Effect of administration of apoptotic blebs on disease development in lupus mice

Abstract

Introduction. Systemic lupus erythematosus (SLE) is an autoimmune disease characterised by the formation of autoantibodies against nuclear components. Disturbed apoptosis and reduced clearance of apoptotic material have been assigned a role in the pathogenesis of SLE. During apoptosis, apoptotic blebs are formed, in which SLE autoantigens are clustered. In vitro, apoptotic blebs can induce maturation of dendritic cells (DC), which in turn can stimulate IL-17 production by T cells. Here, we investigated the effects of administration of apoptotic blebs, separate or in combination with dendritic cells, on disease progression and autoantibody production in lupus and normal mice. Methods. A preparation of apoptotic blebs, with or without DC, was intravenously administered to MRL/lpr and CBA mice at weeks 7, 9, and 11 of age. T-cell responses against autoantigens present in blebs were examined by delayed type hypersensitivity reactions. Disease progression of the mice was evaluated by determining proteinuria and the titers of anti-DNA, anti-histone, and anti-nucleosome autoantibodies in plasma. Results. Repeated administration of apoptotic blebs, with or without DC, had no effect on the course of proteinuria or on anti-DNA, anti-histone and anti-nucleosome autoantibody levels in MRL/lpr mice. Intravenous injections of apoptotic blebs resulted in a decrease in the DTH response towards s.c. administered blebs in MRL/lpr mice and in reduced anti-nucleosome antibody titers in CBA mice. These tolerizing effects were lost when apoptotic blebs were administered together with syngeneic DC after 2 hours of co-incubation. Discussion and Conclusions. In contrast to previous studies with apoptotic cells, and deviating from our in vitro findings with apoptotic blebs, we observed no stimulating effect of the administration of apoptotic blebs on disease progression in MRL/lpr lupus mice. The tolerogenic effects that were observed may be associated with rapid removal of i.v. administered blebs by phagocytes in an immune-silencing way.

Keywords::

• apoptosis
• apoptotic blebs
• dendritic cells
• systemic lupus erythematosus
• MRL/lpr mice

Acknowledgements

We thank Dr. J. Greenberger (University of Pittsburgh Cancer Institute, Pennsylvania, USA) and Dr. S. Baker (Temple University, Philadelphia, Pennsylvania, USA) for kindly providing the 32D clone 3 cell line. Dr. J. Dieker, Mr. J. Ruben, Mr. C. Jacobs, Mrs. M. Bakker-van Bebber, Mr. G. Poelen and Mrs. D. Smits are acknowledged for their kind technical assistance. Thanks are also extended to the Ph.D. programme of the Radboud University Nijmegen Medical Centre and the Dutch Kidney Foundation (Grant C05.2119).

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.