Indirect Recognition ofTargets Opsonic Receptors

In order to increase the efficiency of recognition and clearance of pathogens, the immune system utilizes more generic receptors that recognize humoral components called opsonins. Opsonin is derived from the Greek word meaning "prepare for eating," and it refers to a serum substance able to coat foreign agents, making them vulnerable to phagocytosis.

The most widely recognized opsonins are complement-derived proteins and antibodies. However other opsonins include the lipopolysaccharide-binding protein (LBP) and the collectins: mannose-binding lectin (MBL), C1q and lung surfactant protein A (SP-A). The most important complement opsonins are the particles iC3b and C3b, which are derived from the complement protein C3 [68]. The C3 protein has a fundamental role in the activation of the classical and alternative complement cascades and C3b is one of the fragments resulting from its cleavage. After cleavage, C3b suffers a conformational change that exposes a highly reactive thioester which covalently attaches the peptide to the pathogen by interaction with free surface hydroxyl or amino groups. C3b may be further cleaved to produce the iC3b peptide.

The complement receptors with phagocytic properties are CR1 and CR3. CR1 can react with pathogens coated predominantly with C3b and can also bind particles coated with MBL, C4b, iC3b and C1q, though with lower affinity [68]. CR3 is a b2 integrin composed of two subunits: CD11b or aM and CD18 or p2. CR3 binds mainly to iC3b but other ligands include fibronectin, factor X and ICAM-1 [68]. Complement receptors need an additional signal in order to elicit uptake. This second signal brings about the activation and clustering of the integrin molecules. Some of these signals are triggered by stimulation of the phagocyte by inflammatory cytokines, LPS, binding of the cell to extracellular matrix molecules such as fibronectin or laminin, or by the stimulation of protein kinase C by phorbol esters [69, 70].

Target particles can also be opsonized by antibodies. IgG is the best known opsonin, however IgA has also been shown to have opsonin activity [68]. The binding of antibodies neutralizes the pathogen and prepares them to be cleared by professional phagocytes. Fcg receptors (FcgR) recognize the Fc portion of the pathogen-bound IgG and by these means initiate ingestion. FcgRs can be divided into two classes according to whether they activate or inhibit the phagocytic response [2]. FcgRI (a high-affinity receptor) and FcgRIIA and FcgRIIIA (low-affinity receptors) are activating receptors that signal through the phosphorylation of ITAM (immu-noreceptor tyrosine-based activation motif) motifs that recruit kinases and activate phosphorylation cascades [6, 71]. By contrast, FcgRIIB contains an ITIM (immunor-eceptor tyrosine-based inhibitory motif) motif that engages phosphatases such as SHIP, and inhibits the phagocytosis signal [6]. The balance between activating and inhibitory FcgRs determines the phagocytic and inflammatory outcome.

The MBL is a circulating opsonin with a C-terminal lectin domain that associates as multimers oftrimers and binds to mannans [72, 73]. MBL is able to bind to a wide variety of organisms, including bacteria, yeasts, parasites and the glycoprotein envelope of viruses and apoptotic cells [74]. MBL-opsonized ligands can interact with the C1q receptor [72, 73], the complement receptor CR3 and collectin receptors [74].

Other opsonins include the SP-A, a C-type lectin that binds to carbohydrate structures on bacterial surfaces [72, 73], and pentraxins such as the C-reactive protein that binds to many bacterial surface ligands.

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