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Abstract Number: 3156

IL17 Promotes Development of Autoreactive Early Stage B Cells in Distinct Regions of the Spleen Follicle

Jennie Hamilton1, Qi Wu2, PingAr Yang3, Jun Li4, Yanna Ding1, Bao Luo5, John Mountz6 and Hui-Chen Hsu2, 1University of Alabama at Birmingham, Birmingham, AL, 2Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, 3Department of Medicine, Clinical Immunology & Rheumatology, University of Alabama at Birmingham, Birmingham, AL, 4Medicine, University of Alabama at Birmingham, Birmingham, AL, 5Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, 6Dept of Med/Rheumatology Div, University of Alabama at Birmingham, Birmingham, AL

Meeting: 2015 ACR/ARHP Annual Meeting

Date of first publication: September 29, 2015

Keywords: autoantigens, B cell tolerance, cytokines and systemic lupus erythematosus (SLE)

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Session Information

Date: Tuesday, November 10, 2015

Session Title: B cell Biology and Targets in Autoimmune Disease: Novel B cell roles in RA and SLE

Session Type: ACR Concurrent Abstract Session

Session Time: 4:30PM-6:00PM

Background/Purpose: The early stage transitional B cell has been shown to be the key peripheral B-cell tolerance control point defect in SLE patients.  Anti-RNP Abs can occur before the onset of SLE, but the mechanism underlying tolerance loss to RNPs is unclear. Our previous B cell RNP Ag tetramer analysis indicates abnormal maturation of La13-27 epitope reactive transitional T1 B cells in autoimmune BXD2 mice.  As B-cell signaling strength and NF-kB p-p65 signaling play an important role in T1 B cell maturation, the purpose of this study was to determine the contribution of elevated IL-17R mediated NF-kp-p65 signaling in autoreactive transitional B cell development. 

Methods: Using a La-peptide specific tetramer, La13-27 autoreactive B cells from the spleens of B6, autoimmune WT BXD2, and BXD2-Il17r‒⁄‒ mice were analyzed by FACS for the development of CD93+ transitional B cell subsets.  T1 B cells were co-transferred into WT vs. BXD2-Il17r‒⁄‒.  B cell proliferative responses to anti-IgM and PMA/Ionomycin were determined by the Dojindo assay, and NF-kB p-p65 and p-Tyr levels were determined by phospho-flow. 

Results: Tetramer analysis of CD93+ transitional B cells revealed a 2-fold accelerated development of La13-27+ T3 transitional spleen B cells (CD23–IgMhi) in BXD2 (38%±5%) compared to that in B6 (18%±3%) mice (n=8, p≤0.01).  Interestingly, we have identified that there was mislocalization of IgMhiCD93+ T1 B cells in the follicles of BXD2 mice.  However, in normal B6 mice, T1 B cells are located in the peri-follicular region.  IL-17R signaling was previously shown to stabilize B-cell retention in the germinal center light zone.  Follicular mislocation of T1 B cells was normalized in BXD2-Il17r‒⁄‒ mice. Interestingly, a deficiency in IL17R signaling in BXD2-Il17r‒⁄‒ mice prevented the abnormal maturation of T1 to T3 La13-27+ B cells (T3=14±2% vs 38±5%, n=8, p≤0.01). In vivo co-transfer of WT and BXD2-Il17r‒⁄‒ into WT or BXD2-Il17r‒⁄‒recipients support a role for IL-17R signaling in transitional B cell development in BXD2 mice.  Phospho-flow experiments suggest IL-17R mediated elevated NF-kB p-p65 activation at the T1 stage in BXD2 compared to B6 mice.  This elevation was associated with increased protein kinase C (PKC) activation and proliferation in BXD2 B cells stimulated in vitro with anti-IgM and PMA/ionomycin (p≤0.01).  A deficiency of IL-17R normalized these responses in BXD2-Il17r‒⁄‒ mice. 

Conclusion:   The present data suggest that follicular exclusion of T1 B cells promotes peripheral tolerance, whereas follicular translocation and retention of T1 B cells promotes maturation.  Furthermore, IL-17 can promote NF-kB signaling in T1 B cells that have entered the follicle, bypassing tolerance checkpoint two in BXD2 mice.  This provides a mechanistic basis for checkpoint two defects.  As anti-La autoAbs can occur before the onset of SLE, these mechanisms may play a key role in initiation of disease.

This work was supported by the NIH (RO1-AI-071110 to JDM, RO1-AI-083705 to HCH, P30-AR-048311 to the UAB Comp. Flow Cyt. Core and the Analytic Imaging & Immunoreagent Core and P30-AI-027767 to the UAB Center for AIDS Research Comp. Flow Cyt. Core) and the VA (Merit Review grant 1I01BX000600-01 to JDM).  IL17R -/- mouse is a generous gift from Amgen Inc.


Disclosure: J. Hamilton, None; Q. Wu, None; P. Yang, None; J. Li, None; Y. Ding, None; B. Luo, None; J. Mountz, None; H. C. Hsu, None.

To cite this abstract in AMA style:

Hamilton J, Wu Q, Yang P, Li J, Ding Y, Luo B, Mountz J, Hsu HC. IL17 Promotes Development of Autoreactive Early Stage B Cells in Distinct Regions of the Spleen Follicle [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/il17-promotes-development-of-autoreactive-early-stage-b-cells-in-distinct-regions-of-the-spleen-follicle/. Accessed January 17, 2021.
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