Biology subjects

Lindeman, I.

Publications and source records attributed to Lindeman, I..

9 recordsLinked to original sources

bioRxiv2025

A predisposing effect of HLA class II genes in celiac disease by skewing the naive CD4+ T-cell receptor repertoire

Polymorphisms of human leukocyte antigen (HLA) genes confer risks for many human diseases. For predisposing effects relating to T-cell receptor (TCR) recognition of peptide-HLA, the effect can be both selection of the TCR repertoire and preferential presentation of disease-driving epitopes. In celiac disease (CeD) HLA-DQ2.5 predisposes by presenting deamidated gluten peptides to CD4+ T cells that typically employ stereotyped TCRs. Here we analyzed whether genetic variants within the HLA and TR loci shape the naive TCR repertoire. We sequenced the {beta} TCR repertoires of naive CD4+ T cells of 103 CeD subjects and 103 controls and performed gene usage quantitative trait loci analyses. The naive CD4+ TCR repertoire was significantly affected by HLA and TRA and TRB polymorphisms. Individuals carrying the HLA-DQ2.5 allotype exhibited increased frequencies of TCR genes involved in stereotyped recognition of gluten epitopes thus demonstrating a disease-predisposing effect of HLA by selection of a disease-relevant TCR repertoire.

immunology↗

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↗

bioRxiv2021

Stereotyped B-cell responses are linked to IgG constant region polymorphisms in multiple sclerosis

Clonally related B cells infiltrate the brain, meninges and cerebrospinal fluid (CSF) of multiple sclerosis (MS) patients, but the mechanisms driving the B-cell response and shaping the immunoglobulin repertoires remain unclear. Here, we used single-cell full-length RNA-seq and B-cell receptor reconstruction to simultaneously assess the phenotypes, isotypes, constant region polymorphisms, and the paired heavy- and light-chain repertoires in intrathecal B-lineage cells. We detected extensive clonal connections between the memory B cell and antibody-secreting cell (ASC) compartments and observed clonally related cells of different isotypes, including IgM/IgG1, IgG1/IgA1, IgG1/IgG2, and IgM/IgA1. There was a strong dominance of the G1m1 allotype constant region polymorphisms in ASCs, but not in memory B cells. Tightly linked to the G1m1 allotype, we found a preferential pairing of the IGHV4 gene family with the {kappa} variable (IGKV)1 gene family. These results link IgG constant region polymorphisms to stereotyped B-cell responses in MS, indicating that the intrathecal B-cell response in these patients could be directed against structurally similar epitopes. The data also suggest that the dominance of the G1m1 allotype in ASCs may occur as a result of biased differentiation of intrathecal memory B cells.

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↗

bioRxiv2020

Polymorphisms in immunoglobulin heavy chain variable genes and their upstream regions

Germline variations in immunoglobulin genes influence the repertoire of B cell receptors and antibodies, and such polymorphisms may impact disease susceptibility. However, the knowledge of the genomic variation of the immunoglobulin loci is scarce. Here, we report 25 novel germline IGHV alleles as inferred from rearranged naive B cell cDNA repertoires of 98 individuals. Thirteen novel alleles were selected for validation, out of which ten were successfully confirmed by targeted amplification and Sanger sequencing of non-B cell DNA. Moreover, we detected a high degree of variability upstream of the V-region in the 5UTR, leader 1, and leader 2 sequences, and found that identical V-region alleles can differ in upstream sequences. Thus, we have identified a large genetic variation not only in the V-region but also in the upstream sequences of IGHV genes. Our findings challenge current approaches used for annotating immunoglobulin repertoire sequencing data.

immunology↗

bioRxiv2018

Mosaic deletion patterns of the human antibody heavy chain gene locus

Analysis of antibody repertoires by high-throughput sequencing is of major importance in understanding adaptive immune responses. Our knowledge of variations in the genomic loci encoding antibody genes is incomplete, mostly due to technical difficulties in aligning short reads to these highly repetitive loci. The partial knowledge results in conflicting V-D-J gene assignments between different algorithms, and biased genotype and haplotype inference. Previous studies have shown that haplotypes can be inferred by taking advantage of IGHJ6 heterozygosity, observed in approximately one third of the population. Here, we propose a robust novel method for determining V-D-J haplotypes by adapting a Bayesian framework. Our method extends haplotype inference to IGHD- and IGHV-based analysis, thereby enabling inference of complex genetic events like deletions and copy number variations in the entire population. We generated the largest multi individual data set, to date, of naive B-cell repertoires, and tested our method on it. We present evidence for allele usage bias, as well as a mosaic, tiled pattern of deleted and present IGHD and IGHV nearby genes, across the population. The inferred haplotypes and deletion patterns may have clinical implications for genetic predispositions to diseases. Our findings greatly expand the knowledge that can be extracted from antibody repertoire sequencing data.

genomics↗

bioRxiv2017

Single cell transcriptomics of regulatory T cells reveals trajectories of tissue adaptation

Non-lymphoid tissues (NLTs) harbour a pool of adaptive immune cells, the development and phenotype of which remains largely unexplored. Here, we used single-cell RNA-seq to characterise CD4+ regulatory (Treg) and memory (Tmem) T cells in mouse skin and colon, the respective draining lymph nodes and spleen. From this data, we modelled a continuous lymphoid-to-NLT trajectory for Treg, and reconstructed the mechanisms of cell migration and NLT adaption. This revealed a shared transcriptional programme of NLT priming in both skin and colon-associated lymph nodes, followed by tissue-specific adaptation. Predicted migration kinetics were validated using a melanoma-induction model, emphasizing the relevance of key regulators and receptors, including Batf, Rora, Ccr8, Samsn1. Finally, we profiled human blood and NLT Treg and Tmem cells, identifying cross-mammalian conserved tissue signatures. In summary, we have identified molecular signals mediating NLT Treg recruitment and tissue adaptation through the combined use of computational prediction and in vivo validation.

immunology↗

bioRxiv2017

BraCeR: Reconstruction of B-cell receptor sequences and clonality inference from single-cell RNA-sequencing

Reconstruction of antigen receptor sequences from single-cell RNA-sequencing (scRNA-seq) data allows the linking of antigen receptor usage to the full transcriptomic identity of individual B lymphocytes, without having to perform additional targeted repertoire sequencing (Rep-seq). Here we report BraCeR (freely available at https://github.com/teichlab/bracer/), an extension of TraCeR [1], for reconstruction of paired full-length B-cell receptor sequences and inference of clonality from scRNA-seq data (Supplementary Note 1).

bioinformatics↗