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Abstract Number: 3

Interferon-Alpha Disrupts DNA-Specific B Cell Tolerance in 3H9 Mice

Dario Ferri1, Yuriy Baglaenko2, Ariana Karanxha1, Kieran Manion1, Carolina Grajales1 and Joan E. Wither1, 1Genetics and Development, Krembil Research Institute, University Health Network, Toronto, ON, Canada, 2Department of Biomedical Informatics, Brigham Women's Hospital, Harvard Medical School, Boston, MA

Meeting: 2018 ACR/ARHP Annual Meeting

Keywords: Auto-immunity, autoantibodies and systemic lupus erythematosus (SLE), B cell tolerance, B cells

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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: A central mediator of Systemic Lupus Erythematosus (SLE) pathogenesis is interferon-alpha (IFNα), which is elevated in the serum of SLE patients. IFNα has been shown to enhance B cell signaling and promote survival. It also plays a major role in the induction of B cell activating factor (BAFF). While past studies have explored the effects BAFF on B cell tolerance, little work has focused on how IFNα itself directly affects this process. We hypothesize that elevated levels of IFNα directly contribute to the breach of B cell tolerance in SLE. To address this question, we have obtained an adenoviral vector encoding mouse IFNα (mDEF201), which we are using to induce sustained elevation of serum IFNα in a mouse model of B cell tolerance (3H9).

Methods: 6-8 week old 3H9 transgenic mice, which contain a knock-in Ig heavy chain derived from a DNA-specific hybridoma, were injected IV with 107 PFU of Ad-mIFNα (mDEF201) or Ad-dI70-3 (empty vector). At 2 weeks post-treatment immune cell populations in the spleen and bone marrow were examined by flow cytometry, and anti-DNA antibody production was measured by ELISA. Serum levels of IFNα and BAFF were quantified by ELISA and IFN-induced gene expression was assessed by qRT-PCR.

Results: Mice administered with mDEF201 showed elevation of serum IFNα from 48h to 2 weeks post infection. At 2 weeks post infection, the mRNA expression of several IFN-inducible genes, but not BAFF, was also elevated in infected mice. There was only a 0.5 fold increase in BAFF expression at the protein level. mDEF201 infection resulted in a marked increase in the level of anti-ss/dsDNA IgMa autoantibodies (OD450 PBS=0.32, Ad-di70-3=0.29, mDEF201=1.46 for ssDNA, and PBS=0.13, Ad-di70-3=0.10, mDEF201=0.56 for dsDNA, p<0.0001) signifying a potential breach of B cell tolerance. Consistent with this idea, mDEF201 infected mice displayed altered B cell activation and homeostasis, with a significant increase in the frequency of CD86+ B cells as well as total number of mature B cells. mDEF201 infection also resulted in increased frequency of plasmablasts, CD138+ plasma cells and IgMa+/IgG2a+ germinal center (GC) B cells. Despite the increase in IgG2a+ GC B cells, anti-ss/dsDNA IgG2a antibodies were not increased with elevated IFNα at 2 weeks post infection. To assess the effect of IFNα on B cell anergy we examined the Igλ1+ population, a well characterized dsDNA-specific anergic B cell population in 3H9 mice. Igλ1+ B cells also displayed increased activation (CD86+) and entry into germinal centers; however, anti-ss/dsDNA Igλ1+ levels were not increased. Infection with mDEF201 resulted in a mild increase in T cell activation (CD69+); although, no difference was seen in the total number of T follicular helper cells.

Conclusion: Taken together, these data suggest that IFNα may be a major contributing factor in breaches of B cell tolerance in SLE not only through the induction of BAFF, but also through direct effects on autoreactive B cells. Elevation of IFNα may promote the activation and differentiation of autoreactive B cells towards an antibody producing state; however, in the absence of other immune defects, some peripheral tolerance mechanisms seem to remain partially intact preventing a whole-cell breach of tolerance.


Disclosure: D. Ferri, None; Y. Baglaenko, None; A. Karanxha, None; K. Manion, None; C. Grajales, None; J. E. Wither, None.

To cite this abstract in AMA style:

Ferri D, Baglaenko Y, Karanxha A, Manion K, Grajales C, Wither JE. Interferon-Alpha Disrupts DNA-Specific B Cell Tolerance in 3H9 Mice [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 9). https://acrabstracts.org/abstract/interferon-alpha-disrupts-dna-specific-b-cell-tolerance-in-3h9-mice/. Accessed .
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