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10.4049/jimmunol.1601725

http://scihub22266oqcxt.onion/10.4049/jimmunol.1601725
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suck abstract from ncbi


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pmid28848067
      J+Immunol 2017 ; 199 (7 ): 2388-2407
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  • 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 #MMPMID28848067
  • Nakayama Y ; Kosek J ; Capone L ; Hur EM ; Schafer PH ; Ringheim GE
  • J Immunol 2017[Oct]; 199 (7 ): 2388-2407 PMID28848067 show ga
  • 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.
  • |*Immunologic Memory/drug effects [MESH]
  • |Adaptor Proteins, Signal Transducing [MESH]
  • |Antibody Formation/drug effects [MESH]
  • |B-Cell Activating Factor/*blood/*immunology/metabolism [MESH]
  • |B-Lymphocyte Subsets/drug effects/*immunology [MESH]
  • |CD40 Ligand/pharmacology [MESH]
  • |Cell Differentiation [MESH]
  • |Heterocyclic Compounds, 4 or More Rings/pharmacology [MESH]
  • |Humans [MESH]
  • |Ikaros Transcription Factor/blood/*genetics [MESH]
  • |Interleukin-2/blood/pharmacology [MESH]
  • |Interleukin-21 [MESH]
  • |Interleukins/pharmacology [MESH]
  • |Lupus Erythematosus, Systemic/*immunology [MESH]
  • |Morpholines [MESH]
  • |Peptide Hydrolases/*metabolism [MESH]
  • |Phthalimides [MESH]
  • |Piperidones [MESH]
  • |Tumor Necrosis Factor Receptor Superfamily, Member 7/deficiency/genetics/immunology [MESH]


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