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The Central Role of Anti-IL-1 Blockade in the Treatment of Monogenic and Multi-Factorial Autoinflammatory Diseases.

Federici S, Martini A, Gattorno M - Front Immunol (2013)

Bottom Line: The study of the pathophysiological consequence of mutations in the cryopyrin gene (NLRP3) allowed the identification of intracellular pathways responsible for the activation and secretion of the potent inflammatory cytokine interleukin-1β (IL-1β).The dramatic effect of interleukin-1 (IL-1) blockade in CAPS opened new perspectives for the treatment of other inherited and multi-factorial autoinflammatory disorders.Several IL-1 blockers are now available on the market.

View Article: PubMed Central - PubMed

Affiliation: 2nd Division of Pediatrics, G. Gaslini Institute , Genoa , Italy.

ABSTRACT
Inherited autoinflammatory diseases are secondary to mutations of proteins playing a pivotal role in the regulation of the innate immunity leading to seemingly unprovoked episodes of inflammation. The understanding of the molecular pathways involved in these disorders has shed new lights on the pattern of activation and maintenance of the inflammatory response and disclosed new molecular therapeutic targets. Cryopyrin-associated periodic syndrome (CAPS) represents the prototype of an autoinflammatory disease. The study of the pathophysiological consequence of mutations in the cryopyrin gene (NLRP3) allowed the identification of intracellular pathways responsible for the activation and secretion of the potent inflammatory cytokine interleukin-1β (IL-1β). It became clear that several multi-factorial inflammatory conditions display a number of pathogenic and clinical similarities with inherited autoinflammatory diseases. The dramatic effect of interleukin-1 (IL-1) blockade in CAPS opened new perspectives for the treatment of other inherited and multi-factorial autoinflammatory disorders. Several IL-1 blockers are now available on the market. In this review we outline the more recent novelties in the treatment with different IL-1 blockers in inherited and multi-factorial autoinflammatory diseases.

No MeSH data available.


Related in: MedlinePlus

Different strategies for IL-1 blockade. Free interleukin (IL)-1b binds to type 1 IL-1 receptor (IL-1R1) and to the adaptor protein IL-1RAcP leads to signal transduction (1). Human recombinant IL-1 receptor antagonist (hrIL-1Ra, Anakinra) (2) competes with free IL-1β for the binding with IL-1R1 but not with the adaptor protein, thus preventing signal transduction. Rilonacept (3) is a fusion protein comprising the extracellular domains of the IL-1β receptor (IL-1RI) and adaptor protein (IL-1RAcP) attached to a human IgG molecule. Its action is to bind to circulating IL-1β. The same mechanism of action is also valid for Canakinumab (4), a fully humanized anti-IL-1 monoclonal antibody.
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Figure 1: Different strategies for IL-1 blockade. Free interleukin (IL)-1b binds to type 1 IL-1 receptor (IL-1R1) and to the adaptor protein IL-1RAcP leads to signal transduction (1). Human recombinant IL-1 receptor antagonist (hrIL-1Ra, Anakinra) (2) competes with free IL-1β for the binding with IL-1R1 but not with the adaptor protein, thus preventing signal transduction. Rilonacept (3) is a fusion protein comprising the extracellular domains of the IL-1β receptor (IL-1RI) and adaptor protein (IL-1RAcP) attached to a human IgG molecule. Its action is to bind to circulating IL-1β. The same mechanism of action is also valid for Canakinumab (4), a fully humanized anti-IL-1 monoclonal antibody.

Mentions: There are two related but distinct IL-1 genes, IL1A and IL1B, encoding IL-1α and IL-1β, respectively. The IL-1α precursor is constitutively present, in an active form, in most of the cells of healthy individuals. Under disease conditions, IL-1α moves to the cell’s surface membrane where it can activate adjacent cells bearing the IL-1 receptor (6, 7). Conversely IL-1β is a product of a limited type of cells (e.g., blood monocytes, tissue macrophages, and dendritic cells). In physiological conditions IL-1β is in an inactive form and requires a series of intracellular events to be activated. In normal conditions both IL-1α and IL-1β bind to type 1 IL-1 receptor (IL-1R1) and to the adaptor protein IL-1RAcP in order to trigger signal transduction (Figure 1).


