Lipid presentation by the protein C receptor links coagulation with autoimmunity

被引：94

作者：

Mueller-Calleja, Nadine ^{[1
,2
,3
]}

Hollerbach, Anne ^{[1
,2
]}

Royce, Jennifer ^{[3
]}

Ritter, Svenja ^{[2
]}

Pedrosa, Denise ^{[1
]}

Madhusudhan, Thati ^{[1
]}

Teifel, Sina ^{[2
]}

Meineck, Myriam ^{[4
]}

Haeuser, Friederike ^{[2
]}

Canisius, Antje ^{[2
]}

Nguyen, T. Son ^{[1
]}

Braun, Johannes ^{[1
]}

Bruns, Kai ^{[2
]}

Etzold, Anna ^{[5
,6
]}

Zechner, Ulrich ^{[5
,6
]}

Strand, Susanne ^{[4
]}

Radsak, Markus ^{[7
]}

Strand, Dennis ^{[4
]}

Gu, Jian-Ming ^{[8
]}

Weinmann-Menke, Julia ^{[4
]}

Esmon, Charles T. ^{[8
]}

Teyton, Luc ^{[3
]}

Lackner, Karl J. ^{[2
]}

Ruf, Wolfram ^{[1
,3
]}

机构：

[1] Johannes Gutenberg Univ Mainz, Ctr Thrombosis & Hemostasis, Med Ctr, D-55131 Mainz, Germany

[2] Johannes Gutenberg Univ Mainz, Inst Clin Chem & Lab Med, Med Ctr, D-55131 Mainz, Germany

[3] Scripps Res, Dept Immunol & Microbiol, La Jolla, CA 92037 USA

[4] Johannes Gutenberg Univ Mainz, Med Ctr, Dept Med 1, D-55131 Mainz, Germany

[5] Johannes Gutenberg Univ Mainz, Inst Human Genet, Med Ctr, D-55131 Mainz, Germany

[6] Senckenberg Zentrum Humangenet, D-60314 Frankfurt, Germany

[7] Johannes Gutenberg Univ Mainz, Med Ctr, Dept Med 3, D-55131 Mainz, Germany

[8] Oklahoma Med Res Fdn, Oklahoma City, OK 73104 USA

来源：

SCIENCE | 2021年 / 371卷 / 6534期

基金：

美国国家卫生研究院;

关键词：

PRIMARY ANTIPHOSPHOLIPID SYNDROME; TISSUE FACTOR; NEUTROPHIL ACTIVATION; PLATELET ACTIVATION; ARTERIAL THROMBOSIS; B-CELLS; ANTIBODIES; PATHWAY; MICE; COMPLEMENT;

D O I：

10.1126/science.abc0956

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Antiphospholipid antibodies (aPLs) cause severe autoimmune disease characterized by vascular pathologies and pregnancy complications. Here, we identify endosomal lysobisphosphatidic acid (LBPA) presented by the CD1d-like endothelial protein C receptor (EPCR) as a pathogenic cell surface antigen recognized by aPLs for induction of thrombosis and endosomal inflammatory signaling. The engagement of aPLs with EPCR-LBPA expressed on innate immune cells sustains interferon- and toll-like receptor 7-dependent B1a cell expansion and autoantibody production. Specific pharmacological interruption of EPCR-LBPA signaling attenuates major aPL-elicited pathologies and the development of autoimmunity in a mouse model of systemic lupus erythematosus. Thus, aPLs recognize a single cell surface lipid-protein receptor complex to perpetuate a self-amplifying autoimmune signaling loop dependent on the cooperation with the innate immune complement and coagulation pathways.

引用

页码：1121 / +

页数：39

共 65 条

[1] Regulation of tissue factor-induced signaling by endogenous and recombinant tissue factor pathway inhibitor [J].