Session Title: B Cell Biology and Targets in Autoimmune Disease I
Session Type: ACR Concurrent Abstract Session
Session Time: 2:30PM-4:00PM
Background/Purpose: Anergic autoreactive B cells are thought to play a critical role in systemic lupus erythematosus (SLE), a chronic autoimmune disease where breach of tolerance to nuclear antigen leads to the production of pathogenic anti-nuclear autoantibodies (ANA). There is evidence that anergic B cells survive longer and are less tolerized in SLE patients and lupus-prone mice; however, their exact contribution to SLE pathogenesis remains unclear. Our laboratory has used congenic derivatives of the lupus-prone New Zealand Black mouse to parse the B and T cell defects involved in SLE, uncovering a B cell defect required for ANA production (in the 170.8-181 Mb interval on chromosome 1 [C1d]) as well as T cell defects (in the 124-181 Mb interval [C1b-d]) that exacerbate disease. Since these defects were sufficient to breach B cell anergy to the neo-self antigen hen egg lysozyme, we hypothesized that a similar breach would occur in the Vκ8/3H9 model of anergy, a better analogue for human SLE.
Methods: The 3H9 heavy chain and Vκ8 light chain were knocked into their correct loci in the C1d and C1b-d strains to generate mice with homogeneous, ssDNA-specific, anergic B cell repertoires. ANAs in female 8 month old non-autoimmune (B6), C1d and C1b-d wild type (WT) and double knock-in (dKI) mice were measured by ELISA, while splenic B and T cells were examined using flow cytometry. Adoptive transfer of B6 or C1d dKI B cells into B6 or C1d WT recipients was conducted to assess the effect of the anergic milieu on B cell activity; recipients were sacrificed after 7 days and splenocytes analyzed via flow cytometry.
Results: C1b-d WT mice had significantly increased anti-ssDNA IgG and IgM, and higher proportions of germinal centre (GC) B cells, CD86+ B cells and T follicular helper (TFH) cells than B6 WT mice, with C1d WT mice also trending to significance. Surprisingly, the autoimmune B cell phenotype was attenuated in both C1 dKI strains, such that C1 dKI mice were equivalent to B6 counterparts. While the levels of TFH cells remained significantly higher in C1 dKI mice than in B6, they were significantly decreased compared to C1 WT mice, suggesting that the attenuated breach of B cell tolerance could result from insufficient T cell priming. This explanation was supported by the observation that anergic C1d dKI B cells adoptively transferred into C1d WT mice showed similar trends to increased GC and CD86+ B cells as in C1d WT mice. Finally, while the proportion of TFH cells was significantly decreased in C1b-d dKI mice compared to their WT counterparts, the proportion of T follicular regulatory (TFR) cells remained similar to WT levels, suggesting that selective survival or induction of TFR cells in the dKI congenic strains may play a role in their decreased autoimmune phenotype.
Conclusion: Our results demonstrate that while the B and T cell defects in New Zealand Black congenic mice generate autoimmunity in an unconstrained immune system, these defects are not sufficient to robustly breach tolerance to endogenous nuclear antigen when the B cell repertoire is predominantly anergic, possibly due to modulation of T cell activation or regulatory cell fate.
To cite this abstract in AMA style:Manion K, Baglaenko Y, Chang NH, Talaei N, Wither J. Anergic B Cells May Preserve Peripheral Tolerance in Lupus-Prone Congenic Mice [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/anergic-b-cells-may-preserve-peripheral-tolerance-in-lupus-prone-congenic-mice/. Accessed November 30, 2020.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/anergic-b-cells-may-preserve-peripheral-tolerance-in-lupus-prone-congenic-mice/