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Triggers for anti-chromatin autoantibody production in SLE
J WC Dieker
J van der Vlag
Nephrology Research Laboratory, Nijmegen Center for Molecular Life Sciences,and Division of Nephrology University Medical Center, Nijmegen, The Netherlands
J HM Berden
Nephrology Research Laboratory, Nijmegen Center for Molecular Life Sciences,and Division of Nephrology University Medical Center, Nijmegen, The Netherlands; Division of Nephrology (545), University Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands
The formation of autoantibodies against chromatin is the main feature of systemic lupus erythematosis (SLE), an autoimmune disease, which is T-cell dependent and autoantigen-driven. Historically, antibodies against dsDNA, one ofthe components of chromatin, are considered as a hallmark of SLE. However, dsDNA is poorly immunogenic. Nucleosome-specific T helper cells have been identified. These T cells propagate not only nucleosome-specific antibodies, but also anti-dsDNA antibodies Nucleosomes are formed during apoptosis by cleavage of chromatin, and evidence of disturbed apoptosis has been foundespecially in certain murine models of lupus. In addition to an increased rate of apoptosis, autoimmunity against chromatin might also result from an impaired phagocytosis ofapoptotic material, for which strong evidence has been provided by studies in certain knock-out mice (C1q, SAP, Dnase I). The induction of an immune response to nucleosomes could be enhanced by modifi cations of histones or DNA during apoptosis, altered presentation by antigen presenting cells or a viral infection. The release of nucleosomes and the formation of anti-chromatin autoantibodies result in formation of complexes, which bind to the glomerular basement membrane via heparan sulfate. This deposition incites glomerulonephritis, the most serious manifestation of SLE.
Key Words: lupus • autoantibodies • chromatin • dysregulated apoptosis; nucleosomes
Lupus, Vol. 11, No. 12,
856-864 (2002)
DOI: 10.1191/0961203302lu307rr
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