The Role of Complement in Age-Related Macular Degeneration: Heparan Sulphate, a ZIP Code for Complement Factor H?
Age-related macular degeneration (AMD) is the leading cause of blindness in developed nations and has been associated with complement dysregulation in the central retina. The Y402H polymorphism in the complement regulatory protein factor H (CFH) can confer a >5-fold increased risk of developing A...
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| Veröffentlicht in: | Journal of innate immunity 2014-01, Vol.6 (4), p.407-416 |
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| description | Age-related macular degeneration (AMD) is the leading cause of blindness in developed nations and has been associated with complement dysregulation in the central retina. The Y402H polymorphism in the complement regulatory protein factor H (CFH) can confer a >5-fold increased risk of developing AMD and is present in approximately 30% of people of European descent. CFH, in conjunction with other factors, regulates complement activation in host tissues, and the Y402H polymorphism has been found to alter the protein's specificity for heparan sulphate (HS) - a complex polysaccharide found ubiquitously in mammals. HS, which is present on the cell surface and also in the extracellular matrix, exhibits huge structural diversity due to variations in the level/pattern of sulphation, where particular structures may act as ‘ZIP codes' for different tissue/cellular locations. Recent work has demonstrated that CFH contains two HS-binding domains that each recognize specific HS ZIP codes, allowing differential recognition of Bruch's membrane (in the eye) or the glomerular basement membrane (in the kidney). Importantly, the Y402H polymorphism impairs the binding of CFH to the HS in Bruch's membrane, which could result in increased complement activation and chronic local inflammation (in 402H individuals) and thereby contribute to AMD pathology. |
| doi_str_mv | 10.1159/000356513 |
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The Y402H polymorphism in the complement regulatory protein factor H (CFH) can confer a >5-fold increased risk of developing AMD and is present in approximately 30% of people of European descent. CFH, in conjunction with other factors, regulates complement activation in host tissues, and the Y402H polymorphism has been found to alter the protein's specificity for heparan sulphate (HS) - a complex polysaccharide found ubiquitously in mammals. HS, which is present on the cell surface and also in the extracellular matrix, exhibits huge structural diversity due to variations in the level/pattern of sulphation, where particular structures may act as ‘ZIP codes' for different tissue/cellular locations. Recent work has demonstrated that CFH contains two HS-binding domains that each recognize specific HS ZIP codes, allowing differential recognition of Bruch's membrane (in the eye) or the glomerular basement membrane (in the kidney). Importantly, the Y402H polymorphism impairs the binding of CFH to the HS in Bruch's membrane, which could result in increased complement activation and chronic local inflammation (in 402H individuals) and thereby contribute to AMD pathology.</description><identifier>ISSN: 1662-811X</identifier><identifier>EISSN: 1662-8128</identifier><identifier>DOI: 10.1159/000356513</identifier><identifier>PMID: 24335201</identifier><language>eng</language><publisher>Basel, Switzerland: S. Karger AG</publisher><subject>Animals ; Bruch Membrane - metabolism ; Complement Activation - genetics ; Complement Factor H - genetics ; Complement Factor H - immunology ; Genetic Predisposition to Disease ; Heparitin Sulfate - metabolism ; Humans ; Macular Degeneration - immunology ; Polymorphism, Genetic ; Protein Binding - genetics ; Protein Interaction Domains and Motifs - genetics ; Retina - immunology ; Retina - pathology ; Review</subject><ispartof>Journal of innate immunity, 2014-01, Vol.6 (4), p.407-416</ispartof><rights>2013 S. Karger AG, Basel</rights><rights>2013 S. Karger AG, Basel.