Nucleic acid specific Toll-like receptors in lupus nephritis
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vor 18 Jahren
Nucleic acids that occur free or as immune complexes may trigger
immune activation leading to aggravation of diseases with
autoimmune predisposition. TLR3 and TLR 9 represent receptors that
signal for viral and bacterial nucleic acids respectively. pI:C
RNA, a synthetic double stranded RNA with identical properties to
that viral origin activates TLR3 led to aggravation of lupus
nephritis, a form of immune complex glomerulonephritis, in
pre-existing lupus in MRLlpr/lpr mice. Exposure to pI:C RNA (a
structural analogue of viral dsRNA) can aggravate lupus nephritis
through TLR3 on antigen-presenting cells and glomerular mesangial
cells. pI:C RNA–induced cytokine and chemokine production
represents a major mechanism in this context. Likewise, CpG DNA a
classical activator for TLR-9 led to disease aggravation in this
mouse model albeit, through mechanisms that shared some commonality
as well as differences to that observed with pI:C RNA. Apparently,
pathogen associated immunomodulation relates to the
cell-type-specific expression pattern of the respective
pattern-recognition receptor. dsRNA-induced disease activity is
independent of B cell activation and humoral antichromatin immunity
in experimental SLE and therefore differs from CpG-DNA–induced
autoimmunity. These findings contribute to the understanding of
pathogen-associated modulation of autoimmunity but may also be
involved in the pathogenesis of other types of inflammatory kidney
diseases, e.g., flares of IgA nephropathy, renal manifestations of
chronic hepatitis C virus infection, and renal vasculitis. Further,
besides signifying the role of foreign and self-DNA as a pathogenic
factor in autoimmune disease activity in lupus, this detailed study
reveals, that certain synthetic G-rich nucleic acids may
potentially block nucleic acid specific TLR functions and thus
prove beneficial in arresting disease activity during progressive
systemic lupus. One such G-rich DNA employed in this study has
proven to be beneficial and suppressed systemic lupus in MRLlpr/lpr
mouse model. Thus, modulating the CpG-DNA - TLR9 pathway may offer
new opportunities for the understanding and treatment of lupus.
immune activation leading to aggravation of diseases with
autoimmune predisposition. TLR3 and TLR 9 represent receptors that
signal for viral and bacterial nucleic acids respectively. pI:C
RNA, a synthetic double stranded RNA with identical properties to
that viral origin activates TLR3 led to aggravation of lupus
nephritis, a form of immune complex glomerulonephritis, in
pre-existing lupus in MRLlpr/lpr mice. Exposure to pI:C RNA (a
structural analogue of viral dsRNA) can aggravate lupus nephritis
through TLR3 on antigen-presenting cells and glomerular mesangial
cells. pI:C RNA–induced cytokine and chemokine production
represents a major mechanism in this context. Likewise, CpG DNA a
classical activator for TLR-9 led to disease aggravation in this
mouse model albeit, through mechanisms that shared some commonality
as well as differences to that observed with pI:C RNA. Apparently,
pathogen associated immunomodulation relates to the
cell-type-specific expression pattern of the respective
pattern-recognition receptor. dsRNA-induced disease activity is
independent of B cell activation and humoral antichromatin immunity
in experimental SLE and therefore differs from CpG-DNA–induced
autoimmunity. These findings contribute to the understanding of
pathogen-associated modulation of autoimmunity but may also be
involved in the pathogenesis of other types of inflammatory kidney
diseases, e.g., flares of IgA nephropathy, renal manifestations of
chronic hepatitis C virus infection, and renal vasculitis. Further,
besides signifying the role of foreign and self-DNA as a pathogenic
factor in autoimmune disease activity in lupus, this detailed study
reveals, that certain synthetic G-rich nucleic acids may
potentially block nucleic acid specific TLR functions and thus
prove beneficial in arresting disease activity during progressive
systemic lupus. One such G-rich DNA employed in this study has
proven to be beneficial and suppressed systemic lupus in MRLlpr/lpr
mouse model. Thus, modulating the CpG-DNA - TLR9 pathway may offer
new opportunities for the understanding and treatment of lupus.
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