Abstract
Nucleosome is a major autoantigen in systemic lupus erythematosus. It is composed of DNA (multiple of 180 bp) and the five histones H1, H2A, H2B, H3 and H4. Previous works have shown the presence of circulating nucleosome in sera of lupus patients, which could be due to increased apoptosis or impaired phagocytosis, both resulting in secondary necrosis and release of nucleosome. On the other hand, it was shown that nucleosome could bind to the surface of cells, such as lymphocytes. In order to better understand the role of this circulating complex, we analysed the effect of purified nucleosome on living murine lymphocytes. Here we show that nucleosome induces necrosis of cells, and not apoptosis, as assessed by different techniques. Similar results were obtained with mono-, di-, tri- and poly-nucleosomes. Moreover, this effect is time and dose dependent, is impaired when nucleosome is heat-inactivated and is not observed with other non related purified proteins. Finally, we analysed in more details the sensitivity of B and T cells to nucleosome. These results suggest that nucleosomes released by apoptotic cells could induce necrosis of neighbouring cells, thus allowing the release of cell contents in high amounts. This phenomenon would act as an amplification loop and could explain how the peripheral tolerance is broken and is in agreement with inflammatory responses which are normally not associated with apoptosis.
Highlights
The presence of autoantibodies directed to citrullinated antigens in serum is highly specific for rheumatoid arthritis (RA)
We discuss the presence of anti-keratin antibodies (AKA) of the IgG class in patients with defined juvenile idiopathic arthritis (JIA)
Our study revealed that AKA was present overall in 18/29 patients (62%) with severe JIA and in 12/26 patients (46,2 %) with non-severe disease, this did not reach statistical significance (P = 0,18)
Summary
The presence of autoantibodies directed to citrullinated antigens in serum is highly specific for RA. Anti-CCP concentrations (expressed in Units per mg total IgG) were on average 1.34 times higher in SF compared to serum (n = 20, P < 0.05) or 1.37 when only positive samples were included (n = 11, P < 0.05) Conclusion: Citrullinated antigens are present in the synovia of both RA and control patients with similar prevalence. At higher concentrations (>1ng/μl) of RNA-oligonucleotides unspecific hybridization-signals prevailed in tissues of all diseases (even in normal controls) The combination of both methods (in situ-hybridization and immunohistochemistry) identifies the single cells inside the synovial lining layer which contains the highly expressed RAB3 “Kreisler” (maf B) gene. Conclusions: These data demonstrates for the first time that statins (and fluvastatin) are able to inhibit an endothelial proadhesive and pro-inflammatory phenotype induced by different stimuli including anti-β2GPI antibodies or pro-inflammatory cytokines These findings suggest a potential usefulness for statins in the prevention of the APS pro-atherothrombotic state
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