Role of nucleosome-induced neutrophil activation in systemic lupus erythematosus
Final Report Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown aetiology in which circulating nucleosomes are major autoantigens playing a key role in disease development. Nevertheless, the mechanisms controlling nucleosome clearance, the deficiencies associated with disease development, the consequences of circulating nucleosomes and particularly the impact on innate immunity are only partly characterised. We have analysed those aspects and found that DNase1 and C1q are involved in nucleosome clearance. When those mechanisms are defective, nucleosomes accumulate and stimulate the innate immunity, leading to the activation of the complement system and neutrophil activation. Particularly, we observed that nucleosome stimulate neutrophils to produce interferon-α, a pathogenic event in SLE and that activation does not require Toll-like receptor 9 (TLR9). In parallel, we also observed in patients an increased concentration of soluble ligands able to bind to natural killer cells. Finally, we have reported that dendritic cells downregulate CD11c upon activation and that neutrophils express a functional cell surface TLR9.
Publications
-
2006. TLR2/TLR4-independent neutrophil activation and recruitment upon endocytosis of nucleosomes reveals a new pathway of innate immunity in systemic lupus erythematosus. J.Immunol. 177:7740-7749
Rönnefarth, V. M., A. I. M. Erbacher, T. Lamkemeyer, J. Madlung, A. Nordheim, H. G. Rammensee, and P. Decker
-
2007. Circulating nucleosomes due to a defective clearance of dying cells: Consequences for systemic lupus erythematosus. Autoimmunity 40:311-314
Erbacher, A. I., V. M. Rönnefarth, and P. Decker
-
2009. Chromatin modifications, oxidative stress and nucleosome autoantibodies. In: The epigenetics of autoimmune diseases. Moncef Zouali, ed., pp. 119-134
Erbacher, A. and P. Decker
-
2009. Neutrophils, dendritic cells and chromatin-mediated pathogenesis in systemic lupus erythematosus. Autoimmunity 42:254-256
Lindau, D. and P. Decker
