Biology subjects

Iversen, R.

Publications and source records attributed to Iversen, R..

5 recordsLinked to original sources

bioRxiv2025

Distinct systemic and gut IgA responses to bacteria of the human upper gastrointestinal tract

The mucosa lining the gastrointestinal tract harbors the bodys largest population of plasma cells, most of which produce dimeric IgA destined for release into the lumen. In addition, there is systemic production of monomeric IgA circulating in the blood. Little is known about the connection between systemic and mucosal IgA. To address this relationship and to explore antibody responses against the microbiota, we isolated bacteria from duodenal biopsies and assessed antibody reactivity. Systemic IgA showed reactivity to bacteria of the upper gastrointestinal tract with a preference for binding Neisseria species, while duodenal IgA showed broader reactivity. We found limited clonal overlap between gut and bone marrow plasma cells of individual donors, yet a few shared clones specific to bacterial antigens were identified. Despite showing clonal overlap, gut and bone marrow plasma cells have distinct IgA subclass distributions, and they likely depend on B-cell activation at discrete anatomical sites.

immunology↗

bioRxiv2023

Generation of circulating autoreactive pre-plasma cells fueled by naive B cells in celiac disease

Autoantibodies against the enzyme transglutaminase 2 (TG2) are characteristic of celiac disease (CeD), and TG2-specific IgA plasma cells are abundant in gut biopsies of patients. We here describe the corresponding population of autoreactive B cells in blood. Circulating TG2-specific IgA cells were found in untreated patients on a gluten-containing diet but not in controls. They were clonally related to TG2-specific small intestinal plasma cells, and they expressed gut-homing molecules, indicating that they are plasma cell precursors. Unlike other IgA-switched cells, the TG2-specific cells were negative for CD27, placing them in the double negative (IgD-CD27-) category. They had a plasmablast or activated memory B-cell phenotype, and they harbored 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.

immunology↗

bioRxiv2023

Separate Gut Plasma Cell Populations Produce Autoantibodies Against Transglutaminase 2 and Transglutaminase 3 in Dermatitis Herpetiformis

Dermatitis herpetiformis (DH) is an inflammatory skin disorder often considered as an extraintestinal manifestation of celiac disease (CeD). Hallmarks of CeD and DH are autoantibodies to transglutaminase 2 (TG2) and transglutaminase 3 (TG3), respectively. DH patients have autoantibodies reactive with both transglutaminase enzymes. We here report that in DH both gut plasma cells and serum autoantibodies 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, we define three conformational epitope groups. Both TG2-specific and TG3-specific gut plasma cells have few immunoglobulin 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, our results demonstrate parallel induction of anti-TG2 and anti-TG3 autoantibody responses involving separate B-cell populations in DH patients.

immunology↗

bioRxiv2022

Antibodies to native gluten arise from cross-reactive B cells with implications for epitope spreading in celiac disease

Antibodies to deamidated gluten peptides are accurate diagnostic markers of celiac disease (CeD). However, antibody binding to all possible gluten epitopes has not previously been investigated. To map antibody reactivity in detail and to understand the connection between disease-relevant B-cell and T-cell epitopes, we took advantage of a high-density peptide array for assessment of serum antibody specificity in CeD across the wheat gluten proteome. We confirm the importance of peptide deamidation for antibody binding, and we show that the response is remarkably focused on the known epitope QPEQPFP (where E results from deamidation of Q). In addition, we describe a new epitope in native (non-deamidated) gluten, QQPEQII (where E is gene encoded), which was associated with both B-cell and T-cell reactivity. By generating monoclonal antibodies from peptide-binding gut plasma cells of CeD patients, we show that antibodies to this native gluten epitope are cross-reactive with the major deamidated epitope due to recognition of the shared PEQ motif. Hence, antibodies to native gluten appear to arise from cross-reactive B cells that are generated as a side effect of the immune response to deamidated gluten. Since cross-reactive B cells could present peptides to different gluten-specific T cells, we suspect that such B cells can play a role in epitope spreading by engaging T cells with multiple specificities.

immunology↗

bioRxiv2020

Longevity, clonal relationship and transcriptional program of celiac disease-specific plasma cells

Disease-specific plasma cells (PCs) reactive with transglutaminase 2 (TG2) or deamidated gluten peptides (DGP) are abundant in celiac disease (CeD) gut lesions. Their contribution toward CeD pathogenesis is unclear. We assessed expression of markers associated with PC longevity in 15 untreated and 26 treated CeD patients in addition to 13 non-CeD controls, and performed RNA-sequencing with clonal inference and transcriptomic analysis of 3251 single PCs. We observed antigen-dependent V-gene selection and stereotypic antibodies. Generation of recombinant DGP-specific antibodies revealed a key role of a heavy-chain residue that displays polymorphism, suggesting that immunoglobulin gene polymorphisms may influence CeD-specific antibody responses. We identified transcriptional differences between CeD-specific vs non-disease-specific PCs and between short-lived vs long-lived PCs. The short-lived CD19+CD45+ phenotype dominated in untreated and short-term-treated CeD, in particular among disease-specific PCs but also in the general PC population. Thus, the disease lesion of untreated CeD is characterized by massive accumulation of short-lived PCs that are not only directed against disease-specific antigens.

immunology↗