ACR Meeting Abstracts

ACR Meeting Abstracts

  • Meetings
    • ACR Convergence 2024
    • ACR Convergence 2023
    • 2023 ACR/ARP PRSYM
    • ACR Convergence 2022
    • ACR Convergence 2021
    • ACR Convergence 2020
    • 2020 ACR/ARP PRSYM
    • 2019 ACR/ARP Annual Meeting
    • 2018-2009 Meetings
    • Download Abstracts
  • Keyword Index
  • Advanced Search
  • Your Favorites
    • Favorites
    • Login
    • View and print all favorites
    • Clear all your favorites
  • ACR Meetings

Abstract Number: 15

Abnormal ZAP-70 Expression in B Cells: New Potential Role in Tolerance Breakdown

Mickaël Martin1, Anne-marie KNAPP1, Dana GHERGUS1, Fabien DELMOTTE2, Laurent Vallat3, Cédric SCHLEISS3, Raoul HERBRECHT4, Anne-sophie KORGANOW1, Frédéric GROS1, Sophie JUNG1, Pauline SOULAS-SPRAUEL1, Eric Meffre2 and Thierry Martin5, 1CNRS UPR 3572 "Immunopathology and Therapeutic Chemistry"/Laboratory of Excellence Medalis, Institute of Molecular and Cellular Biology (IBMC), STRASBOURG, France, 2Department of Immunobiology, Yale University School of Medicine, NEW HAVEN, CT, 3Laboratoire d'hematologie, Hopital Hautepierre, STRASBOURG, France, 4Service d'Hématologie et Oncologie, Hôpitaux universitaires de Strasbourg, STRASBOURG, France, 5CNRS UPR 3572 "Immunopathology and Therapeutic Chemistry"/Laboratory of Excellence Medalis, Institute of Molecular and Cellular Biology (IBMC), STRSBOURG, France

Meeting: 2018 ACR/ARHP Annual Meeting

Keywords: B cell tolerance, Immune Dysregulation and auto-immunity

  • Tweet
  • Click to email a link to a friend (Opens in new window) Email
  • Click to print (Opens in new window) Print
Session Information

Date: Sunday, October 21, 2018

Title: B Cell Biology and Targets in Autoimmune and Inflammatory Disease Poster

Session Type: ACR Poster Session A

Session Time: 9:00AM-11:00AM

Background/Purpose: Abnormal expression of the tyrosine kinase ZAP-70 by tumoral B cells in chronic lymphocytic leukemia (CLL) is associated with B cell receptor (BCR) hypersignalling and autoimmune cytopenia (AIC), mostly induced by polyclonal IgG from non-tumoral B cells. We previously shown that ZAP-70 is also expressed by residual non tumoral B cells in CLL and associated with AIC occurrence. We therefore hypothesized that ZAP-70 expression in non tumoral B cells could generally predispose to tolerance breakdown.

Methods: Ig heavy and light chain were amplified from FACS-sorted non tumoral mature switched ZAP-70+ B cells of CLL patients with AIC, for production of recombinant antibodies (rAb). Reactivity of these rAB was tested in ELISA and on HEp-2 cells. A knock in Zap-70+/Mb1-Cre+mouse model (KI ZAP) was generated to conditionally express ZAP-70 in B cells since proB stage, to study functional consequences of ZAP-70 expression in B cells in vivo. Zap-70+/Mb1-Cre–mice were used as controls (CTRL).

Results: Among the 13 rAb produced to date from 5 different patients, 2 (15,5%) have an antinuclear autoreactivity and two others (15,5%) were polyreactive (DNA, lipopolysaccharide, insulin), compared respectively to 6% and 4,3% of control B cells. Compared to CTRL, microarrays revealed that KI ZAP mice were significantly enriched in circulating IgG and IgM autoantibodies against various antigens (mainly nuclear). These mice had reduced apoptosis rates of proB, preB and immatures B cells, enrichment in marginal zone (p=0.01) and reduction in B1a B cells (p=0.008). In the other part, KI ZAP mice had persistent hypogammaglobulinemia since 16 weeks-old (p=0.003 for IgG and p=0.03 for IgM), together with a reduction in matures naive, matures switched as well as in germinal center B cells (p=0.001, p=0.002 and p<0.001 respectively) and a trend was observed for plasma cells (p=0.07). After immunization by ovalbumin + Freund’s adjuvant, a reduced production of specific IgG and IgM was observed (p=0.01 and p=0.03 respectively). KI ZAP B cells shown increased spontaneous activation and proliferation levels holding after BCR stimulation, as well as an increased intracellular calcic flow. Preliminary data suggested a reduced SYK phosphorylation after BCR stimulation in KI ZAP B cells compared to CTRL.

