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Parietal and intravascular innate mechanisms of vascular inflammation.

Ramirez GA, Rovere-Querini P, Sabbadini MG, Manfredi AA - Arthritis Res. Ther. (2015)

Bottom Line: Here we discuss some recent advances in the effector and regulatory action of neutrophils and in the outcome of their interaction with circulating platelets.In parallel, we discuss novel insights into the role of humoral innate immunity in vascular inflammation.All these topics are discussed in light of potential clinical and therapeutic implications in the near future.

View Article: PubMed Central - PubMed

Affiliation: IRCCS Ospedale San Raffaele, via Olgettina 60, 20132, Milan, Italy. ramirez.giuseppealvise@hsr.it.

ABSTRACT
Sustained inflammation of the vessel walls occurs in a large number of systemic diseases (ranging from atherosclerosis to systemic vasculitides, thrombotic microangiopathies and connective tissue diseases), which are ultimately characterized by ischemia and end-organ failure. Cellular and humoral innate immunity contribute to a common pathogenic background and comprise several potential targets for therapeutic intervention. Here we discuss some recent advances in the effector and regulatory action of neutrophils and in the outcome of their interaction with circulating platelets. In parallel, we discuss novel insights into the role of humoral innate immunity in vascular inflammation. All these topics are discussed in light of potential clinical and therapeutic implications in the near future.

No MeSH data available.


Related in: MedlinePlus

The complement system. Effectors: Irrespective of the activation pathway, three families of molecules are generated during the complement cascade: complement opsonins (C3b and C4b), complement anaphylotoxins (C3a and C5a) and the terminal complement complex (TCC). The key common step in the progression of the complement cascade is the generation of a C3-convertase, which cleaves inactive C3 into C3a and C3b. The latter binds to the C3-convertase to generate a C5-convertase, which generates C5a and C5b from inactive C5. C5b interacts with factors 6 to 9 to establish the TCC, which induces cell lysis by acting as a membrane attack complex or accumulates in the fluid phase or in extravascular spaces as an inactive moiety (iTCC). It can also bind to cell membranes as a sublytic membrane attack complex. Activators: Both in the classical and the lectin pathway, cleaving enzymes (namely component C1r and C1s of the C1 factor in the classical pathway and mannose binding lectin (MBL)-associated serine proteases in the MBL pathway) are destabilized and activated by antigen–antibody interactions (either directly in the case of MBL or with the intermediation of component C1q in the classical pathway) to process C4 to C4a, C4b and C2a, C2b respectively. The C4bC2a complex corresponds to the first variant of C3-convertase. Moieties expressed on the bacterial surface determine in the alternative pathway the spontaneous generation of the C3bBb complex, which acts as the second solid phase variant of C3-convertase. This atypical form of C3-convertase develops when partial spontaneous activation of C3 (tickover) is accompanied by binding of C3 with factor B, which in turn is cleaved to factor Ba and Bb by factor D to generate the C3(H2O)Bb complex or fluid-phase C3-convertase.
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Fig4: The complement system. Effectors: Irrespective of the activation pathway, three families of molecules are generated during the complement cascade: complement opsonins (C3b and C4b), complement anaphylotoxins (C3a and C5a) and the terminal complement complex (TCC). The key common step in the progression of the complement cascade is the generation of a C3-convertase, which cleaves inactive C3 into C3a and C3b. The latter binds to the C3-convertase to generate a C5-convertase, which generates C5a and C5b from inactive C5. C5b interacts with factors 6 to 9 to establish the TCC, which induces cell lysis by acting as a membrane attack complex or accumulates in the fluid phase or in extravascular spaces as an inactive moiety (iTCC). It can also bind to cell membranes as a sublytic membrane attack complex. Activators: Both in the classical and the lectin pathway, cleaving enzymes (namely component C1r and C1s of the C1 factor in the classical pathway and mannose binding lectin (MBL)-associated serine proteases in the MBL pathway) are destabilized and activated by antigen–antibody interactions (either directly in the case of MBL or with the intermediation of component C1q in the classical pathway) to process C4 to C4a, C4b and C2a, C2b respectively. The C4bC2a complex corresponds to the first variant of C3-convertase. Moieties expressed on the bacterial surface determine in the alternative pathway the spontaneous generation of the C3bBb complex, which acts as the second solid phase variant of C3-convertase. This atypical form of C3-convertase develops when partial spontaneous activation of C3 (tickover) is accompanied by binding of C3 with factor B, which in turn is cleaved to factor Ba and Bb by factor D to generate the C3(H2O)Bb complex or fluid-phase C3-convertase.

Mentions: The complement system comprises an arsenal of plasma proteins sequentially activated by diverse stimuli to converge towards the generation of opsonins, anaphylotoxins and a terminal complement complex with prominent cytolytic functions [45] (Figure 4). Activation of the complement system, of the endothelium and of neutrophils and platelets is intermingled in vivo [45]. Recognition of complement metabolites (such as the anaphylotoxins C3a and C5a or of noncytolytic forms of terminal complement complex) by the endothelial layer enforces a feed-forward loop, with enhanced surface expression of adhesion molecules, tissue factor and vWF [45], which in turn favors the activation of blood neutrophils and platelets. The generation of anaphylotoxins directly impacts on neutrophil activation, while platelet activation facilitates the further activation of the complement cascade, which in turn amplifies thrombin-dependent platelet aggregation. Humoral immunity triggers complement activation and genetically determined or acquired immune defects influence the risk of developing vascular inflammation (Table 2) [45,46]. On the other hand, surface molecules (for example, CD46, CD55, CD59) and soluble molecules (for example, factor H, factor I, vitronectin, clusterin) that quench the complement activation play a crucial role in the protection of vessels and of the perivascular tissues [45].Figure 4


Parietal and intravascular innate mechanisms of vascular inflammation.

