Toll-like receptor 9

In evolutionary terms, TLRs are old, conserved PRRs (Pattern Recognition Receptors).Toll-like receptors are primarily used to recognize so-called "Pathogen Associated Molecular Patterns" (PAMPs). TLRs are transmembrane glycoproteins. Their extracellular, N-terminal domain consists of an LRR that specifically binds different ligands. This is followed by a transmembrane domain. Signal transduction takes place via the cytoplasmic "Toll-interleukin-1 receptor homology" domain, TIR for short. This recruits molecules that also contain a TIR domain, but can differ from TLR to TLR.

To date, 11 (TLR-1 to 11) and 12 murine (TLR-1 to 9 + 11 and 13) TLRs have been identified in humans. 6 of the human TLRs bind PAMPs extracellularly (TLR-1, 2, 4, 5, 6, 10, 11) while 4 are only localized intracellularly (TLR-3, 7, 8 and 9).

TLRs are expressed in immune cells of the innate and also of cells of the adaptive immune system (B and , CD286T cells) as well as in various epithelial cells (e.g. intestinal epithelia, McDermott AJ et al. 2014; Husseinzadeh N et al. 2014). This widespread distribution makes TLRs an excellent tool for the innate and acquired immune system. TLRs thus ensure the comprehensive recognition of pathogens and the activation of antigen-specific acquired immunity. The activity of TLRs enables the innate defense mechanisms (see below Immunity, innate) to differentiate between "self" and "foreign". When recognizing pathogens, the various TLRs require different adaptor molecules to activate intracellular signalling cascades such as: MyD88, TICAM-1 (TRIF), TIRAP/MAL, TRAM, and SARM.

Toll-like receptor 9 is bound in intracellular compartments such as the endolysosome. Toll-like receptor 9 (TLR9) is a cellular DNA receptor of the innate immune system. DNA recognition via TLR9 resultsin an inflammatory response, which also leads to a Th1-based adaptive immune attack (Sandholm J et al. 2014)

TLR9 mRNA is abundantly expressed in breast carcinoma. However, the pathophysiological role of TLR9 is not clear, although high expression of TLR9 tends to be associated with a good prognosis (possible therapeutic consequences?). Furthermore, TLR9 also plays a role in certain forms of CLL (Efremov DG et al. 2013).

Toll-like receptors, in particular TLR2, TLR4 and TLR9, are involved in the pathogenesis of inflammatory processes in atherosclerosis. This also applies to coronary arterial disease (CAD). TLR9 stimulates interferon-alphα and increases the cytotoxic activity of CD4+ T cells (Roshan MH et al. 2016).

Various studies have shown that single nucleotide polymorphisms, or SNPs, in the TLR9 gene are associated with an increased risk of developing tuberculosis in certain populations (Chen Z et al. 2015).

TLR9 recognizes intracellular viral dsDNA. This "pattern recognition" results in the initiation of a specific immune response against HBV. Defects in this immunological defense chain result in a delayed immune response and a protracted HBV infection (Shahrakyvahed A et al. 2014).

Polymorphisms of TLR7 and TLR9 are associated with the development of systemic lupus erythematosus in Asian populations (Lee YH et al. 2012).

1. Chen Z et al (2015) Association between toll-like receptors 9 (TLR9) gene polymorphism and risk of pulmonary tuberculosis: meta-analysis. BMC Pulm Med 15:57.
2. Efremov DG et al (2013) TLR9 signaling defines distinct prognostic subsets in CLL. Front Biosci (Landmark Ed) 18:371-386.
3. Lee YH et al.(2012) Associations between TLR
4. polymorphisms and systemic lupus erythematosus: a systematic review and meta-analysis. Clin Exp Rheumatol 30:262-265.
5. Roshan MH et al(2016) The Role of TLR2, TLR4, and TLR9 in the Pathogenesis of Atherosclerosis. Int J Inflam 2016:1532832.
6. Shahrakyvahed A et al.(2014) TLR9: an important molecule in the fight against hepatitis B virus. Postgrad Med J 90:396-401.
7. Sandholm J et al.(2014) Toll-like receptor 9 in breast cancer. Front Immunol 5:330.