The Functional Polymorphism Ala258Ser in the Innate Receptor Gene Ficolin-2 in the Donor Predicts Improved Renal Transplant Outcome

被引：19

作者：

Eikmans, Michael ^{[1
]}

de Canck, Ilse ^{[2
]}

van der Pol, Pieter ^{[3
]}

Baan, Carla C. ^{[4
]}

Haasnoot, Geert W. ^{[1
]}

Mallat, Marko J. K. ^{[3
]}

Vergunst, Manon ^{[1
]}

de Meester, Els ^{[2
]}

Roodnat, Joke I. ^{[4
]}

Anholts, Jacqueline D. H. ^{[1
]}

van Thielen, Martine ^{[2
]}

Doxiadis, Ilias I. N. ^{[1
]}

de Fijter, Johan W. ^{[3
]}

van der Linden, Pieter J. E. ^{[1
]}

van Beelen, Els ^{[1
]}

van Kooten, Cees ^{[3
]}

Kal-van Gestel, Judith A. ^{[4
]}

Peeters, Annemiek M. A. ^{[4
]}

Weimar, Willem ^{[4
]}

Roelen, Dave L. ^{[1
]}

Rossau, Rudi ^{[2
]}

Claas, Frans H. J. ^{[1
]}

机构：

[1] Leiden Univ, Med Ctr, Dept Immunohematol & Blood Transfus, NL-2333 ZA Leiden, Netherlands

[2] Innogenetics, R&D Discovery, Ghent, Belgium

[3] Leiden Univ, Med Ctr, Dept Nephrol, NL-2333 ZA Leiden, Netherlands

[4] Erasmus Univ, Dept Internal Med, Med Ctr, Rotterdam, Netherlands

来源：

TRANSPLANTATION | 2012年 / 94卷 / 05期

关键词：

Kidney transplantation; Acute rejection; Graft outcome; Innate immunity; DNA polymorphism; Ficolin; Cell death; MANNOSE-BINDING LECTIN; TOLL-LIKE RECEPTORS; ISCHEMIA-REPERFUSION INJURY; ACUTE ALLOGRAFT-REJECTION; APOPTOTIC CELLS; KIDNEY-TRANSPLANTATION; NECROTIC CELLS; GRAFT-SURVIVAL; ORGAN-TRANSPLANTATION; COMPLEMENT ACTIVATION;

D O I：

10.1097/TP.0b013e31825c5967

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Background. Innate immunity plays a role in controlling adaptive immune responses. Methods. We investigated the clinical relevance of single nucleotide polymorphisms in 22 genes encoding innate, secreted, and signaling pattern recognition receptors in a total of 520 donor-recipient pairs of postmortem, human leukocyte antigen-DR-compatible kidney transplantations. Associations with rejection incidence were tested in an a priori randomized training set and validation set. Results. Polymorphisms in TLR-3 (rs3775296) in the recipients and in Ficolin-2 (rs7851696; Ala258Ser) and C1qR1 (rs7492) in the donors showed the strongest association with severe rejection. In multivariate analysis, presence of the Ficolin-2 Ala258Ser variant in the donor predicted lower incidence of severe rejection (odds ratio=0.3; 95% confidence interval, 0.1-0.9; P=0.024) and of graft loss (hazard ratio=0.5; 95% confidence interval, 0.2-1.0; P=0.046) independently of clinical risk factors. Ficolin-2 messenger RNA expression was detected in pretransplantation biopsies from 69 donor grafts. Serum and tissue Ficolin-2 levels were unaffected by genotype. Ficolin-2 protein, which bound to dying cells, was detected in donor kidneys in a passenger leukocyte-like pattern. Indeed, monocytes, monocyte-derived macrophages, and peripheral blood mononuclear cells expressed Ficolin-2. Donor grafts with the Ficolin-2 Ala258Ser variant contained significantly elevated expression of interleukin 6, having ascribed cytoprotective effects. It has been described that Ala258Ser leads to increased binding capacity of Ficolin-2 to N-acetylglucosamine. Conclusions. Presence of the Ficolin-2 Ala258Ser polymorphism in the donor independently predicts improved graft outcome. Based on mechanistic data, we propose that this functional polymorphism leads to more efficient handling of injured cells by phagocytozing cells, resulting in decreased intragraft exposure to danger signals and dampened alloimmune responses.

引用

页码：478 / 485

页数：8

共 56 条

[1] The multiple facets of toll-like receptors in transplantation biology [J].