trial of Celiac Disease. Clinical Gastroenterology and Hepatology. ISSN 1542-3565. 23(5), s. 758–765.e8. doi: 10.1016/j.cgh.2024.08.005. Fulltekst i vitenarkiv Vis sammendrag

  Background and Aims Development of novel treatments for celiac disease is dependent on precise tools to monitor changes in gluten-induced mucosal damage. Current histology measures are subjective and difficult to standardize. Biopsy proteome scoring is an objective alternative to histology which is based on robust changes in biological pathways that directly reflect gluten-induced mucosal damage. In this study, we aimed to evaluate biopsy proteome scoring as an effect measure in a clinical trial setting by measuring intestinal remodeling in response to oral gluten challenge. Methods We analyzed biopsies from a 14-day gluten challenge trial of treated celiac disease patients that consumed 3 g (n = 6) or 10 g (n = 7) gluten per day. Sections from individually embedded biopsies collected before and after challenge were processed for proteome scoring (n = 109) and measurement of villus height-to-crypt depth ratio (n = 58). Proteome scores were compared with histology, intraepithelial lymphocyte frequency and plasma interleukin-2. Results Change in proteome scores were significant for the group of patients who consumed 10 g gluten, but not for the group who consumed 3 g gluten. Altogether, 8 of 13 patients had changes in delta proteome scores above the cutoff. Proteome scores correlated with villus height-to-crypt depth ratios both at run-in and at day 15. Proteome scores at day 15 correlated with intraepithelial lymphocyte frequency and with plasma interleukin-2 levels measured 4 hours post–gluten intake. Conclusion Biopsy proteome scoring is a simple and reliable measure of gluten-induced mucosal remodeling in response to 14-day oral gluten challenge. ClinicalTrials.gov, Number: NCT03409796.

• Johansen, Anette; Sandve, Geir Kjetil Ferkingstad; Ibsen, Jostein Holen; Lundin, Knut; Sollid, Ludvig Magne & Stamnæs, Jorunn (2024). Biopsy Proteome Scoring to Determine Mucosal Remodeling in Celiac Disease. Gastroenterology. ISSN 0016-5085. 167(3), s. 493–504. doi: 10.1053/j.gastro.2024.03.006. Fulltekst i vitenarkiv Vis sammendrag

  Background & Aims Histologic evaluation of gut biopsies is a cornerstone for diagnosis and management of celiac disease (CeD). Despite its wide use, the method depends on proper biopsy orientation, and it suffers from interobserver variability. Biopsy proteome measurement reporting on the tissue state can be obtained by mass spectrometry analysis of formalin-fixed paraffin-embedded tissue. Here we aimed to transform biopsy proteome data into numerical scores that give observer-independent measures of mucosal remodeling in CeD. Methods A pipeline using glass-mounted formalin-fixed paraffin-embedded sections for mass spectrometry-based proteome analysis was established. Proteome data were converted to numerical scores using 2 complementary approaches: a rank-based enrichment score and a score based on machine learning using logistic regression. The 2 scoring approaches were compared with each other and with histology analyzing 18 patients with CeD with biopsies collected before and after treatment with a gluten-free diet as well as biopsies from patients with CeD with varying degree of remission (n = 22). Biopsies from individuals without CeD (n = 32) were also analyzed. Results The method yielded reliable proteome scoring of both unstained and H&E-stained glass-mounted sections. The scores of the 2 approaches were highly correlated, reflecting that both approaches pick up proteome changes in the same biological pathways. The proteome scores correlated with villus height-to-crypt depth ratio. Thus, the method is able to score biopsies with poor orientation. Conclusions Biopsy proteome scores give reliable observer and orientation-independent measures of mucosal remodeling in CeD. The proteomic method can readily be implemented by nonexpert laboratories in parallel to histology assessment and easily scaled for clinical trial settings.

