Session Type: ACR Poster Session B
Session Time: 9:00AM-11:00AM
Background/Purpose: Changes in the ratio of circulating memory, naive, and double negative CD27–IgD– B cell subsets are associated with a higher disease activity index in systemic lupus erythematosus (SLE) patients. Little is known about the soluble factors that may induce plasmablast differentiation from B-cell subtypes infiltrating inflamed tissue environments where they have proximity to, but often spatially separated from T-cells. We investigated the potential for SLE-associated soluble BAFF, IL-2 and IL-21 to drive plasmablast differentiation from B-cell subsets in a T-cell contact independent manner and whether CC-220, a Cullin Ring Ligase 4 Cereblon (CRL4CRBN) E3 Ubiquitin Ligase Modulator, has an impact on generating potential autoantibody producing cells. The objective of the study was to d
Methods: We investigated the effects of CC-220 on plasmablast differentiation from purified B-cell subsets in in vitro models mimicking germinal center T cell contact dependent (CD40L, IL-2, IL-21) and extra-germinal center T-cell contact independent (BAFF, IL-2, IL-21) systems. Plasmablast differentiation and antibody secretion was measured 5 days post treatment of CD27+ memory B-cells and CD27– naive B-cells. Sorted B-cell subsets based on the CD27 memory and the IgD class switch markers were also tested: CD27–IgD+ naïve; CD27+IgD– switched memory (SMe); CD27+IgD+ non switched memory (NSM); and CD27–IgD– double negative (DN) B cells. Plasmablast differentiation and antibody production in the absence or presence of CC-220 were analyzed by flow cytometry and ELISA, respectively.
Conclusion: In the presence of IL-2 and IL-21, BAFF induced proliferative and plasmablast differentiation effects are only observed on class switched CD27+IgD– memory and DN CD27–IgD– B-cells. This is in contrast to CD40L, IL-2, and IL-21,which drives B-cell proliferation and differentiation in all four subpopulations tested. In all conditions used to induce B-cell proliferation and plasmablast differentiation, CC-220 inhibited these processes at clinically relevant concentrations (1-10 nM).
To cite this abstract in AMA style:Nakayama Y, Kosek J, Capone L, Schafer PH, Ringheim G. The CRL4CRBN E3 Ubiquitin Ligase Modulator CC-220 Inhibits BAFF-Mediated Plasmablast Differentiation and Immunoglobulin Secretion from Class Switched CD27+IgD- Memory and Lupus-Associated CD27-IgD- Double Negative B-Cells [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/the-crl4crbn-e3-ubiquitin-ligase-modulator-cc-220-inhibits-baff-mediated-plasmablast-differentiation-and-immunoglobulin-secretion-from-class-switched-cd27igd-memory-and-lupus-associated-cd27-igd-do/. Accessed September 19, 2019.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-crl4crbn-e3-ubiquitin-ligase-modulator-cc-220-inhibits-baff-mediated-plasmablast-differentiation-and-immunoglobulin-secretion-from-class-switched-cd27igd-memory-and-lupus-associated-cd27-igd-do/