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AI-05 Response gene to complement-32 promotes plasma cell differentiation and enhances lupus-like chronic graft versus host disease
  1. Alexandru Tatomir1,2,
  2. Vinh Nguyen1,2,
  3. Cosmin Tegla1,2,
  4. Cornelia Cudrici1,2,
  5. Tudor Badea3,
  6. Horea Rus1,2 and
  7. Violeta Rus1,2
  1. 1University of Maryland School of Medicine
  2. 2VA Maryland Health Care System, Baltimore, MD
  3. 3NIH, National Eye institute, Bethesda, MD


Background Response Gene to Complement (RGC)−32 is an intracellular protein that plays a role in cell growth and promotes cell cycle activation and Akt phosphorylation. RGC-32 is also a downstream target of TGF-β in fibroblasts and renal proximal tubular cells and plays a role in renal fibrogenesis. In immune cells, RGC-32 is expressed by both T and B lymphocytes. Our prior studies showed that RGC-32 promotes Th17 differentiation of mouse CD4 T cells and is highly expressed in human IL-17 CD4 cells. Whether RGC-32 plays a role in the activation and differentiation of B cells and the development of autoimmunity is not known. We used WT and RGC-32 KO mice to determine whether lack of RGC-32 impairs B cell differentiation and activation and alters autoimmune parameters in the chronic graft versus host disease (cGVHD) model of lupus.

Materials and methods B cells were cultured with lps, anti-CD40 mAb, IL-21 and IL-6, IL-4 or TGFβ and RGC-32 mRNA and protein expression was determined. TLR-dependent and T dependent B cell differentiation to plasma cells (PC) was induced with lps and with CD40mAb plus IL-4. cGVHD was induced with 100×106 Bm12 splenocytes injected into WT or RGC-32 KO recipients. Host B cell number and activation, anti-dsDNA Ab production, germinal centre (GC) B cell number and proliferation, PC number, expression of transcription factors IRF4 and Blimp1 were assessed at 2 and 4 weeks.

Results RGC-32 mRNA was upregulated in B cells by lps, anti-CD40 mAb, IL-21 and IL-6. RGC-32 KO B cells failed to differentiate normally to PC as demonstrated by a 2-fold reduction in PC numbers generated after lps and anti-CD40+ IL-4 stimulation and impaired upregulation of Prdm1 and IRF4 mRNA. RGC-32 transcripts were upregulated in spleen cells from cGVHD mice and protein expression was detected in B cells and GC cells. RGC-32KO hosts displayed an attenuated autoimmune phenotype as demonstrated by: 1) decreased production of anti-dsDNA autoAb. 2) decreased number and proliferation of GC B cells. 3) decreased number of IgG anti-dsDNA secreting PC and 4) decreased IRF4 and Prdm1 mRNA expression.

Conclusions These results suggest that expression of RGC-32 in B cells is critical for optimal GC proliferation, PC differentiation and autoantibody production in a murine model of lupus. These data support the idea that RGC-32 blockade has the potential to attenuate autoimmune parameters of cGVHD and possibly reverse abnormalities in the T and B cell pathways that contribute to lupus pathogenesis.

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