Conclusion: We report for the first time that non tumoral ZAP-70+ B cells could be enriching in autoreactive cells in vitroand that ZAP-70 expression in B cells is associated in vivowith medullar selective advantage, enrichment in circulating autoreactive Ig and potential autoreactive B cells (marginal zone) with reduced immunoregulatory B cells (B1a). This expression is also associated with partial block in B cells peripheral development, but with a conversely early increased activation and proliferation status. ZAP-70 could interfere early with SYK leading to an altered BCR signaling responsible for defect in normal B maturation promoting emergence of autoreactive B cells. Mechanistic role of ZAP-70 in BCR signaling has to be further analyzed but our data open new opportunities involving ZAP-70 in the understanding of B cell development and physiopathology of tolerance breakdown.


Disclosure: M. Martin, None; A. M. KNAPP, None; D. GHERGUS, None; F. DELMOTTE, None; L. Vallat, None; C. SCHLEISS, None; R. HERBRECHT, None; A. S. KORGANOW, None; F. GROS, None; S. JUNG, None; P. SOULAS-SPRAUEL, None; E. Meffre, None; T. Martin, None.

To cite this abstract in AMA style:

Martin M, KNAPP AM, GHERGUS D, DELMOTTE F, Vallat L, SCHLEISS C, HERBRECHT R, KORGANOW AS, GROS F, JUNG S, SOULAS-SPRAUEL P, Meffre E, Martin T. Abnormal ZAP-70 Expression in B Cells: New Potential Role in Tolerance Breakdown [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 9). https://acrabstracts.org/abstract/abnormal-zap-70-expression-in-b-cells-new-potential-role-in-tolerance-breakdown/. Accessed .
  • Tweet
  • Click to email a link to a friend (Opens in new window) Email
  • Click to print (Opens in new window) Print

« Back to 2018 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/abnormal-zap-70-expression-in-b-cells-new-potential-role-in-tolerance-breakdown/

Advanced Search

Your Favorites

You can save and print a list of your favorite abstracts during your browser session by clicking the “Favorite” button at the bottom of any abstract. View your favorites »

All abstracts accepted to ACR Convergence are under media embargo once the ACR has notified presenters of their abstract’s acceptance. They may be presented at other meetings or published as manuscripts after this time but should not be discussed in non-scholarly venues or outlets. The following embargo policies are strictly enforced by the ACR.

Accepted abstracts are made available to the public online in advance of the meeting and are published in a special online supplement of our scientific journal, Arthritis & Rheumatology. Information contained in those abstracts may not be released until the abstracts appear online. In an exception to the media embargo, academic institutions, private organizations, and companies with products whose value may be influenced by information contained in an abstract may issue a press release to coincide with the availability of an ACR abstract on the ACR website. However, the ACR continues to require that information that goes beyond that contained in the abstract (e.g., discussion of the abstract done as part of editorial news coverage) is under media embargo until 10:00 AM ET on November 14, 2024. Journalists with access to embargoed information cannot release articles or editorial news coverage before this time. Editorial news coverage is considered original articles/videos developed by employed journalists to report facts, commentary, and subject matter expert quotes in a narrative form using a variety of sources (e.g., research, announcements, press releases, events, etc.).

Violation of this policy may result in the abstract being withdrawn from the meeting and other measures deemed appropriate. Authors are responsible for notifying colleagues, institutions, communications firms, and all other stakeholders related to the development or promotion of the abstract about this policy. If you have questions about the ACR abstract embargo policy, please contact ACR abstracts staff at [email protected].

Wiley

  • Online Journal
  • Privacy Policy
  • Permissions Policies
  • Cookie Preferences

© Copyright 2025 American College of Rheumatology