Toll like receptors and adaptive immune responses in experimental murine glomerulonephritis

Toll like receptors (TLRs) are well characterised pattern recognition receptors which recognise conserved molecular motifs from microbes and promote host defence. Stimulation of TLRs results in the recruitment of innate immune cells as well as promotion of adaptive immune responses including humoral and cellular immunity. The induction of host immune responses is central to survival after bacterial or viral infection. However an over active immune response can result in the development of autoimmunity and organ inflammation with subsequent injury. TLRs are likely active participants in the development of autoimmunity and renal injury. This thesis studies the role of 2 extracellular TLRs, TLR2 and TLR4, and one intracellular TLR, TLR9 in the development of autoimmunity and auto-inflammation. I have studied the effect of these TLRs in experimental models of auto-immune diseases which frequently induce glomerulonephritis and renal injury. Chapter 2 discusses the role of TLR4 recruitment of innate immune cells in experimental anti-myeloperoxidase (MPO) induced glomerulonephritis. Administration of a TLR4 ligand with anti-MPO globulin increased glomerular neutrophil recruitment which later resulted in functional (albuminuria), and histological renal injury. Renal injury required bone marrow and renal cell TLR4, which was produced by glomerular endothelial cells and was CXCL1 and CXCL2 dependant. In Chapter 3 I have assessed the effect of TLR9 ligation on adaptive immune responses and renal injury in experimental crescentic glomerulonephritis. TLR9 ligation promoted strong Th1 and Th17 responses and exacerbated renal injury. A TLR9 inhibitor was able to successfully decrease renal injury by attenuating immune responses and decreasing glomerular macrophage recruitment. Chapter 4 describes how TLR2 and TLR9 promote the development of Th17 and Th1 autoimmunity respectively, when administered in combination with MPO. When renal injury is triggered the TLR2/ Th17 and TLR9/ Th1 immune responses enhance renal injury acting through different glomerular effectors. In Chapter 5 I demonstrate that importance of both Th1 and Th17 driven nephritogenic immunity in the initiation of renal injury. Both Th1 and Th17 immune responses induce proliferative glomerulonephritis, with functional renal injury. Th1 associated injury is predominantly macrophage mediated, while Th17 induced injury is neutrophil mediated. Chapter 6 assesses the endogenous role of TLR9 and TLR4 in experimental lupus nephritis, after injecting mice with pristane. TLR9-/- and TLR4-/- were protected from ‘full-blown’ autoimmunity and lupus nephritis was significantly attenuated. In this thesis I have demonstrated how TLR2, 4 and 9 can influence autoimmune glomerulonephritis and renal injury. The enhanced TLR driven renal injury can be a consequence of enhanced innate or adaptive immune responses. These results add considerably to the existing knowledge of TLRs in experimental nephritis and furthermore identify TLRs as therapeutic targets.