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User:JSdeutsch/TLR-2

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[This is the 3 November 2008 English rendering of the German Wikipedia article TLR-2. Translator's notes can be found under the discussion tab above.]


TLR-2 is the name of a biomolecule that plays a role in the human immune system. It is a membrane protein, referred to as a receptor, that sits on the surface of certain cells and is able to recognize foreign or host molecules and transmit corresponding signals to the cell or to the nervous system.

TLR-2 belongs to a large family of homologous toll-like receptors (TLRs) and is described here as an example.

Introduction

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The immune system recognizes foreign pathogens and eliminates them. This occurs in several phases. In the early inflammation phase, the pathogens are recognized by antibodies that are already present (innate or acquired through prior infection; see also cross-reactivity). Immune-system components (e.g. complement) that are bound to the antibodies and kept around in reserve then disable them, and they are phagocytized by scavenger cells (e.g. macrophages). Dendritic cells are likewise capable of phagocytizing but do not do it for the purpose of direct pathogen elimination. Rather, they infiltrate the spleen and lymph nodes, and each presents components of an antigen there, as the result of which specific antibodies are formed that recognize precisely that antigen.

These newly formed antibodies would arrive too late in an acute infection, however, so what we think of as "immunology" constitutes only the second half of the process. Because this phase would always start too late to play an essential role in the defense process, a faster-acting principle is applied ahead of it, one that occurs only in forms of life that are phylogenetically more highly developed.

So-called pattern recognition receptors come into play here. This refers to receptors that recognize the gross, primarily structural features of molecules not innate to the host organism. These include, for example, lipids with a totally different basic chemical structure. Such receptors are bound directly to cells of the immune system and cause immediate activation of their respective nonspecific immune cells.

A prime example of such a foreign ligand is bacterial endotoxin, whose effects have been known for generations. When it enters the bloodstream it causes systematic activation of the early-phase response, with all the side effects of septic shock. This is known in the laboratory as the Shwartzman phenomenon. The intended effect is to mobilize the organism for combat, so to speak, and eliminate most of the pathogens.

Occurrence

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TLR-2 is expressed on microglia, Schwann cells, monocytes, macrophages, dendritic cells, polymorphonuclear leukocytes (PMNs or PMLs), B cells (B1a, MZ B, B2), and T cells, including Tregs (CD4+CD25+ regulatory T cells). In some cases it occurs in a heterodimer (combination molecule), e.g. paired with TLR 1 or TLR 6. TLR-2 is also found in the epithelia of air passages, pulmonary alveoli, renal tubules, and the Bowman's capsules in renal corpuscles. In the skin it is found on keratinocytes and sebaceous glands; spc1 is induced here, allowing a bactericidal sebum to be formed.

Mechanism

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As a membrane surface receptor, TLR-2 recognizes many bacterial, fungal, viral, and certain endogenous substances. In general, this results in the uptake (internalization, phagocytosis) of bound molecules by endosomes/phagosomes and in cellular activation; thus such elements of innate immunity as macrophages, PMNs and dendritic cells assume functions of nonspecific immune defense, B1a and MZ B cells form the first antibodies, and specific antibody formation gets started in the process. Cytokines participating in this include tumor necrosis factor alpha (TNF-α) and various interleukins (IL-1α, IL-1β, IL-6, IL-8, IL-12). Before the TLRs were known, several of the substances mentioned were classified as modulins. Due to the cytokine pattern, which corresponds more closely to Th1, an immune deviation is seen in this direction in most experimental models, away from Th2 characteristics. Conjugates are being developed as vaccines or are already being used without a priori knowledge.

A peculiarity first recognized in 2006 is the expression of TLR-2 on Tregs (a type of T cell), which experience both TCR-controlled proliferation and functional inactivation. This leads to disinhibition of the early inflammation phase and of specific antibody formation. Following a reduction in pathogen count, many pathogen-specific Tregs are present that, now without a TLR-2 signal, become active and inhibit the specific and inflammatory immune reactions (see also TNF-β, IL-10). Older literature that ascribes a direct immunity-stimulating effect via TLR-2 to a given molecule must be interpreted in light of the fact that the TLR-2 knockouts employed typically have very few Tregs.

Functionally relevant polymorphisms are reported that cause functional impairment and thus generally reduced survival rates, particularly in infections/sepsis with Gram-positive bacteria.

Signal transduction is depicted under Toll-like receptor.

Agonists

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Microbiological

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Endogenous

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  • HSP60, as a peptide transporter and adjuvant for antigen presentation
  • gp96, as a peptide transporter and adjuvant for antigen presentation
  • HMGB1, originally a DNA-associated protein, now important as a mediator in sepsis

Pharmacological

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As vaccine

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  • For this purpose a molecule that _targets TLR-2 is typically used with an antigenic molecule for B cells or cytotoxic T cells plus a peptide to be presented to helper T cells.
  • Pam2Cys
  • Troybody
  • OMPC components of Haemophilus influenzae glycoconjugate vaccines
  • Model of nephrotoxic serum nephritis (good pathological immunization against renal tissue is achieved here, but no contribution to the triggered tissue reaction in the kidney can be inferred from this)
  • The fact that the human and murine promoters are completely different has significant implications for the regulation of gene expression.

Positive gene expression

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Negative gene expression

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Pathology

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  • Ischemia-reperfusion injury of the kidney: heightened inflammatory reaction
  • Meningitis: heightened inflammatory reaction
  • Pneumonia: altered survival rate
  • Sepsis (overexpression on monocytes, ICU patients): altered survival rate
  • Acne (on lesional macrophages and on keratinocytes)
  • COPD (less TLR-2 on alveolar macrophages, more on blood monocytes)
  • Allergic rhinitis (induced by allergen exposure)
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