5) and also the metal nickel (six).*authors for correspondence. Address correspondence and reprint requests to Dr. Tom Monie, Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge, CB2 1QW, United kingdom, and Prof. Clare Bryant, Department of Veterinary Medicine, University of Cambridge, 80 Madingley Road, Cambridge, CB3 0ES, United kingdom. [email protected] (T.M.) and [email protected] (C.B.).Herre et al.PageDer p 2 is usually a lipid binding protein that sensitizes ligand-induced signalling by means of TLR4 and TLR2 (three, four, 7). TLR4, in mixture with MD2 and CD14, recognizes bacterial lipopolysaccharides (LPS); and TLR2, within a heterodimer with either TLR1 or TLR6, recognizes di- and tri- acylated lipoproteins (8) and lipoteichoic acid (LTA). TLR5 recognises the bacterial protein flagellin (9, ten). Ligand recognition by TLRs then activates innate immune signalling pathways (11). Each MD2 and Der p 2 belong to a tiny family members of lipid binding proteins that have a ?sandwich or cup form fold (12). These proteins recognize lipid by intercalating their acyl chains in to the hydrophobic core in the ?sandwich. Therefore, one particular potential mechanism by which Der p 2 enhances TLR4 signalling will be to mimic MD2 by binding to TLR4. The Der p 2/TLR4 protein complex could then signal like MD2/TLR4 to activate innate immune signalling (four). In mouse models of allergic asthma the effects of Der p 2 are markedly lowered in TLR4 knockout mice and may be prevented in wild variety mice by administration of a TLR4 antagonist (7). House dust mite extracts carrying flagellin can induce TLR5-dependent allergic responses in mice, although the molecular mechanism by which this happens is unclear (5).Bis(4-chlorophenyl)amine site Nickel sensitization in humans results from direct, lipid independent activation of TLR4 by Ni2+.6-Chloro-5-methylpyridazin-3(2H)-one Chemscene Receptor activation is dependent on the presence of two histidine residues, H456 and H458, which co-ordinate the Ni2+ atom (or other metal ions including Co2+), promoting TLR4 dimerisation and subsequent receptor activation. Murine TLR4 lacks these histidines and consequently just isn’t activated by nickel (6, 13). A further clinically essential allergen would be the cat dander protein Fel d 1, which can be the commonest cause of extreme allergic responses to cats in man (14).PMID:23771862 In contrast to Der p 2 this allergen has an completely alpha-helical structure (15) and is thus unlikely to act as a mimetic of MD2. Fel d 1 can bind towards the mannose receptor, but immune signalling is just not initiated following engagement of this receptor (16). As a result the mechanism by which this protein initiates an allergic response remains unclear. In this paper we propose a mechanism by which Fel d 1 is recognized by the host to activate immune signalling. Fel d 1 enhances LPS and LTA, but not flagellin-induced TLR signalling. As opposed to Der p 2, the mechanism for Fel d 1 enhancement of LPS-induced TLR4/ MD2 activation does not involve the protein binding for the TLRs, but does need the presence of CD14. The dog dander protein Can f six (17), a structurally distinct allergen from Fel d 1 in addition to a member on the lipocalin household of allergens, also enhances LPS-induced activation of TLR4 signalling despite the fact that, unlike Fel d 1, this protein has some MD2 independent effects. We propose, consequently, that animal allergen proteins kind a novel class of immune modulator proteins (IMPs) that enhance TLR signalling and hence play a important function in initiating allergic responses. The mechanism for TLR enhancement of signalling requires formation of a.