</rights><rights>Copyright (c) 2014 S. Karger AG, Basel</rights><rights>Copyright © 2013 by S. Karger AG, Basel 2013</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c485t-2776b242d7fcc7cf5cc9e4bf101506b2a439bd5b77614132f964bf800f6424a23</citedby><cites>FETCH-LOGICAL-c485t-2776b242d7fcc7cf5cc9e4bf101506b2a439bd5b77614132f964bf800f6424a23</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4086042/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4086042/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24335201$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Langford-Smith, Alex</creatorcontrib><creatorcontrib>Keenan, Tiarnan D.L.</creatorcontrib><creatorcontrib>Clark, Simon J.</creatorcontrib><creatorcontrib>Bishop, Paul N.</creatorcontrib><creatorcontrib>Day, Anthony J.</creatorcontrib><title>The Role of Complement in Age-Related Macular Degeneration: Heparan Sulphate, a ZIP Code for Complement Factor H?</title><title>Journal of innate immunity</title><addtitle>J Innate Immun</addtitle><description>Age-related macular degeneration (AMD) is the leading cause of blindness in developed nations and has been associated with complement dysregulation in the central retina. The Y402H polymorphism in the complement regulatory protein factor H (CFH) can confer a >5-fold increased risk of developing AMD and is present in approximately 30% of people of European descent. CFH, in conjunction with other factors, regulates complement activation in host tissues, and the Y402H polymorphism has been found to alter the protein's specificity for heparan sulphate (HS) - a complex polysaccharide found ubiquitously in mammals. HS, which is present on the cell surface and also in the extracellular matrix, exhibits huge structural diversity due to variations in the level/pattern of sulphation, where particular structures may act as ‘ZIP codes' for different tissue/cellular locations. Recent work has demonstrated that CFH contains two HS-binding domains that each recognize specific HS ZIP codes, allowing differential recognition of Bruch's membrane (in the eye) or the glomerular basement membrane (in the kidney). Importantly, the Y402H polymorphism impairs the binding of CFH to the HS in Bruch's membrane, which could result in increased complement activation and chronic local inflammation (in 402H individuals) and thereby contribute to AMD pathology.</description><subject>Animals</subject><subject>Bruch Membrane - metabolism</subject><subject>Complement Activation - genetics</subject><subject>Complement Factor H - genetics</subject><subject>Complement Factor H - immunology</subject><subject>Genetic Predisposition to Disease</subject><subject>Heparitin Sulfate - metabolism</subject><subject>Humans</subject><subject>Macular Degeneration - immunology</subject><subject>Polymorphism, Genetic</subject><subject>Protein Binding - genetics</subject><subject>Protein Interaction Domains and Motifs - genetics</subject><subject>Retina - immunology</subject><subject>Retina - pathology</subject><subject>Review</subject><issn>1662-811X</issn><issn>1662-8128</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>M--</sourceid><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNqN0c-L1DAUB_AiivtDD95FAntxwWp-t_GgLKPrjKw_WFcQLyFNX2a6mzbdtBX8780wa1nFg6eEvE--vORl2SOCnxMi1AuMMRNSEHYn2ydS0rwktLw778m3vexgGC4xlpyr4n62RzljgmKyn11fbACdBw8oOLQIbe-hhW5ETYdO1pCfgzcj1OiDsZM3Eb2BNXQQzdiE7iVaQm-i6dCXyfeb5J4hg76vPqecGpAL8XbgqbFjOlm-fpDdc8YP8PBmPcy-nr69WCzzs0_vVouTs9zyUow5LQpZUU7rwllbWCesVcArRzAROFUMZ6qqRZUY4YRRp2Sqlhg7ySk3lB1mr3a5_VS1UNvURDRe97FpTfypg2n0n5Wu2eh1-KE5LiXm24CnNwExXE8wjLptBgvemw7CNGgiBFdCMCr-gzLFpSKKJ3r0F70MU-zSTyTF06OklFt1vFM2hmGI4Oa-Cdbbmet55sk-uf3QWf4ecgKPd-DKxDXEGcz3j_5Zfr_6uBO6rx37BdU2uWs</recordid><startdate>20140101</startdate><enddate>20140101</enddate><creator>Langford-Smith, Alex</creator><creator>Keenan, Tiarnan D.L.</creator><creator>Clark, Simon J.</creator><creator>Bishop, Paul N.</creator><creator>Day, Anthony J.</creator><general>S. 