Mast cell infiltration of the choroid and protease release are early events in age-related macular degeneration associated with genetic risk at both chromosomes 1q32 and 10q26.
Mast cell infiltration of the choroid and protease release are early events in age-related macular degeneration associated with genetic risk at both chromosomes 1q32 and 10q26.
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DOI：
10.1073/pnas.2118510119
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发表时间：
2022-05-17
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
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全基因组关联研究已经确定了年龄相关性黄斑变性（AMD）的两个主要风险位点，位于染色体（Chr）1和Chr 10上。在这里，我们使用蛋白质组学来分析来自无AMD的老年眼供体的黄斑下基质组织穿孔，将来自Chr1或Chr10高风险等位基因纯合供体的组织与来自这两个位点低风险供体的组织进行比较。在Chr1/Chr10风险眼中发现的一个常见变化是肥大细胞蛋白酶增加，免疫组织化学证实了肥大细胞数量增加的存在。因此，本研究提供了Chr1和Chr10风险之间的统一机制联系，并表明脉络膜肥大细胞浸润和脱粒是AMD发病机制的早期事件。视网膜相关性黄斑变性（AMD）是视力丧失的主要原因。它有很强的遗传基础，染色体（Chr）1（CFH Y402 H变体）和Chr10（靠近HTRA1/ARMS 2）上的常见单倍型贡献了最大的风险。关于AMD的早期分子和细胞过程知之甚少，我们假设分析来自具有遗传风险但没有AMD临床特征的老年供体的黄斑下组织将提供生物学见解。因此，我们使用基于质谱的定量蛋白质组学来比较来自Chr1或Chr10的高风险等位基因纯合的供体与来自在这些位点具有保护性单倍型的供体的人黄斑下基质组织穿孔中的蛋白质，所有这些都没有AMD的临床特征。另外，还对来自高危Chr1等位基因纯合子和早期AMD供体的组织进行了比较。与低风险组相比，Chr1和Chr10风险组有共同的变化，特别是肥大细胞特异性蛋白酶水平升高，包括类胰蛋白酶、糜蛋白酶和羧肽酶A3。对来自具有AMD遗传风险但无AMD临床特征的供体以及来自具有Chr1风险和AMD的供体的黄斑下组织的组织学分析表明，与来自低遗传风险供体的组织相比，肥大细胞增加，特别是类胰蛋白酶阳性/糜蛋白酶阴性细胞种类增加，沿着变性胶原蛋白水平增加。我们的结论是，增加肥大细胞浸润的脉络膜内层，脱颗粒，和随后的细胞外基质重塑是AMD发病机制的早期事件，代表了一个统一的机制之间的联系Chr1和Chr10介导的AMD。
Genome-wide association studies have identified two major risk loci for age-related macular degeneration (AMD) on chromosome (Chr) 1 and Chr10. Here, we use proteomics to analyze submacular stromal tissue punches from older eye donors without AMD, comparing tissue from donors who were homozygous for high-risk alleles at Chr1 or Chr10 with tissue from donors with low risk at these two loci. A common change found in Chr1/Chr10–risk eyes was increased mast cell proteases, and immunohistochemistry confirmed the presence of increased mast cell numbers. This study, therefore, provides a unifying mechanistic link between Chr1 and Chr10 risk and suggests that mast cell infiltration of the choroid and degranulation are early events in AMD pathogenesis. Age-related macular degeneration (AMD) is a leading cause of visual loss. It has a strong genetic basis, and common haplotypes on chromosome (Chr) 1 (CFH Y402H variant) and on Chr10 (near HTRA1/ARMS2) contribute the most risk. Little is known about the early molecular and cellular processes in AMD, and we hypothesized that analyzing submacular tissue from older donors with genetic risk but without clinical features of AMD would provide biological insights. Therefore, we used mass spectrometry–based quantitative proteomics to compare the proteins in human submacular stromal tissue punches from donors who were homozygous for high-risk alleles at either Chr1 or Chr10 with those from donors who had protective haplotypes at these loci, all without clinical features of AMD. Additional comparisons were made with tissue from donors who were homozygous for high-risk Chr1 alleles and had early AMD. The Chr1 and Chr10 risk groups shared common changes compared with the low-risk group, particularly increased levels of mast cell–specific proteases, including tryptase, chymase, and carboxypeptidase A3. Histological analyses of submacular tissue from donors with genetic risk of AMD but without clinical features of AMD and from donors with Chr1 risk and AMD demonstrated increased mast cells, particularly the tryptase-positive/chymase-negative cells variety, along with increased levels of denatured collagen compared with tissue from low–genetic risk donors. We conclude that increased mast cell infiltration of the inner choroid, degranulation, and subsequent extracellular matrix remodeling are early events in AMD pathogenesis and represent a unifying mechanistic link between Chr1- and Chr10-mediated AMD.