The Central Role of Anti-IL-1 Blockade in the Treatment of Monogenic and Multi-Factorial Autoinflammatory Diseases.

Federici S, Martini A, Gattorno M - Front Immunol (2013)

Different strategies for IL-1 blockade. Free interleukin (IL)-1b binds to type 1 IL-1 receptor (IL-1R1) and to the adaptor protein IL-1RAcP leads to signal transduction (1). Human recombinant IL-1 receptor antagonist (hrIL-1Ra, Anakinra) (2) competes with free IL-1β for the binding with IL-1R1 but not with the adaptor protein, thus preventing signal transduction. Rilonacept (3) is a fusion protein comprising the extracellular domains of the IL-1β receptor (IL-1RI) and adaptor protein (IL-1RAcP) attached to a human IgG molecule. Its action is to bind to circulating IL-1β. The same mechanism of action is also valid for Canakinumab (4), a fully humanized anti-IL-1 monoclonal antibody.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3814084&req=5

Figure 1: Different strategies for IL-1 blockade. Free interleukin (IL)-1b binds to type 1 IL-1 receptor (IL-1R1) and to the adaptor protein IL-1RAcP leads to signal transduction (1). Human recombinant IL-1 receptor antagonist (hrIL-1Ra, Anakinra) (2) competes with free IL-1β for the binding with IL-1R1 but not with the adaptor protein, thus preventing signal transduction. Rilonacept (3) is a fusion protein comprising the extracellular domains of the IL-1β receptor (IL-1RI) and adaptor protein (IL-1RAcP) attached to a human IgG molecule. Its action is to bind to circulating IL-1β. The same mechanism of action is also valid for Canakinumab (4), a fully humanized anti-IL-1 monoclonal antibody.
Mentions: There are two related but distinct IL-1 genes, IL1A and IL1B, encoding IL-1α and IL-1β, respectively. The IL-1α precursor is constitutively present, in an active form, in most of the cells of healthy individuals. Under disease conditions, IL-1α moves to the cell’s surface membrane where it can activate adjacent cells bearing the IL-1 receptor (6, 7). Conversely IL-1β is a product of a limited type of cells (e.g., blood monocytes, tissue macrophages, and dendritic cells). In physiological conditions IL-1β is in an inactive form and requires a series of intracellular events to be activated. In normal conditions both IL-1α and IL-1β bind to type 1 IL-1 receptor (IL-1R1) and to the adaptor protein IL-1RAcP in order to trigger signal transduction (Figure 1).

Bottom Line: The study of the pathophysiological consequence of mutations in the cryopyrin gene (NLRP3) allowed the identification of intracellular pathways responsible for the activation and secretion of the potent inflammatory cytokine interleukin-1β (IL-1β).The dramatic effect of interleukin-1 (IL-1) blockade in CAPS opened new perspectives for the treatment of other inherited and multi-factorial autoinflammatory disorders.Several IL-1 blockers are now available on the market.

View Article: PubMed Central - PubMed

Affiliation: 2nd Division of Pediatrics, G. Gaslini Institute , Genoa , Italy.

ABSTRACT
Inherited autoinflammatory diseases are secondary to mutations of proteins playing a pivotal role in the regulation of the innate immunity leading to seemingly unprovoked episodes of inflammation. The understanding of the molecular pathways involved in these disorders has shed new lights on the pattern of activation and maintenance of the inflammatory response and disclosed new molecular therapeutic targets. Cryopyrin-associated periodic syndrome (CAPS) represents the prototype of an autoinflammatory disease. The study of the pathophysiological consequence of mutations in the cryopyrin gene (NLRP3) allowed the identification of intracellular pathways responsible for the activation and secretion of the potent inflammatory cytokine interleukin-1β (IL-1β). It became clear that several multi-factorial inflammatory conditions display a number of pathogenic and clinical similarities with inherited autoinflammatory diseases. The dramatic effect of interleukin-1 (IL-1) blockade in CAPS opened new perspectives for the treatment of other inherited and multi-factorial autoinflammatory disorders. Several IL-1 blockers are now available on the market. In this review we outline the more recent novelties in the treatment with different IL-1 blockers in inherited and multi-factorial autoinflammatory diseases.

No MeSH data available.


Related in: MedlinePlus