Gain-of-Function Mutations R249C and S250C in Complement C2 Protein Increase C3 Deposition in the Presence of C-Reactive Protein

被引:11
作者
Urban, Aleksandra [1 ,2 ]
Kowalska, Daria [1 ,2 ]
Stasilojc, Grzegorz [1 ,2 ]
Kuzniewska, Alicja [1 ,2 ]
Skrobinska, Anna [1 ,2 ]
Arjona, Emilia [3 ,4 ]
Alonso, Eugenia Castellote [5 ]
Fenollosa Segarra, Maria Angeles [6 ]
Jongerius, Ilse [7 ,8 ,9 ]
Spaapen, Robbert [7 ,8 ]
Satchell, Simon [10 ]
Thiel, Marcel [2 ,11 ]
Oldziej, Stanislaw [2 ,11 ]
Rodriguez de Cordoba, Santiago [3 ,4 ]
Okroj, Marcin [1 ,2 ]
机构
[1] Univ Gdansk, Intercollegiate Fac Biotechnol, Dept Cell Biol & Immunol, Gdansk, Poland
[2] Med Univ Gdansk, Gdansk, Poland
[3] Ctr Invest Biol, Madrid, Spain
[4] Ctr Invest Biomed Enfermedades Raras, Madrid, Spain
[5] Consorci Hosp Vic, Serv Nefrol, Barcelona, Spain
[6] Hosp Gen Univ Castellon, Serv Nefrol, Castellon de La Plana, Spain
[7] Sanquin Res, Dept Immunopathol, Amsterdam, Netherlands
[8] Univ Amsterdam, Amsterdam Univ Med Ctr, Landsteiner Lab, Amsterdam, Netherlands
[9] Amsterdam Univ Med Ctr, Emma Childrens Hosp, Dept Pediat Immunol Rheumatol & Infect Dis, Amsterdam, Netherlands
[10] Univ Bristol, Bristol Med Sch, Bristol Renal, Bristol, Avon, England
[11] Univ Gdansk, Intercollegiate Fac Biotechnol, Lab Biopolymers Struct, Gdansk, Poland
关键词
complement system; aHUS; C3; glomerulopathy; complement C2; endothelial cells; ENDOTHELIAL-CELLS; FACTOR-B; GLOMERULOPATHY;
D O I
10.3389/fimmu.2021.724361
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
The impairment of the alternative complement pathway contributes to rare kidney diseases such as atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy (C3G). We recently described an aHUS patient carrying an exceptional gain-of-function (GoF) mutation (S250C) in the classical complement pathway component C2 leading to the formation of hyperactive classical convertases. We now report the identification of the same mutation and another C2 GoF mutation R249C in two other patients with a glomerulopathy of uncertain etiology. Both mutations stabilize the classical C3 convertases by a similar mechanism. The presence of R249C and S250C variants in serum increases complement-dependent cytotoxicity (CDC) in antibody-sensitized human cells and elevates deposition of C3 on ELISA plates coated with C-reactive protein (CRP), as well as on the surface of glomerular endothelial cells. Our data justify the inclusion of classical pathway genes in the genetic analysis of patients suspected of complement-driven renal disorders. Also, we point out CRP as a potential antibody-independent trigger capable of driving excessive complement activation in carriers of the GoF mutations in complement C2.
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页数:8
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