Ramirez GA, Rovere-Querini P, Sabbadini MG, Manfredi AA - Arthritis Res. Ther. (2015)

The complement system. Effectors: Irrespective of the activation pathway, three families of molecules are generated during the complement cascade: complement opsonins (C3b and C4b), complement anaphylotoxins (C3a and C5a) and the terminal complement complex (TCC). The key common step in the progression of the complement cascade is the generation of a C3-convertase, which cleaves inactive C3 into C3a and C3b. The latter binds to the C3-convertase to generate a C5-convertase, which generates C5a and C5b from inactive C5. C5b interacts with factors 6 to 9 to establish the TCC, which induces cell lysis by acting as a membrane attack complex or accumulates in the fluid phase or in extravascular spaces as an inactive moiety (iTCC). It can also bind to cell membranes as a sublytic membrane attack complex. Activators: Both in the classical and the lectin pathway, cleaving enzymes (namely component C1r and C1s of the C1 factor in the classical pathway and mannose binding lectin (MBL)-associated serine proteases in the MBL pathway) are destabilized and activated by antigen–antibody interactions (either directly in the case of MBL or with the intermediation of component C1q in the classical pathway) to process C4 to C4a, C4b and C2a, C2b respectively. The C4bC2a complex corresponds to the first variant of C3-convertase. Moieties expressed on the bacterial surface determine in the alternative pathway the spontaneous generation of the C3bBb complex, which acts as the second solid phase variant of C3-convertase. This atypical form of C3-convertase develops when partial spontaneous activation of C3 (tickover) is accompanied by binding of C3 with factor B, which in turn is cleaved to factor Ba and Bb by factor D to generate the C3(H2O)Bb complex or fluid-phase C3-convertase.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4308901&req=5

Fig4: The complement system. Effectors: Irrespective of the activation pathway, three families of molecules are generated during the complement cascade: complement opsonins (C3b and C4b), complement anaphylotoxins (C3a and C5a) and the terminal complement complex (TCC). The key common step in the progression of the complement cascade is the generation of a C3-convertase, which cleaves inactive C3 into C3a and C3b. The latter binds to the C3-convertase to generate a C5-convertase, which generates C5a and C5b from inactive C5. C5b interacts with factors 6 to 9 to establish the TCC, which induces cell lysis by acting as a membrane attack complex or accumulates in the fluid phase or in extravascular spaces as an inactive moiety (iTCC). It can also bind to cell membranes as a sublytic membrane attack complex. Activators: Both in the classical and the lectin pathway, cleaving enzymes (namely component C1r and C1s of the C1 factor in the classical pathway and mannose binding lectin (MBL)-associated serine proteases in the MBL pathway) are destabilized and activated by antigen–antibody interactions (either directly in the case of MBL or with the intermediation of component C1q in the classical pathway) to process C4 to C4a, C4b and C2a, C2b respectively. The C4bC2a complex corresponds to the first variant of C3-convertase. Moieties expressed on the bacterial surface determine in the alternative pathway the spontaneous generation of the C3bBb complex, which acts as the second solid phase variant of C3-convertase. This atypical form of C3-convertase develops when partial spontaneous activation of C3 (tickover) is accompanied by binding of C3 with factor B, which in turn is cleaved to factor Ba and Bb by factor D to generate the C3(H2O)Bb complex or fluid-phase C3-convertase.
Mentions: The complement system comprises an arsenal of plasma proteins sequentially activated by diverse stimuli to converge towards the generation of opsonins, anaphylotoxins and a terminal complement complex with prominent cytolytic functions [45] (Figure 4). Activation of the complement system, of the endothelium and of neutrophils and platelets is intermingled in vivo [45]. Recognition of complement metabolites (such as the anaphylotoxins C3a and C5a or of noncytolytic forms of terminal complement complex) by the endothelial layer enforces a feed-forward loop, with enhanced surface expression of adhesion molecules, tissue factor and vWF [45], which in turn favors the activation of blood neutrophils and platelets. The generation of anaphylotoxins directly impacts on neutrophil activation, while platelet activation facilitates the further activation of the complement cascade, which in turn amplifies thrombin-dependent platelet aggregation. Humoral immunity triggers complement activation and genetically determined or acquired immune defects influence the risk of developing vascular inflammation (Table 2) [45,46]. On the other hand, surface molecules (for example, CD46, CD55, CD59) and soluble molecules (for example, factor H, factor I, vitronectin, clusterin) that quench the complement activation play a crucial role in the protection of vessels and of the perivascular tissues [45].Figure 4

Bottom Line: Here we discuss some recent advances in the effector and regulatory action of neutrophils and in the outcome of their interaction with circulating platelets.In parallel, we discuss novel insights into the role of humoral innate immunity in vascular inflammation.All these topics are discussed in light of potential clinical and therapeutic implications in the near future.

View Article: PubMed Central - PubMed

Affiliation: IRCCS Ospedale San Raffaele, via Olgettina 60, 20132, Milan, Italy. ramirez.giuseppealvise@hsr.it.

ABSTRACT
Sustained inflammation of the vessel walls occurs in a large number of systemic diseases (ranging from atherosclerosis to systemic vasculitides, thrombotic microangiopathies and connective tissue diseases), which are ultimately characterized by ischemia and end-organ failure. Cellular and humoral innate immunity contribute to a common pathogenic background and comprise several potential targets for therapeutic intervention. Here we discuss some recent advances in the effector and regulatory action of neutrophils and in the outcome of their interaction with circulating platelets. In parallel, we discuss novel insights into the role of humoral innate immunity in vascular inflammation. All these topics are discussed in light of potential clinical and therapeutic implications in the near future.

No MeSH data available.


Related in: MedlinePlus