Table 1.
Examples of microbial and endogenous ligands of Toll-like receptors
| TLR | Microbial ligand* | Endogenous ligand | ||||
|---|---|---|---|---|---|---|
| Autoantigen | Natural source of autoantigen | Experimental source of autoantigen | Disease association | Refs | ||
| TLR2 and/or TLR4 |
• Lipoteichoic acid (Gram-positive bacteria) • Lipoarabinomannan (Mycobacterium spp.) • Glycosylphos-phatidylinositol (Trypanosoma cruzi) • Glycolipids (Treponema pallidum) • Porins (Neisseria meningitidis) • Zymosan (fungi) • Lipopeptides, LPS and lipid A (Gramnegative bacteria) • Paclitaxel (Taxus brevifolia)‡ • F protein (RSV) • Hyphae(Aspergillus fumigatus) • HSP60 (Chlamydia trachomatis) • Envelope proteins (MMTV) • Triacyl lipopeptides (bacteria) (with TLR1)§ • Diacyl lipopeptides (Mycobacterium spp.) (with TLR6)§ |
• Necrotic cells | • Cellular injury | • Necrotic cells |
• Inflammation • Tissue repair |
111 |
| • Renal ischaemia–reperfusion injury |
• Pro-inflammatory cytokine production • Renal injury |
103 | ||||
|
• HSP60 • HSP70 • gp96 |
• Cellular injury |
• Recombinant proteins • Transgenic cell-surface proteins |
• Arthritis | 112,113 | ||
| • HMGB1 |
• Passive release from dead or damaged cells • Secretion by activated macrophages |
• Pig thymus |
• Arthritis • Chronic myositis |
114 | ||
| • Hyaluronate |
• Degradation of extracellular matrix • Synovial fluid |
• Clinical-grade sodium hyaluronate • Human umbilical cord |
• Inflammation • Arthritis |
115,116 | ||
|
• Streptococcus equi • Sera from patients with ARDS |
• Pro-inflammatory cytokine production | 106 | ||||
| • High-molecular-weight extracellular matrix | • Transgenic hyaluronate synthase 2 | • Protection from acute non-infectious lung injury | 106 | |||
| • Fibronectin (extra domain A) | • Release from cells in response to tissue damage | • Recombinant protein | • Arthritis | 117 | ||
| • Minimally modified LDL | • Atherosclerotic lesion | • Human plasma LDL exposed to 15-lipoxygenase | • Atherosclerosis | 118 | ||
| • Heparan sulphate | • Release from plasma membrane or extracellular matrix during injury or inflammation | • Bovine kidneys | • Systemic inflammatory-response syndrome | 119 | ||
| • Fibrinogen | • Leakage from vasculature to extravascular space during inflammation | • Clinical-grade fibrinogen |
• Inflammation • Arthritis |
120 | ||
|
• HSPB8 • α crystallin |
• Synovial tissue | • Recombinant proteins | • Arthritis | 121 | ||
| TLR3 | • Double-stranded RNA (viruses) | • Double-stranded RNA | • Necrotic cells | • Synovial fluid | • Arthritis | 122 |
| TLR5 | • Flagellin (bacteria) | ND | – | – | – | – |
| TLR7 and TLR8 (TLR8 in humans only) | • Single-stranded RNA (viruses) | • Single-stranded RNA |
• Dead or dying cells • Purified snRNPs |
• Apoptotic- or necrotic-cell debris • Purified snRNPs • RNA-based oligonucleotides |
• SLE • Scleroderma • Sjögren's syndrome |
17,30,32,46 |
| TLR9 | • DNA (bacteria or HSV) | • DNA | • Dead or dying cells | • Apoptotic- or necrotic-cell debris | • SLE | 27,28,45 |
| TLR11 (mice only) |
• Uropathogenic Escherichia coli • Profilin (Toxoplasma gondii) |
ND | – | – | – | – |
| *Summarized from Refs 123–126. The ligands (both microbial and endogenous) for Toll-like receptor 10 (TLR10; present in humans only), TLR12 (present in mice only) and TLR13 (present in mice only) are not known. | ||||||
| ‡Paclitaxel (Taxol; Bristol-Myer Squibb). | ||||||
| §TLR2 can form heterodimers with TLR1 or TLR6. ARDS, adult respiratory-distress syndrome; F protein, fusion protein; gp96, glycoprotein 96; HMGB1, high-mobility group box 1 protein; HSP, heat-shock protein; HSV, herpes simplex virus; LDL, low-density lipoprotein; LPS, lipopolysaccharide; MMTV, mouse mammary tumour virus; ND, not determined; RSV, respiratory syncytial virus; SLE, systemic lupus erythematosus; snRNP, small nuclear ribonucleoprotein. | ||||||