Immune responses to human factor IX in haemophilia B mice of different genetic backgrounds are distinct and modified by TLR4

Immune responses to human factor IX in haemophilia B mice of different genetic backgrounds are distinct and modified by TLR4 - Sack - 2014 - Haemophilia - Wiley Online Library Skip to Main Content Log in / Register Log In E-Mail Address Password Forgotten Password?

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You have full text access to this OnlineOpen articleImmune responses to human factor IX in haemophilia B mice of different genetic backgrounds are distinct and modified by TLR4B. K. Sack1,2, X. Wang2, A. Sherman2, G. L. Rogers2 andD. M. Markusic2,*Article first published online: 23 NOV 2014

DOI: 10.1111/hae.12522

© 2014 The Authors. Haemophilia Published by John Wiley & Sons Ltd.

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Issue

HaemophiliaVolume 21, Issue 1, pages 133–139, January 2015

Additional Information

How to CiteSack, B. K., Wang, X., Sherman, A., Rogers, G. L. and Markusic, D. M. (2015), Immune responses to human factor IX in haemophilia B mice of different genetic backgrounds are distinct and modified by TLR4. Haemophilia, 21: 133–139. doi: 10.1111/hae.12522

Author Information1

Seattle Biomedical Research Institute, Seattle, WA, USA

2

Department of Pediatrics, University of Florida, Gainesville, FL, USA

* Correspondence: David M. Markusic, PhD, University of Florida, Cancer and Genetics Research Complex, 2033 Mowry Road, Room 206, Gainesville, FL 32610, USA.
Tel.: 352-273-8149; fax: 352-273-8342;
e-mail: dmarkusic@ufl.edu

Publication HistoryIssue published online: 29 DEC 2014Article first published online: 23 NOV 2014Manuscript Accepted: 21 JUL 2014Funded byBayer Hemophilia Awards ProgramBasic and Clinical Research and Education SEARCH Search Scope All contentPublication titlesIn this journalIn this issue Search String Advanced >Saved Searches > SEARCH BY CITATION Volume: Issue: Page: ARTICLE TOOLSGet PDF (344K)Save to My ProfileE-mail Link to this ArticleExport Citation for this ArticleGet Citation AlertsRequest Permissions AbstractArticleReferencesCited By View Full Article (HTML) Enhanced Article (HTML) Get PDF (344K) Keywords:anaphylaxis;BALBc;C3H/HeJ;factor IX;haemophilia B murine model;immune responseSummary

Our laboratory develops protocols to prevent or reverse ongoing anti-hFIX IgG inhibitors in haemophilia B mice with a F9 gene deletion on BALB/c and C3H/HeJ backgrounds. C3H/HeJ F9-/Y mice develop high titre anti-hFIX IgG1 inhibitors and anaphylaxis, whereas most BALB/c F9-/Y mice have mild anti-hFIX IgG1 inhibitors and no anaphylaxis. Our aim was to determine if hFIX-specific B- and T-cell responses in BALB/c and C3H/HeJ F9-/Y mice trigger the difference in anti-hFIX immune responses. BALB/c and C3H/HeJ F9-/Y mice were challenged weekly with recombinant hFIX protein. Humoral immune responses were determined by IgG1 and IgG2a anti-hFIX ELISA, Bethesda assay for inhibitors and B-cell ELISpot on bone marrow and spleen cells. T-cell studies measured the TH1 (IFN-?) and TH2 (IL-4) cytokine responses in splenocytes at the mRNA and protein level in response to hFIX protein. Antibody responses were also measured in C3H/HeJ/OuJ F9-/Y mice with restored toll-like receptor 4 (TLR4) function. BALB/c F9-/Y mice have a TH2 skewed response and a reduction in anti-hFIX secreting plasma cells in the bone marrow. Independent antigen challenge revealed both strains generated equivalent IgG1 antibody titres to an intravenously delivered antigen. C3H/HeJ F9-/Y mice have a mixed TH1 and TH2 response (mainly TH2). Importantly, TLR4 signalling has a modulatory role in the C3H background on the levels of anti-hFIX IgG1 and incidence of anaphylaxis. The background strain strongly impacts the immune response to hFIX, which can be significantly impacted by mutations in innate immune sensors.

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