• Das, Saykat; Stamnæs, Jorunn; Høydahl, Lene Støkken; Skagen, Christine; Lundin, Knut & Jahnsen, Jørgen [Vis alle 8 forfattere av denne artikkelen] (2024). Selective activation of naïve B cells with unique epitope specificity shapes autoantibody formation in celiac disease. Journal of Autoimmunity. ISSN 0896-8411. 146, s. 1–10. doi: 10.1016/j.jaut.2024.103241. Fulltekst i vitenarkiv Vis sammendrag

  Many antibody responses induced by infection, vaccination or autoimmunity show signs of convergence across individuals with epitope-dependent selection of particular variable region gene segments and complementarity determining region 3 properties. However, not much is known about the relationship between antigen-specific effector cells and antigen-specific precursors present in the naïve B-cell repertoire. Here, we sought to address this relationship in the context of celiac disease, where there is a stereotyped autoantibody response against the enzyme transglutaminase 2 (TG2). By generating TG2-specific monoclonal antibodies from both duodenal plasma cells and circulating naïve B cells, we demonstrate a discord between the naïve TG2-specific repertoire and the cells that are selected for autoantibody production. Hence, the naïve repertoire does not fully reflect the epitope preference and gene usage observed for memory B cells and plasma cells. Instead, distinct naïve B cells that target particular TG2 epitopes appear to be selectively activated at the expense of TG2-binding B cells targeting other epitopes.

• Heggelund, Julie Elisabeth; Das, Saykat; Stamnæs, Jorunn; Iversen, Rasmus & Sollid, Ludvig Magne (2023). Autoantibody binding and unique enzyme-substrate intermediate conformation of human transglutaminase 3. Nature Communications. 14:6216 (1), s. 1–11. doi: 10.1038/s41467-023-42004-z. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Transglutaminase 3 (TG3), the autoantigen of dermatitis herpetiformis (DH), is a calcium dependent enzyme that targets glutamine residues in polypeptides for either transamidation or deamidation modifications. To become catalytically active TG3 requires proteolytic cleavage between the core domain and two C-terminal β-barrels (C1C2). Here, we report four X-ray crystal structures representing inactive and active conformations of human TG3 in complex with a TG3-specific Fab fragment of a DH patient derived antibody. We demonstrate that cleaved TG3, upon binding of a substrate-mimicking inhibitor, undergoes a large conformational change as a β-sheet in the catalytic core domain moves and C1C2 detaches. The unique enzyme-substrate conformation of TG3 without C1C2 is recognized by DH autoantibodies. The findings support a model where B-cell receptors of TG3-specific B cells bind and internalize TG3-gluten enzyme-substrate complexes thereby facilitating gluten-antigen presentation, T-cell help and autoantibody production.

• Das, Saykat; Stamnæs, Jorunn; Kemppainen, Esko; Hervonen, Kaisa; Lundin, Knut & Parmar, Naveen [Vis alle 12 forfattere av denne artikkelen] (2023). Separate Gut Plasma Cell Populations Produce Auto-Antibodies against Transglutaminase 2 and Transglutaminase 3 in Dermatitis Herpetiformis. Advanced Science. 10:2300401(25), s. 1–10. doi: 10.1002/advs.202300401. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Dermatitis herpetiformis (DH) is an inflammatory skin disorder often considered as an extra intestinal manifestation of celiac disease (CeD). Hallmarks of CeD and DH are auto‐antibodies to transglutaminase 2 (TG2) and transglutaminase 3 (TG3), respectively. DH patients have auto‐antibodies reactive with both transglutaminase enzymes. Here it is reported that in DH both gut plasma cells and serum auto‐antibodies are specific for either TG2 or TG3 with no TG2–TG3 cross reactivity. By generating monoclonal antibodies from TG3‐specific duodenal plasma cells of DH patients, three conformational epitope groups are defined. Both TG2‐specific and TG3‐specific gut plasma cells have few immunoglobulin (Ig) mutations, and the two transglutaminase‐reactive populations show distinct selection of certain heavy and light chain V‐genes. Mass spectrometry analysis of TG3‐specific serum IgA corroborates preferential usage of IGHV2‐5 in combination with IGKV4‐1 . Collectively, these results demonstrate parallel induction of anti‐TG2 and anti‐TG3 auto‐antibody responses involving separate B‐cell populations in DH patients.