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影响因子：
6
作者：
Bousquet, Elodie;Zhao, Min;de Kozak, Yvonne
通讯作者：
de Kozak, Yvonne
DOI：
10.4049/jimmunol.1401613
发表时间：
2014-11-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Clark SJ;Schmidt CQ;White AM;Hakobyan S;Morgan BP;Bishop PN
通讯作者：
Bishop PN
影响因子：
30.8
作者：
Fritsche, Lars G.;Chen, Wei;Schu, Matthew;Yaspan, Brian L.;Yu, Yi;Thorleifsson, Gudmar;Zack, Donald J.;Arakawa, Satoshi;Cipriani, Valentina;Ripke, Stephan;Igo, Robert P., Jr.;Buitendijk, Gabrielle H. S.;Sim, Xueling;Weeks, Daniel E.;Guymer, Robyn H.;Merriam, Joanna E.;Francis, Peter J.;Hannum, Gregory;Agarwal, Anita;Armbrecht, Ana Maria;Audo, Isabelle;Aung, Tin;Barile, Gaetano R.;Benchaboune, Mustapha;Bird, Alan C.;Bishop, Paul N.;Branham, Kari E.;Brooks, Matthew;Brucker, Alexander J.;Cade, William H.;Cain, Melinda S.;Campochiaroll, Peter A.;Chan, Chi-Chao;Cheng, Ching-Yu;Chew, Emily Y.;Chin, Kimberly A.;Chowers, Itay;Clayton, David G.;Cojocaru, Radu;Conley, Yvette P.;Cornes, Belinda K.;Daly, Mark J.;Dhillon, Baljean;Edwards, Albert;Evangelou, Evangelos;Fagemess, Jesen;Ferreyra, Henry A.;Friedman, James S.;Geirsdottir, Asbjorg;George, Ronnie J.;Gieger, Christian;Gupta, Neel;Hagstrom, Stephanie A.;Harding, Simon P.;Haritoglou, Christos;Heckenlively, John R.;Hoz, Frank G.;Hughes, Guy;Ioannidis, John P. A.;Ishibashi, Tatsuro;Joseph, Peronne;Jun, Gyungah;Kamatani, Yoichiro;Katsanis, Nicholas;Keilhauer, Claudia N.;Khan, Jane C.;Kim, Ivana K.;Kiyohara, Yutaka;Klein, Barbara E. K.;Klein, Ronald;Kovach, Jaclyn L.;Kozak, Igor;Lee, Clara J.;Lee, Kristine E.;Lichtner, Peter;Lotery, Andrew J.;Meitinger, Thomas;Mitchell, Paul;Mohand-Saied, Saddek;Moore, Anthony T.;Morgan, Denise J.;Morrison, Margaux A.;Myers, Chelsea E.;Naj, Adam C.;Nakamura, Yusuke;Okada, Yukinori;Orlin, Anton;Ortube, M. Carolina;Othman, Mohammad I.;Pappas, Chris;Park, Kyu Hyung;Pauer, Gayle J. T.;Peachey, Neal S.;Poch, Olivier;Priya, Rinki Ratna;Reynolds, Robyn;Richardson, Andrea J.;Ripp, Raymond;Rudolph, Guenther;Ryu, Euijung;Sahel, Jose-Alain;Schaumberg, Debra A.;Scholl, Hendrik P. N.;Schwartz, Stephen G.;Scott, William K.;Shahid, Humma;Sigurdsson, Haraldur;Silvestri, Giuliana;Sivakumaran, Theru A.;Smith, R. Theodore;Sobrin, Lucia;Souied, Eric H.;Stambolian, Dwight E.;Stefansson, Hreinn;Sturgill-Short, Gwen M.;Takahashi, Atsushi;Tosakulwong, Nirubol;Truitt, Barbara J.;Tsironi, Evangelia E.;Uitterlinden, Andre G.;van Duijn, Cornelia M.;Vijaya, Lingam;Vingerling, Johannes R.;Vithana, Eranga N.;Webster, Andrew R.;Wichmann, H-Erich;Winkler, Thomas W.;Wong, Tien Y.;Wright, Alan F.;Zelenika, Diana;Zhang, Ming;Zhao, Ling;Zhang, Kang;Klein, Michael L.;Hageman, Gregory S.;Lathrop, G. Mark;Stefansson, Kari;Allikmets, Rando;Baird, Paul N.;Gorin, Michael B.;Wang, Jie Jin;Klaver, Caroline C. W.;Seddon, Johanna M.;Pericak-Vance, Margaret A.;Iyengar, Sudha K.;Yates, John R. W.;Swaroop, Anand;Weber, Bernhard H. F.;Kubo, Michiaki;DeAngelis, Margaret M.;Leveillard, Thierry;Thorsteinsdottir, Unnur;Haines, Jonathan L.;Farrer, Lindsay A.;Heid, Iris M.;Abecasis, Goncalo R.
通讯作者：
Abecasis, Goncalo R.
影响因子：
17.1
作者：
Hwang J;Huang Y;Burwell TJ;Peterson NC;Connor J;Weiss SJ;Yu SM;Li Y
通讯作者：
Li Y
影响因子：
4.4
作者：
Keenan, Tiarnan D. L.;Toso, Marc;Hageman, Gregory S.
通讯作者：
Hageman, Gregory S.