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Editorials |
Department of Medicine, Monash University, Clayton, Victoria, Australia
Address correspondence to: Dr. Peter Tipping, Department of Medicine, Monash University, Level 5, Block E, 246 Clayton Road, Clayton, Victoria 3168, Australia. Phone: +61–39-594–5547; Fax: +61–39-594–6495; peter.tipping{at}med.monash.edu.au
Innate and adaptive immunity have traditionally been considered as largely separate though complimentary mechanisms of defense against microbial threats. The adaptive system, being evolutionally newer and having the capacity for selectivity, adaptation, amplification, and memory, has arguably been regarded as more sophisticated and potent. However, recent advances in our understanding of the nature and functions of Toll-like receptors (TLR) has sparked a new appreciation of the extensive interdependence and cross-talk between innate and adaptive responses and has led to renewed interest and higher regard for the contribution of the innate arm of the immune network.
TLR consist of a family of at least 11 mammalian receptors (currently 10 in humans) that bind a restricted repertoire of ligands and recruit common adaptor molecules to induce cell signaling. Their description as "pattern recognition receptors" reflects their ability to recognize exogenous ligands (lipid, nucleic acid, or protein) associated with pathogenic microorganisms—the so-called pathogen-associated molecular patterns (PAMP) (1). It is apparent now that they also have the capacity to recognize ligands from nonpathogenic organisms as well as various endogenous ligands (2), including components of necrotic cells that activate TLR2 (3), heat shock proteins (4), extracellular matrix components (5), and Tamm-Horsfall proteins in urine (6), which activate TLR4. In addition to their ability to augment innate immune defense mechanisms (opsonization and phagocytosis of bacteria and viruses, activation of the complement and coagulation cascades, and production of type 1 interferons), TLR have been shown to play an important role in initiation and modulation of adaptive immune responses (via effects on dendritic cells), T helper subset differentiation, and immune tolerance (7).
As epithelial surfaces provide the first line of defense against infection, it is not surprising that they prominently express TLR. In the kidney, TLR (mainly TLR2 and TLR4) are constitutively expressed on renal epithelial cells, including the cells of Bowman’s capsule (8), proximal and distal tubules (8,9), and the lower urinary tract and bladder (10). Their expression is upregulated in response to inflammation (8,11), and various potential roles for TLR have been proposed in renal inflammation (12). In innate inflammation, TLR4 on renal epithelia is required for protection against Escherichia coli challenge from within the urinary tract (13,14), although in response to systemic E. coli lipopolysaccharide challenge, TLR4 on intrinsic renal cells makes only a minor contribution to acute renal injury (15). Systemic administration of exogenous ligands for TLR2, TLR3, TLR4, or TLR5, but not TLR9, in combination with immunoglobulin Fc receptor activation, can induce glomerular inflammation (16). Endogenous TLR ligands have also been demonstrated to modulate renal inflammation. Heat shock proteins released after acute renal ischemia activate TLR2 and TLR4 (11) and amplify renal injury. 
-defensin 2, an antibacterial peptide released from tubular epithelial cells in response to bacterial infection (17), also serves as an endogenous ligand for TLR4 (18).
Observations of exacerbation or relapse of glomerulonephritis after infections raise the possibility of clinically important roles for TLR and their ligands in immunologically mediated renal disease. With this in mind, Brown et al. (in this issue of JASN) (19) used a murine model of crescentic glomerulonephritis and a synthetic exogenous TLR2 ligand (Pam3Cys) that mimics bacterial lipoprotein (20) to study the effect of TLR2 stimulation on inflammatory renal injury initiated by an adaptive nephritogenic immune response. Wild-type and TLR2-deficient mice were immunized with the nephritogenic antigen (sheep IgG) in the presence (or absence) of Pam3Cys. Renal injury was initiated 5 days later by "planting" the antigen (by administration of sheep anti-mouse glomerular basement membrane IgG) in the glomerulus. Exposure to the TLR agonist at the time of immune initiation resulted in an early and transient increase in circulating anti-sheep IgG antibody (IgG1, IgG2b, and IgG3), aggravated crescentic glomerulonephritis, and was associated with a 50% mortality (not observed in the absence of lipopeptide exposure) in wild-type mice. The specificity of the agonist and requirement for TLR2 was demonstrated by the absence of any Pam3Cys-induced augmentation of disease in TLR2-deficient mice. Glomerular localization of Ig (IgG2b and IgG3), CD4+ T cells, and macrophages was significantly augmented by the TLR2 ligand in wild-type (but not TLR2-deficient) mice, indicating that TLR2 augments both humoral and cellular effector responses.
