Biology subjects

Lossius, A.

Publications and source records attributed to Lossius, A..

6 recordsLinked to original sources

bioRxiv2026

MS-BCR-DB: an integrated BCR repertoire database to mine humoral multiple sclerosis signatures

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) in which B cells play a critical role. While B-cell receptor (BCR) sequencing studies in MS are increasing, progress in understanding MS-associated BCR repertoire features and convergent patterns across patients has been limited by small cohorts, heterogeneous experimental methodologies, and fragmented data storage. To overcome these challenges, we developed the MS-BCR-Database, the first publicly accessible and uniformly processed collection of human MS BCR sequencing datasets. We harmonized raw BCR-sequencing data into an AIRR-compliant database incorporating clinical and technical metadata, enabling coherent cross-study analyses. Using this resource, we identified putative disease-associated BCR-sequence features, including CNS-biased V-gene usage, marked oligoclonal expansion in cerebrospinal fluid, and convergent clonotype clusters shared exclusively among MS patients. Integration with antigen-annotated BCR databases revealed matches to antibodies recognizing both viral antigens, including Epstein-Barr virus, and CNS self-proteins. The MS-BCR-Database provides a scalable foundation for mechanistic discovery and biomarker development in MS, while establishing a broadly applicable resource for integrative analyses of BCR repertoires.

bioinformatics↗

bioRxiv2026

Putative target antigens of the stereotyped intrathecal B cell response in multiple sclerosis

Intrathecal antibody production is a hallmark of multiple sclerosis (MS), yet the antigenic targets of these antibodies remain elusive. Intrathecal antibody-secreting cells in MS patients characteristically produce IgG1 antibodies carrying the G1m1 allotype and preferentially use IGHV4 heavy-chain genes paired with IGKV1 or IGKV3 light chains. This stereotyped pattern points to a common antigen-driven selection process. To test this hypothesis, we generated monoclonal antibodies from intrathecal B-lineage cells bearing this stereotyped B-cell receptor configuration and screened them against a comprehensive library of human and Epstein-Barr virus proteins. In parallel, we developed and validated an immunoprecipitation-tandem mass-spectrometry (IPMS/MS) workflow for fresh-frozen brain tissue that preserves conformational epitopes. Several proteins, like CLDN11 and PLD1, were enriched by antibodies from multiple patients. Other targets, like MED21 and GIPC2, were unique to individual patients. Our study delivers a scalable pipeline for antigen discovery in MS and nominates candidate antigens for future validation. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=167 SRC="FIGDIR/small/697481v1_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@b522eaorg.highwire.dtl.DTLVardef@76240org.highwire.dtl.DTLVardef@c36205org.highwire.dtl.DTLVardef@1587019_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2025

GATHeR: Graph-based Accurate Tool for Immunoglobulin HEavy- and Light-chain Reconstruction

Recovering full-length, paired B-cell receptor (BCR) sequences from scRNA-seq reads remains difficult, especially in naive and memory B cells where immunoglobulin transcripts are sparse. Current methods provide incomplete constant-region coverage, limiting isoform, subclass, and allele resolution. We present GATHeR, an open-source tool that assembles and annotates paired heavy- and light-chain BCR sequences and extends assembled sequences into constant regions. This enables confident subclass and allele assignment and recovery of the membrane-bound isoform, including the transmembrane segment and cytoplasmic tail, thereby distinguishing surface BCRs from secreted antibodies. GATHeR supports Smart-seq2/3 and 10x Genomics libraries and outperforms existing methods across benchmarks, with the largest gains in naive and memory B cells. Notably, in these populations the constant-region extension also revealed splice variation, including heavy-chain intron retention. By delivering high-fidelity receptor, isoform, and clonal lineage information, GATHeR broadens the analytical reach of scRNA-seq for B-cell immunology.

immunology↗

bioRxiv2025

SH2D2A is an indicator of favourable prognosis in bladder cancer and is enriched in Treg cells

Given the expanding availability of RNA-seq and other such high dimensional data it is now possible to consider a complementary approach working in the opposite direction i.e., from transcriptomics up towards protein function. This approach may prove fruitful in producing information on the function of cytosolic-bound proteins such as adapter proteins. To test the validity of this method, we made use of several public datasets to interrogate the cancer-specific role of the adapter protein SH2D2A: a protein enriched in T and NK cells and a known interactor of the kinase LCK, whose function remains uncertain. We found that SH2D2A is a favourable marker for prognosis in urothelial bladder cancer (BLCA). Digging further, we identified a population of SH2D2A+ FOXP3+ IL2RAhi activated Tregs as the main expressors of SH2D2A in BLCA. This suggests that the expression of SH2D2A in these Tregs contributes to a beneficial prognostic effect. Further comprehension of SH2D2As function in these cells holds the potential for advancing treatment in BLCA and diversifying possible targets for immunotherapies.

bioinformatics↗

bioRxiv2024

Ultra-long sequencing for contiguous haplotype resolution of the human immunoglobulin heavy chain locus

Genetic diversity within the human immunoglobulin heavy chain (IGH) locus influences the expressed antibody repertoire and susceptibility to infectious and autoimmune diseases. However, repetitive sequences and complex structural variation pose significant challenges for large-scale characterization. Here, we introduce a method using Oxford Nanopore ultra-long sequencing and adaptive sampling, coupled with a bioinformatic pipeline, to generate haplotype-resolved single-contig IGH assemblies. We compared our method to a well-established IGH characterization framework using Pacific Biosciences HiFi sequencing in four donors and observed almost complete sequence congruence between our haplotype-resolved assemblies and the HiFi reads. Applying our approach to the HG002 reference material revealed no base differences to the Telomere-to-Telomere genome benchmark over the IGH locus. Importantly, among the four donors, our approach uncovered 30 novel alleles and previously uncharacterized large structural variants, including a 120 kb segmental duplication spanning IGHE to IGHA1 and an expanded seven-copy IGHV3-23 gene haplotype.

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↗