Nucleic acid specific Toll-like receptors in lupus nephritis

Patole, Prashant (2006): Nucleic acid specific Toll-like receptors in lupus nephritis. Dissertation, LMU München: Faculty of Medicine

Abstract

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.

• Item Type: Theses (Dissertation, LMU Munich)
• Keywords: Toll-like receptors, autoimmune disease, immunity, glomerulonephritis
• Subjects: 600 Technology, Medicine; 600 Technology, Medicine > 610 Medical sciences and medicine
• Faculties: Faculty of Medicine
• Language: English
• Date of oral examination: 9. May 2006
• 1. Referee: Anders, Hans-Joachim
• Signature of the printed copy: 0700/UMD 11561