Evidence map›Paper›PMID 39476969›Full record

ArticleJournal of thrombosis and haemostasis : JTH2025

Persistent splenic-derived IgMs preferentially recognize factor VIII A2 and C2 domain epitopes but do not alter antibody production.

Elizabeth S York, Benjamin D Dratch, Jasmine Ito, Samantha M Horwitz, Sahand Emamian, Joseph A Ambarian, Surinder Gill, Jayre Jones, Satheesh Chonat, Pete Lollar and 3 more

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In one paragraph

Article in Journal of thrombosis and haemostasis : JTH, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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0cells of the map it votes in
0citing papers in PubMed
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1 · What the graph read from it

What it found

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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

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Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

13 authors.

Elizabeth S YorkDepartment of Pediatrics, Stanford University, Palo Alto, California, USA; Department of Pediatrics, Emory University, Atlanta, Georgia, USA; Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, Georgia, USA.
Benjamin D DratchDepartment of Chemistry, Emory University, Atlanta, Georgia, USA.
Jasmine ItoDepartment of Pediatrics, Emory University, Atlanta, Georgia, USA; Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, Georgia, USA.
Samantha M HorwitzDepartment of Chemistry, Emory University, Atlanta, Georgia, USA.
Sahand EmamianDepartment of Physics, Emory University, Atlanta, Georgia, USA.
Joseph A AmbarianDepartment of Chemistry, Emory University, Atlanta, Georgia, USA.
Surinder GillDepartment of Pediatrics, Emory University, Atlanta, Georgia, USA; Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, Georgia, USA.
Jayre JonesDepartment of Pediatrics, Emory University, Atlanta, Georgia, USA; Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, Georgia, USA.
Satheesh ChonatDepartment of Pediatrics, Emory University, Atlanta, Georgia, USA; Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, Georgia, USA.
Pete LollarDepartment of Pediatrics, Emory University, Atlanta, Georgia, USA; Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, Georgia, USA.
Shannon L MeeksDepartment of Pediatrics, Emory University, Atlanta, Georgia, USA; Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, Georgia, USA.
Katherine M DavisDepartment of Chemistry, Emory University, Atlanta, Georgia, USA. Electronic address: katherine.davis@emory.edu.
Glaivy BatsuliDepartment of Pediatrics, Stanford University, Palo Alto, California, USA; Department of Pediatrics, Emory University, Atlanta, Georgia, USA; Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, Georgia, USA. Electronic address: gbatsuli@stanford.edu.

Funding

Unraveling the immune response to factor VIIIU54HL141981 · NHLBI · EMORY UNIVERSITY · PI MEEKS, SHANNON L. · 2018 to 2022
$8.1M
Utilizing Dendritic Cell Biology to Characterize the Innate Immune Response to Blood Coagulation ProteinsK99HL150595 · NHLBI · STANFORD UNIVERSITY · PI BATSULI, GLAIVY · 2020 to 2024
$1.0M
NHLBI NIH HHS K99 HL150595NHLBI NIH HHS U54 HL141981
6 · The paper itself

Abstract

backgroundThe most significant treatment complication for patients with hemophilia A is the development of neutralizing immunoglobins (Igs) G, termed inhibitors, against factor VIII (FVIII), which prevent FVIII replacement therapy. Low titers of FVIII-specific IgMs have been identified in hemophilia A patients with and without inhibitors, as well as in healthy individuals. However, the duration and influence of IgMs on the immune response to FVIII remains unclear.

objectivesTo characterize the binding interactions of persistently secreted FVIII-specific IgMs in hemophilia A mice and assess their effect on IgG antibody development.

methodsSplenic-derived monoclonal antibodies (mAbs) from immunized FVIII knockout mice were isolated and purified using hybridoma technology. Binding interactions were assessed utilizing a novel fluid-phase enzyme-linked immunosorbent assay and computational modeling with High Ambiguity-Driven protein-protein DOCKing to account for weak IgM binding.

resultsSixteen porcine cross-reactive and noninhibitory FVIII-specific IgM mAbs were identified. RNA sequencing of FVIII-specific IgMs revealed 13 unique variable, diversity, and joining (VDJ)/variable and joining (VJ) sequences indicating derivation from 13 unique B cell clones. The IgMs demonstrated polyclonal and polyreactive binding to FVIII in vitro and in silico. Molecular docking studies with reconstructed IgM variable, diversity, and joining/variable and joining regions identified frequent IgM interactions with amino acid residues K376, T381, K437, R2215, or K2249 within the FVIII A2 and C2 domains. Injections of individual IgMs prior to FVIII exposure and co-injection of FVIII/IgM immune complexes did not affect de novo FVIII antibody production.

conclusionPersistent FVIII-specific IgMs are polyclonal but preferentially bind the A2 and C2 domains. FVIII/IgM immune complex formation does not significantly alter inhibitor development.

Indexed as

Antibody FormationEpitopesFactor VIIIHemophilia AImmunoglobulin MSpleenAnimalsAntibodies, MonoclonalAntibodies, NeutralizingBinding Sites, AntibodyCross ReactionsHumansImmunoglobulin GMiceMice, Inbred C57BLMice, KnockoutAntibodies, MonoclonalAntibodies, NeutralizingEpitopesF8 protein, humanFactor VIIIImmunoglobulin GImmunoglobulin Mblood coagulation factorsfactor VIIIhemophilia Ahumoral immune responseimmunoglobulin M

Identifiers

PMID39476969
PMCPMC11786990

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.