Factor H dysfunction in patients with atypical hemolytic uremic syndrome contributes to complement deposition on platelets and their activation.
نویسندگان
چکیده
Atypical hemolytic uremic syndrome (aHUS) may be associated with mutations in the C-terminal of factor H (FH). FH binds to platelets via the C-terminal as previously shown using a construct consisting of short consensus repeats (SCRs) 15 to 20. A total of 4 FH mutations, in SCR15 (C870R) and SCR20 (V1168E, E1198K, and E1198Stop) in patients with aHUS, were studied regarding their ability to allow complement activation on platelet surfaces. Purified FH-E1198Stop mutant exhibited reduced binding to normal washed platelets compared with normal FH, detected by flow cytometry. Washed platelets taken from the 4 patients with aHUS during remission exhibited C3 and C9 deposition, as well as CD40-ligand (CD40L) expression indicating platelet activation. Combining patient serum/plasma with normal washed platelets led to C3 and C9 deposition, CD40L and CD62P expression, aggregate formation, and generation of tissue factor-expressing microparticles. Complement deposition and platelet activation were reduced when normal FH was preincubated with platelets and were minimal when using normal serum. The purified FH-E1198Stop mutant added to FH-deficient plasma (complemented with C3) allowed considerable C3 deposition on washed platelets, in comparison to normal FH. In summary, mutated FH enables complement activation on the surface of platelets and their activation, which may contribute to the development of thrombocytopenia in aHUS.
منابع مشابه
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Factor H dysfunction in patients with atypical hemolytic uremic syndrome contributes to complement deposition on platelets and their activation
1Department of Pediatrics, Clinical Sciences Lund, Lund University, Lund, Sweden; 2Department of Biological Infection, Hans Knoell Institute for Natural Products Research, Jena, Germany; 3Department of Internal Medicine, Regional Hospital, Halmstad, Sweden; 4Department of Pediatric Nephrology, University of Texas Health Science Center at San Antonio, TX; 5Division of Renal Medicine, Karolinska ...
متن کاملGenome-wide DNA methylation profiling predicts relapse in childhood B-cell acute lymphoblastic leukaemia
Chapin, J., Wekslezr, B., Magro, C. & Laurence, J. (2012) Eculizumab in the treatment of refractory idiopathic thrombotic thrombocytopenic purpura. British Journal of Haematology, 157, 772–774. Furlan, M., Robles, R., Galbusera, M., Remuzzi, G., Kyrle, P.A., Brenner, B., Krause, M., Scharrer, I., Aumann, V., Mittler, U., Solenthaler, M. & Lammle, B. (1998) von Willebrand factor-cleaving proteas...
متن کاملCritical role of the C-terminal domains of factor H in regulating complement activation at cell surfaces.
The plasma protein factor H primarily controls the activation of the alternative pathway of complement. The C-terminal of factor H is known to be involved in protection of host cells from complement attack. In the present study, we show that domains 19-20 alone are capable of discriminating between host-like and complement-activating cells. Furthermore, although factor H possesses three binding...
متن کاملHyperfunctional C3 convertase leads to complement deposition on endothelial cells and contributes to atypical hemolytic uremic syndrome.
Complement is a major innate immune defense against pathogens, tightly regulated to prevent host tissue damage. Atypical hemolytic uremic syndrome (aHUS) is characterized by endothelial damage leading to renal failure and is highly associated with abnormal alternative pathway regulation. We characterized the functional consequences of 2 aHUS-associated mutations (D(254)G and K(325)N) in factor ...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
- Blood
دوره 111 11 شماره
صفحات -
تاریخ انتشار 2008