• Amundsen, Sunniva Furre; Stamnæs, Jorunn; Lundin, Knut & Sollid, Ludvig Magne (2023). Expression of transglutaminase 2 in human gut epithelial cells: Implications for coeliac disease. PLOS ONE. 18:e0287662(6), s. 1–15. doi: 10.1371/journal.pone.0287662. Fulltekst i vitenarkiv Vis sammendrag

  Background Formation of complexes between transglutaminase 2 (TG2) and gluten can mechanistically explain why TG2 serves both as B-cell autoantigen and as an enzyme that creates deamidated gluten epitopes in coeliac disease (CeD). A model has been proposed where TG2 released from shed epithelial cells encounters high concentrations of dietary gluten peptides to form these TG2:gluten complexes. In this work we have characterised TG2 protein expression in gut epithelial cells in humans. Methods Western blot analysis, immunofluorescence staining and mass spectrometry in combination with laser capture microdissection to gain spatial resolution were used to characterise TG2 expression in the epithelial cell layer of healthy and coeliac disease affected duodenum. Findings TG2 is expressed in human duodenal epithelial cells, including cells in the apical region that are shed into the gut lumen. In untreated CeD the apical expression of TG2 is doubled. Enzymatically active TG2 is readily released from isolated human intestinal epithelial cells. Conclusion Shed epithelial cells are a plausible source of pathogenic TG2 enzyme in CeD. Increased epithelial TG2 expression and increased epithelial shedding in active CeD may reinforce action of luminal TG2 in this condition.

• Amundsen, Sunniva Furre; Stamnæs, Jorunn; Pré, Marie Fleur du & Sollid, Ludvig Magne (2022). Transglutaminase 2 affinity and enzyme-substrate intermediate stability as determining factors for T-cell responses to gluten peptides in celiac disease. European Journal of Immunology. ISSN 0014-2980. 52(9), s. 1474–1481. doi: 10.1002/eji.202249862. Fulltekst i vitenarkiv Vis sammendrag

  The adaptive immune response of celiac disease (CeD) involves presentation of gluten peptides to CD4+ T cells by transglutaminase 2 (TG2) specific B cells. This B-cell/T-cell crosstalk is facilitated by involvement of TG2:gluten peptide complexes that act principally in the form of enzyme-substrate intermediates. Here, we have addressed how gluten peptide affinity and complex stability in the presence of secondary substrates affect the uptake of TG2:gluten peptide complexes by TG2-specific B cells and the activation of gluten-specific T cells. We studied affinity of various gluten peptides for TG2 by biochemical assay, and monitored uptake of gluten peptides by TG2-specific B cells by flow cytometry. Crosstalk between TG2-specific B cells and gluten-specific T cells was assayed with transfectants expressing antigen receptors derived from CeD patients. We found that gluten peptides with high TG2 affinity showed better uptake by TG2-specific B cells. Uptake by B cells, and subsequent activation of T cells, was negatively affected by polyamines acting as secondary TG2 substrates. These results show that affinity between gluten peptide and TG2 governs the selection of T-cell epitopes via enhanced uptake of TG2:gluten complexes by TG2-specific B cells, and that exogenous polyamines can influence the CeD immune responses by disrupting TG2:gluten complexes.

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• Risum, Kristine; Stamnæs, Jorunn; Alexanderson, Helene; Molberg, Øyvind & Sanner, Helga (2026). Altered acute inflammatory response to maximal treadmill exercise in children and adolescents with juvenile idiopathic arthritis. Fulltekst i vitenarkiv

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