Aiolos Overexpression in Systemic Lupus Erythematosus B Cell Subtypes and BAFF-Induced Memory B Cell Differentiation Are Reduced by CC-220 Modulation of Cereblon Activity

J Immunol. 2017 Oct 1;199(7):2388-2407. doi: 10.4049/jimmunol.1601725. Epub 2017 Aug 28.

Abstract

BAFF is a B cell survival and maturation factor implicated in the pathogenesis of systemic lupus erythematosus (SLE). In this in vitro study, we describe that soluble BAFF in combination with IL-2 and IL-21 is a T cell contact-independent inducer of human B cell proliferation, plasmablast differentiation, and IgG secretion from circulating CD27+ memory and memory-like CD27-IgD- double-negative (DN) B cells, but not CD27-IgD+ naive B cells. In contrast, soluble CD40L in combination with IL-2 and IL-21 induces these activities in both memory and naive B cells. Blood from healthy donors and SLE patients have similar circulating levels of IL-2, whereas SLE patients exhibit elevated BAFF and DN B cells and reduced IL-21. B cell differentiation transcription factors in memory, DN, and naive B cells in SLE show elevated levels of Aiolos, whereas Ikaros levels are unchanged. Treatment with CC-220, a modulator of the cullin ring ligase 4-cereblon E3 ubiquitin ligase complex, reduces Aiolos and Ikaros protein levels and BAFF- and CD40L-induced proliferation, plasmablast differentiation, and IgG secretion. The observation that the soluble factors BAFF, IL-2, and IL-21 induce memory and DN B cell activation and differentiation has implications for extrafollicular plasmablast development within inflamed tissue. Inhibition of B cell plasmablast differentiation by reduction of Aiolos and Ikaros may have utility in the treatment of SLE, where elevated levels of BAFF and Aiolos may prime CD27+ memory and DN memory-like B cells to become Ab-producing plasmablasts in the presence of BAFF and proinflammatory cytokines.

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Antibody Formation / drug effects
  • B-Cell Activating Factor / blood*
  • B-Cell Activating Factor / immunology*
  • B-Cell Activating Factor / metabolism
  • B-Lymphocyte Subsets / drug effects
  • B-Lymphocyte Subsets / immunology*
  • CD40 Ligand / pharmacology
  • Cell Differentiation
  • Heterocyclic Compounds, 4 or More Rings / pharmacology
  • Humans
  • Ikaros Transcription Factor / blood
  • Ikaros Transcription Factor / genetics*
  • Immunologic Memory* / drug effects
  • Interleukin-2 / blood
  • Interleukin-2 / pharmacology
  • Interleukins / pharmacology
  • Lupus Erythematosus, Systemic / immunology*
  • Peptide Hydrolases / metabolism*
  • Tumor Necrosis Factor Receptor Superfamily, Member 7 / deficiency
  • Tumor Necrosis Factor Receptor Superfamily, Member 7 / genetics
  • Tumor Necrosis Factor Receptor Superfamily, Member 7 / immunology
  • Ubiquitin-Protein Ligases

Substances

  • Adaptor Proteins, Signal Transducing
  • B-Cell Activating Factor
  • CRBN protein, human
  • Heterocyclic Compounds, 4 or More Rings
  • IKZF1 protein, human
  • IKZF3 protein, human
  • Interleukin-2
  • Interleukins
  • TNFSF13B protein, human
  • Tumor Necrosis Factor Receptor Superfamily, Member 7
  • CD40 Ligand
  • Ikaros Transcription Factor
  • iberdomide
  • Ubiquitin-Protein Ligases
  • Peptide Hydrolases
  • interleukin-21