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Complement regulator CD46: genetic variants and disease associations.

Liszewski MK, Atkinson JP - Hum. Genomics (2015)

Bottom Line: More than 60 disease-associated mutations in MCP have now been identified.The majority of the mutations are linked to a rare thrombotic microangiopathic-based disease, atypical hemolytic uremic syndrome (aHUS), but new putative links to systemic lupus erythematosus, glomerulonephritis, and pregnancy-related disorders among others have also been identified.This review summarizes our current knowledge of disease-associated mutations in this complement inhibitor.

View Article: PubMed Central - PubMed

Affiliation: Division of Rheumatology, Department of Medicine, Washington University School of Medicine, 660 South Euclid, Saint Louis, MO, 63110, USA. kliszews@dom.wustl.edu.

ABSTRACT
Membrane cofactor protein (MCP; CD46) is an ubiquitously expressed complement regulatory protein that protects host cells from injury by complement. This type-I membrane glycoprotein serves as a cofactor for the serine protease factor I to mediate inactivation of C3b and C4b deposited on host cells. More than 60 disease-associated mutations in MCP have now been identified. The majority of the mutations are linked to a rare thrombotic microangiopathic-based disease, atypical hemolytic uremic syndrome (aHUS), but new putative links to systemic lupus erythematosus, glomerulonephritis, and pregnancy-related disorders among others have also been identified. This review summarizes our current knowledge of disease-associated mutations in this complement inhibitor.

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Complement function. The two primary functions of the complement system are to modify pathogens and self-debris with clusters of complement fragments (opsonization). This, in turn, facilitates interaction with complement receptors and, in some bacteria and viruses, induces lysis. The second function is to promote the inflammatory response. Complement fragments C3a and C5a generated during activation of the cascades stimulate many cell types. In the case of mast cells, release of immunomodulatory granules also attracts phagocytic cells into the area of inflammation (chemotaxis)
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Fig1: Complement function. The two primary functions of the complement system are to modify pathogens and self-debris with clusters of complement fragments (opsonization). This, in turn, facilitates interaction with complement receptors and, in some bacteria and viruses, induces lysis. The second function is to promote the inflammatory response. Complement fragments C3a and C5a generated during activation of the cascades stimulate many cell types. In the case of mast cells, release of immunomodulatory granules also attracts phagocytic cells into the area of inflammation (chemotaxis)

Mentions: The vertebrate-complement system consists of a set of sequentially interacting proteins featuring three major pathways that provide a swift and powerful host-defense system. It promotes the inflammatory response and mediates the identification and destruction of pathogens. This is accomplished in two major ways (Fig. 1). First, complement modifies the membranes of microbes. Activated fragments are covalently deposited in large amounts on microorganisms, immune complexes, and damaged tissue. For example, several million C3-derived activation fragments can attach in clusters to a bacterial surface in less than five minutes. The most important function of these covalently deposited complement proteins is to opsonize the target, thus serving as ligands for complement receptors on peripheral blood cells; specifically, erythrocytes, neutrophils, B lymphocytes and monocytes, as well as dendritic cells, and tissue monocytes. The receptors serve to bind (immune adherence), internalize (in some cases), transport, and clear the microbe. Additionally, the membranes of some pathogens (especially gram-negative bacteria) can be disrupted by the terminal-complement components (membrane-attack complex, MAC) leading to osmotic lysis.Fig 1


Complement regulator CD46: genetic variants and disease associations.

Liszewski MK, Atkinson JP - Hum. Genomics (2015)

Complement function. The two primary functions of the complement system are to modify pathogens and self-debris with clusters of complement fragments (opsonization). This, in turn, facilitates interaction with complement receptors and, in some bacteria and viruses, induces lysis. The second function is to promote the inflammatory response. Complement fragments C3a and C5a generated during activation of the cascades stimulate many cell types. In the case of mast cells, release of immunomodulatory granules also attracts phagocytic cells into the area of inflammation (chemotaxis)
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4469999&req=5

Fig1: Complement function. The two primary functions of the complement system are to modify pathogens and self-debris with clusters of complement fragments (opsonization). This, in turn, facilitates interaction with complement receptors and, in some bacteria and viruses, induces lysis. The second function is to promote the inflammatory response. Complement fragments C3a and C5a generated during activation of the cascades stimulate many cell types. In the case of mast cells, release of immunomodulatory granules also attracts phagocytic cells into the area of inflammation (chemotaxis)
Mentions: The vertebrate-complement system consists of a set of sequentially interacting proteins featuring three major pathways that provide a swift and powerful host-defense system. It promotes the inflammatory response and mediates the identification and destruction of pathogens. This is accomplished in two major ways (Fig. 1). First, complement modifies the membranes of microbes. Activated fragments are covalently deposited in large amounts on microorganisms, immune complexes, and damaged tissue. For example, several million C3-derived activation fragments can attach in clusters to a bacterial surface in less than five minutes. The most important function of these covalently deposited complement proteins is to opsonize the target, thus serving as ligands for complement receptors on peripheral blood cells; specifically, erythrocytes, neutrophils, B lymphocytes and monocytes, as well as dendritic cells, and tissue monocytes. The receptors serve to bind (immune adherence), internalize (in some cases), transport, and clear the microbe. Additionally, the membranes of some pathogens (especially gram-negative bacteria) can be disrupted by the terminal-complement components (membrane-attack complex, MAC) leading to osmotic lysis.Fig 1

Bottom Line: More than 60 disease-associated mutations in MCP have now been identified.The majority of the mutations are linked to a rare thrombotic microangiopathic-based disease, atypical hemolytic uremic syndrome (aHUS), but new putative links to systemic lupus erythematosus, glomerulonephritis, and pregnancy-related disorders among others have also been identified.This review summarizes our current knowledge of disease-associated mutations in this complement inhibitor.

View Article: PubMed Central - PubMed

Affiliation: Division of Rheumatology, Department of Medicine, Washington University School of Medicine, 660 South Euclid, Saint Louis, MO, 63110, USA. kliszews@dom.wustl.edu.

ABSTRACT
Membrane cofactor protein (MCP; CD46) is an ubiquitously expressed complement regulatory protein that protects host cells from injury by complement. This type-I membrane glycoprotein serves as a cofactor for the serine protease factor I to mediate inactivation of C3b and C4b deposited on host cells. More than 60 disease-associated mutations in MCP have now been identified. The majority of the mutations are linked to a rare thrombotic microangiopathic-based disease, atypical hemolytic uremic syndrome (aHUS), but new putative links to systemic lupus erythematosus, glomerulonephritis, and pregnancy-related disorders among others have also been identified. This review summarizes our current knowledge of disease-associated mutations in this complement inhibitor.

Show MeSH
Related in: MedlinePlus