TLR can influence adaptive immune responses at various levels. They induce dendritic cell maturation, expression co-stimulatory molecules, and exert complex effects on Th1 and Th2 polarization of CD4+ helper cell responses (7). Lipopolysaccharide from Gram-negative bacteria stimulates TLR4 to induce IL-12 production by mouse and human dendritic cells, which drives Th1 responses (21), although this effect can be modulated according to its dose, route of administration (22), and bacterial origin (23). Lipoproteins from Gram-positive bacteria signal through TLR2–TLR1 heterodimers and induce low levels of IL-12 (24), and mycoplasma-derived lipopeptide (25) and proteoglycans (26) stimulate IL10 production by dendritic cells, favoring Th2 or regulatory T cell responses. The TLR2 ligand, Pam3Cys, has been reported to suppress IL-12, enhance IL-10, stimulate extracellular kinase receptor signaling and the transcription factor c-Fos, and promote Th2 responses (20,27).
Although Th1 helper responses play an important role in murine crescentic anti–glomerular basement membrane antibody-induced glomerulonephritis (28), changes in the nephritogenic antibody isotypes do not argue convincingly that effects on the Th1/Th2 bias of the nephritogenic response contribute to the augmentation of injury following TLR2 stimulation in Brown’s model (19). TLR also stimulate B cell proliferation, expression of MHC II, and production of low affinity IgM antibodies (29). The transient increases in circulating antibodies and increased glomerular deposition of IgG2b and IgG3 (Th1 isotypes), observed by Brown et al., may be indicative of B cell–mediated effects. Interestingly, TLR2 and the ligand Pam3Cys have been recently shown to inhibit regulatory T cell function (30). This observation provides another intriguing possibility to explain exacerbation of immune renal injury in the study by Brown et al. (19).
Effects of TLR on adaptive autoimmune responses have also been demonstrated in murine models of lupus nephritis, but again their precise role is unclear. TLR9 is of particular interest because of evidence that some currently effective therapies for human lupus (e.g., chloroquine) inhibit TLR9 (31) and recent human testing of a synthetic TLR9 agonist (32). In lupus-prone MRLlpr/lpr mice, ligands that activate TLR9 augment production of IgG2a anti-DNA antibodies and glomerulonephritis (33), whereas inhibitory ligands block disease (34). However, studies in TLR9-deficient mice prone to lupus have produced conflicting results, with reports of increased autoimmunity and glomerulonephritis (35), as well as reduction of anti-DNA antibodies without protection from renal disease (36). There is also conflicting evidence for the involvement of TLR3 in lupus nephritis. pI:C RNA, a synthetic ligand for TLR3, aggravated nephritis in MRLlpr/lpr mice without altering anti-DNA antibodies (37) (suggesting the possibility of direct effects on mesangial cells), whereas, in TLR3-deficient, lupus-prone mice, renal injury and anti-DNA antibodies were unaffected (36). The ability of a TLR7 ligand to aggravate nephritis in MRLlpr/lpr mice has also been reported (38).
Clearly, we are only just scratching the surface with regard to understanding the complex interactions between the innate and adaptive immune systems. TLR play an important role at this interface and they are likely to be highly relevant to various inflammatory renal diseases. Does this study have relevance to reports that nasal carriage of Staphylococcus aureus is associated with relapse of antineutrophil antibody–associated vasculitis and that infections exacerbate Goodpasture’s disease? At this stage, the association remains circumstantial, but some potential mechanistic pathways are now being revealed. In the future, TLR may provide useful targets for development of new therapeutic strategies in inflammatory diseases, where activation at the innate and adaptive immune interface is critical.
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