TLR 2

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TLR-2/translation of German TLR-2 page

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.

The TLR-2 under discussion is a member of a large family of homologous toll-like receptors (TLRs) and is described here as an example.

Introduction

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). These are then disabled by immune-system components (e.g. complement) bound to the antibodies and deposited in the vicinity and are phagocytized by scavenger cells (e.g. macrophages). Dendritic cells can phagocytize, too, but do not perform this for the purpose of direct pathogen elimination. Rather, they infiltrate the spleen and lymph nodes and present components of an antigen there, as the result of which specific antibodies are formed that recognize exactly that antigen.

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

What are called pattern-recognition receptors come into play here. This refers to receptors that recognize the gross, primarily structural features of molecules that do not occur in 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 the individual nonspecific immune cell.

The first example of such a foreign ligand is the 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 reaction. The intended effect is to mobilize the organism for "war", so to speak, and eliminate most of the pathogens.

Occurrence

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 .combined with TLR-1 or TLR-6. TLR-2 is also found in the epithelia of the air passages, the pulmonary alveoli, the renal tubules, and the Bowman's capsules of renal corpuscles. In the skin it is found on keratinocytes and sebaceous glands; spc1 in induced here, allowing a bactericidal sebum to be formed.

Mechanism

As a membrane surface receptor, TLR-2 recognizes many bacterial, fungal, viral, and certain endogenous molecules. In general, this results in the uptake (internalization, phagocytosis) of bound materials by endosomes/phagosomes and in cellular activation; thus such elements of innate immunity as macrophages, PMNs and dendritic cells assume functions of non-specific immune defense, B1a and MZ B cells form the first antibodies, and specific antibody formation eventually gets started. 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 T_h1, an immune deviation is seen in this direction in most experimental models, away from T_h2 characteristics. Conjugates are being developed as vaccines or are already being used without advance information.

A peculiarity first recognized in 2006 is the expression of TLR-2 on Tregs (a type of T cell), which are similarly brought to TCR-controlled proliferation and functional inactivity. This leads to disinhibition of the early inflammation phase andof 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 both the specific and the inflammatory immune reactions (see also TGF-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 that were used generally have very few Tregs.

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

Signal transduction is shown in the article on the Toll-like receptor.

Agonists

Microbiological

Lipoteichoic acid from Gram-positive bacteria
Peptidoglycan from Gram-negative and Gram-positive bacteria
Atypical LPS from Leptospira interrogans and Porphyromonas gigivitis
MALP-2 (e.g. Mycoplasma fermentans), a lipopeptide
MALP-404, a lipoprotein similar to MALP-2
Lipoprotein from Mycoplasma pneumoniae: F0F1 ATPase subunit b, Pam2C motif
Lipoproteins from Mycoplasma arthritidis
Chlamydia pneumoniae
OspA from Borrelia burgdorferi
Porin from Haemophilus influenzae
Antigen mixtures from Propionibacterium acnes and the like
LcrV from Yersinia
Lipomannan from Mycobacterium:Mycobacterium tuberculosis
GPI anchor from Trypanosoma cruzi
Lysophosphatidylserine from Schistosoma mansoni
Lipophosphoglycan from Leishmania major
Zymosan from Saccharomyces cerevisae
Malassezia furfur, a commensal yeast
Antigen mixtures from Aspergillus fumigatus, Candida albicans and the like
HSP60, as a peptide transporter and adjuvant for antigen presentation
Herpes simplex virus
Varicella zoster virus
Cytomegalovirus (CMV)
Measles virus hemagglutinin

Endogenous

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

MDP derivatives (originally peptidoglycan structural units of Gram-positive bacteria)
MALP-2 derivatives such as Pam3CSK4; see Pam3C
CGP 40774 (LP 40)
HSP60 derivatives such as DiaPep277
Bleomycin from Streptomyces verticillus
Amphotericin B from Streptomyces nodosus
Penicillin — releases cell-wall components indirectly (LytA autolysin)

As vaccine

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 cell]s.
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 concluded from this)
The fact that the human and murine promoters are completely different has significance for the regulation of gene expression.