Antibodies disrupt bacterial adhesion by ligand mimicry and allosteric interference DOI Creative Commons
Kelli L. Hvorecny, Gianluca Interlandi, Tim S. Veth

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 12, 2024

Abstract A critical step in infections is the attachment of many microorganisms to host cells using lectins that bind surface glycans, making promising antimicrobial targets. Upon binding mannosylated FimH, most studied lectin adhesin type 1 fimbriae E. coli , undergoes an allosteric transition from inactive active conformation can act as a catch-bond. Monoclonal antibodies alter FimH glycan various ways are available, but mechanisms these remain unclear. Here, we use cryoEM, mass spectrometry, assays, and molecular dynamics simulations determine structure-function relationships underlying antibody-FimH binding. Our study reveals four distinct antibody action: ligand mimicry by N-linked, high-mannose glycan; stabilization pocket state; conformational trapping states; locking through long-range effects. These structures reveal multiple responses protein provide blueprints for new target adhesins.

Language: Английский

Cell cross talk within the lymphoma tumor microenvironment: follicular lymphoma as a paradigm DOI
Camille Laurent, Sascha Dietrich, Karin Tarte

et al.

Blood, Journal Year: 2023, Volume and Issue: 143(12), P. 1080 - 1090

Published: Dec. 14, 2023

Language: Английский

Citations

16
Perspective on Immunoglobulin N-Glycosylation Status in Follicular Lymphoma: Uncovering BCR-Dependent and Independent Mechanisms Driving Subclonal Evolution DOI Open Access
Gloria Pokuaa Manu,

Mariette Odabashian,

Sergey Krysov

et al.

Cancers, Journal Year: 2025, Volume and Issue: 17(7), P. 1219 - 1219

Published: April 4, 2025

Follicular lymphoma (FL) is a heterogeneous and incurable disease. One of the hallmark features FL cells introduction N-glycosylation (N-gly) amino acid sequence motifs into immunoglobulin variable (IgV) region through ongoing somatic hypermutation (SHM) in early stages development. These N-gly motifs, containing oligomannoses, are rarely found healthy B but evidently play crucial role clonal evolution survival hostile environment germinal centers. The random nature SHM occasionally results loss productive (Ig) genes or elimination genes. Such events typically lead to deletion, as demonstrated by longitudinal analysis samples. However, rare N-gly-negative subclones demonstrate prolonged with evidence SHM, giving rise new before eventual deletion. This observation suggests presence specific mechanisms supporting their proliferation. perspective examines current literature explores whether detailed transcriptomic functional comparison characterized different statuses, particular focus on subclones, will comprehensive understanding both N-gly-dependent independent pro-survival proliferative transcriptional signatures. Specifically, it aims deepen our pathobiology identify novel therapeutic targets for better disease management.

Language: Английский

Citations

0
B cell receptor silencing reveals the origin of high-grade B cell lymphomas with MYC and BCL2 rearrangements DOI
Paola Del Sindaco, Silvia Lonardi, Gabriele Varano

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: July 17, 2024

Abstract The B cell receptor (BCR) is essential for mature lymphomas, serving as therapeutic target. Here, we show that high-grade lymphomas with MYC and BCL2 rearrangements (HGBCL-DH- ) predominantly exhibit immunoglobulin heavy (IGH) chain silencing, leading to BCR shutdown. HGBCL-DH- undetectable IGH (IGH UND differ from IGH-expressing counterparts germinal center-zone gene programs, expression T infiltration. While + prefer IGM/IG-Kappa expression, have completed class-switching, favoring IG-Lambda (IGL) light chains. preserve IGHV integrity, overcoming antigen-driven selection. silencing precedes onset shapes evolution of Follicular Lymphoma (FL) or FL/HGBCL-DH- common precursor. In pairs models, promoted RAG1/2-dependent IG editing, causing t(8;22)(q24;q11)/ IGL :: . protected models killing by CD79B-targeting Polatuzumab-Vedotin. Collectively, primarily originate BCR-silenced isotype-switched t(14;18)/ IGH::BCL2 -positive (pre)FL cells acquiring I GL::MYC translocations during revision, clinical implications. Significance These findings link in t(14;18) (or their precursors) RAG1/2 re-expression, promoting IGL::MYC responsible transformation into (HGBCL). Predominant the complex HGBCL protects tumor CD79B-directed Polatuzumab-Vedotin killing.

Language: Английский

Citations

0
IgSeqR: a protocol for the identification, assembly, and characterization of full-length tumor Immunoglobulin transcripts from unselected RNA sequencing data DOI Creative Commons
Dean Bryant, Benjamin Sale, Giorgia Chiodin

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 4, 2024

Abstract Immunoglobulin (IG) gene analysis provides fundamental insight into B-cell receptor structure and function. In tumors, it can inform the cell of origin clinical outcomes. Its value has been established in two types chronic lymphocytic leukemia with unmutated or mutated IGHV genes is emerging other tumors. The traditional PCR-based techniques, which are labor-intensive, rely on attainment either a dominant sequence small number subclonal sequences do not allow automated matching clonal phenotypic features. Extraction expressed tumor IG transcripts using high-throughput RNA sequencing (RNA-seq) be faster collection multiple matched transcriptome profile. Analytical tools regularly sought to increase accuracy, depth, speed acquisition full IGV-(IGD)-IGJ-IGC combine characteristics RNA-seq data. We provide here user-friendly protocol for rapid extraction, identification, accurate determination (leader constant region) templated non-templated transcript from RNA-seq. derived amino acid interrogated their physico-chemical and, certain lymphomas, predict glycan occupying acquired N-glycosylation sites. These features will then available association studies transcriptome. resulting information also help refine diagnosis, prognosis, potential therapeutic targeting most common lymphomas.

Language: Английский

Citations

0
Antibodies disrupt bacterial adhesion by ligand mimicry and allosteric interference DOI Creative Commons
Kelli L. Hvorecny, Gianluca Interlandi, Tim S. Veth

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 12, 2024

Abstract A critical step in infections is the attachment of many microorganisms to host cells using lectins that bind surface glycans, making promising antimicrobial targets. Upon binding mannosylated FimH, most studied lectin adhesin type 1 fimbriae E. coli , undergoes an allosteric transition from inactive active conformation can act as a catch-bond. Monoclonal antibodies alter FimH glycan various ways are available, but mechanisms these remain unclear. Here, we use cryoEM, mass spectrometry, assays, and molecular dynamics simulations determine structure-function relationships underlying antibody-FimH binding. Our study reveals four distinct antibody action: ligand mimicry by N-linked, high-mannose glycan; stabilization pocket state; conformational trapping states; locking through long-range effects. These structures reveal multiple responses protein provide blueprints for new target adhesins.

Language: Английский

Citations

0