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Most physicians can identify B lymphocytes and T lymphocytes, and perhaps
dendritic cells, as the cells involved in the pathogenesis of systemic lupus
erythematosus (SLE). This systemic autoimmune disease is characterized by the
loss of tolerance to nuclear antigens, the deposition of immune complexes in tissues,
and multiorgan involvement. Recent studies, such as those by Lande et al.1 and
Garcia-Romo et al.,2 have pushed the neutrophil to the forefront of the pathogenesis
of SLE and have provided insight into how the implicated biochemical and cellular
events are linked.
The chronic activation of plasmacytoid dendritic cells by circulating immune
complexes is a key, early trigger of autoimmunity in patients with SLE. These
immune complexes provoke the plasmacytoid dendritic cells to secrete type I
interferons. In lupus, the prevalence of circulating plasmacytoid dendritic cells is
markedly reduced because these cells migrate to the tissues and remain therein;
however, residual, single circulating plasmacytoid dendritic cells can produce
interferon- normally3 and in huge amounts, which can have a systemic effect. A
single plasmacytoid dendritic cell synthesizes around a billion interferon- molecules
in a 12hour period 200 to 1000 times as many as other cell types.4 Genomic
studies indicate that around 95% of children and 70% of adults with SLE have a type
I interferon signature, of which interferon- is a hallmark. Also characteristic of this
disorder is the expression of neutrophil-specific genes, which correlates with disease
activity. Thus, neutrophil-specific genes are the second most prevalent peripheral-
blood mononuclear-cell transcriptional signature in children with SLE.5 Furthermore,
the presence of neutrophil-specific proteins in the urine, a surrogate marker of
disease activity in lupus, may be an indicator of their possible role in its
pathogenesis.
The studies by Lande et al. and Garcia-Romo et al. suggest that a peculiar
chromatin-based substance that is spewed into the extracellular matrix as the
neutrophil undergoes a unique form of cell death so-called NETosis represents
the link between interferon- production and neutrophil death. The discovery of this
substance, dubbed the neutrophil extracellular trap (NET), revealed that neutrophils
can immobilize and kill invading microbes by means of NET formation. In some
patients with SLE, the degradation of NETs is impaired owing to DNase I inhibitors or
antibodies to NETs.
Lande et al. observed that the antimicrobial peptide LL-37 a key mediator of
plasmacytoid dendritic cell activation in psoriasis was expressed at high levels in
the blood of persons with SLE, suggesting that LL-37 is involved in the
immunogenicity of self nucleic acids in immune complexes. They confirmed that LL-
37 and human neutrophil peptide (HNP) are essential for the immunogenicity of
DNA-containing immune complexes in SLE and that free human DNA entered and
activated plasmacytoid dendritic cells through toll-like receptor 9 when complexed
with LL-37. Likewise, autoantibodies in immune complexes interacted with the Fc
surface receptor II (FcRII) on plasmacytoid dendritic cells and triggered receptor-
mediated endocytosis of self DNA.
Self DNAantimicrobial peptide complexes, LL-37 and HNP, which would seem to be
pivotal components of NETs, activate plasmacytoid dendritic cells to produce
Disclosure forms provided by the author are available with the full text of this article
at NEJM.org.
SOURCE INFORMATION
From the Department of Internal Medicine, Hospital Clinic, University of Barcelona,
Institut d'Investigacions Biomdiques August Pi i Sunyer, Barcelona.