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Keenan, Tiarnan D.L. ; Clark, Simon J. ; Bishop, Paul N. ; Day, Anthony J.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c485t-2776b242d7fcc7cf5cc9e4bf101506b2a439bd5b77614132f964bf800f6424a23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Animals</topic><topic>Bruch Membrane - metabolism</topic><topic>Complement Activation - genetics</topic><topic>Complement Factor H - genetics</topic><topic>Complement Factor H - immunology</topic><topic>Genetic Predisposition to Disease</topic><topic>Heparitin Sulfate - metabolism</topic><topic>Humans</topic><topic>Macular Degeneration - immunology</topic><topic>Polymorphism, Genetic</topic><topic>Protein Binding - genetics</topic><topic>Protein Interaction Domains and Motifs - genetics</topic><topic>Retina - immunology</topic><topic>Retina - pathology</topic><topic>Review</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Langford-Smith, Alex</creatorcontrib><creatorcontrib>Keenan, Tiarnan D.L.</creatorcontrib><creatorcontrib>Clark, Simon J.</creatorcontrib><creatorcontrib>Bishop, Paul N.</creatorcontrib><creatorcontrib>Day, Anthony J.</creatorcontrib><collection>Karger Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Nursing & Allied Health Database</collection><collection>Immunology Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of innate immunity</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Langford-Smith, Alex</au><au>Keenan, Tiarnan D.L.</au><au>Clark, Simon J.</au><au>Bishop, Paul N.</au><au>Day, Anthony J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The Role of Complement in Age-Related Macular Degeneration: Heparan Sulphate, a ZIP Code for Complement Factor H?</atitle><jtitle>Journal of innate immunity</jtitle><addtitle>J Innate Immun</addtitle><date>2014-01-01</date><risdate>2014</risdate><volume>6</volume><issue>4</issue><spage>407</spage><epage>416</epage><pages>407-416</pages><issn>1662-811X</issn><eissn>1662-8128</eissn><abstract>Age-related macular degeneration (AMD) is the leading cause of blindness in developed nations and has been associated with complement dysregulation in the central retina. The Y402H polymorphism in the complement regulatory protein factor H (CFH) can confer a >5-fold increased risk of developing AMD and is present in approximately 30% of people of European descent. CFH, in conjunction with other factors, regulates complement activation in host tissues, and the Y402H polymorphism has been found to alter the protein's specificity for heparan sulphate (HS) - a complex polysaccharide found ubiquitously in mammals. HS, which is present on the cell surface and also in the extracellular matrix, exhibits huge structural diversity due to variations in the level/pattern of sulphation, where particular structures may act as ‘ZIP codes' for different tissue/cellular locations. Recent work has demonstrated that CFH contains two HS-binding domains that each recognize specific HS ZIP codes, allowing differential recognition of Bruch's membrane (in the eye) or the glomerular basement membrane (in the kidney). Importantly, the Y402H polymorphism impairs the binding of CFH to the HS in Bruch's membrane, which could result in increased complement activation and chronic local inflammation (in 402H individuals) and thereby contribute to AMD pathology.</abstract><cop>Basel, Switzerland</cop><pub>S. Karger AG</pub><pmid>24335201</pmid><doi>10.1159/000356513</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central |
| subjects | Animals Bruch Membrane - metabolism Complement Activation - genetics Complement Factor H - genetics Complement Factor H - immunology Genetic Predisposition to Disease Heparitin Sulfate - metabolism Humans Macular Degeneration - immunology Polymorphism, Genetic Protein Binding - genetics Protein Interaction Domains and Motifs - genetics Retina - immunology Retina - pathology Review |
| title | The Role of Complement in Age-Related Macular Degeneration: Heparan Sulphate, a ZIP Code for Complement Factor H? |
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