ライフサイエンスコーパス: properdin

1 of 10 Neisserial strains tested bound native properdin.

2 at high (80%) serum concentrations required properdin.

3 AP and led to the consumption of C3, fB, and properdin.

4 cifically using native versus unfractionated properdin.

5 we demonstrate that the target of Salp20 is properdin.

6 pathway C3 convertase, and all reacted with properdin.

7 d endothelial labeling for C3, factor B, and properdin.

8 nd C1q, whereas acLDL bound to C1q, IgM, and properdin.

9 ce; here, we show that these effects require properdin.

10 position on activated platelets with surface properdin.

11 lar HS, although to a different epitope than properdin.

12 pping epitopes on HS/heparin by factor H and properdin.

13 ituting properdin-depleted serum with native properdin a priori enhanced C3 deposition on all strains

14 Properdin, a plasma component that is also released by a

15 We demonstrate that physiological properdin, a positive regulator of complement alternativ

16 study, we examined the impact of the lack of properdin, a positive regulator of complement, in C. rod

17 Properdin, a positive regulator of the alternative pathw

18 Recently, properdin, a positive regulator of the alternative pathw

19 scular injury, are among the main sources of properdin, a positive regulator of the alternative pathw

20 a common global fold that is very similar to properdin, a protein with six TSRs.

21 ed increased production of the antibacterial properdin, a regulator of the complement activation, as

22 to the effects of the alternative pathway is properdin, a serum glycoprotein that can both initiate a

23 Displacement of properdin accelerated the decay of the C3 convertase, le

24 We also determine that blockade of properdin activity prevents aneurysm formation.

25 ytometry was used to further explore whether properdin acts as an initial recognition molecule reacti

26 Properdin also promotes a large displacement of the TED

27 iscrimination between the initial binding of properdin and binding secondary to C3b deposition is a c

28 with complement components C1q, C3, C5, and properdin and blocking antibody-dependent cellular cytot

29 C3bBb complexes, because blocking decay with properdin and C3 nephritic factor did not restore C3bBb

30 Coincubation of properdin and factor H did not hamper HS/heparin binding

31 t in the mesangial immunodeposits, including properdin and factor H in the alternative pathway and ma

32 rt consensus repeat domains of CFHR5 contact properdin and mediate dimer formation.

33 urther, they demonstrate a critical role for properdin and support its therapeutic targeting in renal

34 Finally, we describe the interplay between properdin and the alternative pathway negative regulator

35 ng for PLA2R, IgG4, C3, C5b-9, factor B, and properdin and very weak staining for C1q, C4d, and IgG1.

36 ssue-specific knockout of Cfp (which encodes properdin) and by generating BM chimeric mice.

37 ernative pathway components factor B, C3 and properdin, and C3a receptor and C5a receptor were detect

38 was described for TSRs of thrombospondin-1, properdin, and F-spondin within the sequence Cys-Xaa(1)-

39 a sequence motif shared with thrombospondin, properdin, and several complement proteins.

40 and C1q deposition, as well as C3, factor B, properdin, and terminal complement (C) components.

41 components of the complement pathway, or of properdin, are susceptible to meningococcal disease.

42 These data implicate systemic properdin as a key contributor to AP complement-mediated

43 We therefore challenge the view of properdin as a pattern recognition molecule, and argue t

44 C3bBb, is well accepted, whereas the role of properdin as pattern recognition molecule is controversi

45 ion conformations of multiple TSR domains in properdin at medium resolution.

46 data show that physiological forms of human properdin bind directly to human platelets after activat

47 obra C3; this finding suggests that gC-1 and properdin bind to different sites on C3b.

48 the physiological P, P, and P forms of human properdin bind to the surface of Chlamydia pneumoniae di

49 on of alternative pathway-mediated lysis and properdin binding to C3b, but not of C5 binding to C3b,

50 in low anticoagulant heparinoids can inhibit properdin binding to tubular HS, with a minor effect on

51 vious work, by inhibiting C3, we showed that properdin binding to zymosan and Escherichia coli is not

52 Properdin binding was facilitated by the glycosaminoglyc

53 din-/- mouse serum correlated with the human properdin-binding affinity of the LPS.

54 t readily bound E. coli LPS mutants, and the properdin-binding capacity of each strain correlated wit

55 These properdin-binding segments are duplicated in two mutant

56 t of properdin on C3bBb would be attained as properdin binds more than one ligand at a time, forming

57 knowledge, that the human complement protein properdin binds to early apoptotic T cells and initiates

58 I also found that properdin binds to preformed alternative pathway C3 conv

59 Recently, we showed that properdin binds to tubular heparan sulfates (HS).

60 Here, we review basic properdin biology, emphasizing the major hurdles that ha

61 Factor H (fH) and properdin both modulate complement; however, fH inhibits

62 In contrast to properdin, both gCs bound to cobra C3; this finding sugg

63 ted in properdin-depleted serum this form of properdin bound efficiently to both substrates in a stri

64 These findings support a model in which properdin, bound to a target surface via C3b, iC3b, or o

65 eage cells as the principal source of plasma properdin by generating mice with global and tissue-spec

66 SA, normal human serum-induced deposition of properdin by zymosan was abolished by the C3-inhibiting

67 Alternatively, properdin can be recruited by C3(H2O) on the platelet su

68 Once bound to a surface, properdin can direct convertase formation and target upt

69 In this report, we demonstrate that properdin can directly bind to microbial targets and pro

70 mplicated the interpretation of results from properdin-centered studies.

71 e, we studied mice deficient in both CFH and properdin (CFH(-/-).P(-/-)).

72 Unfractionated properdin contains aggregates or high-order oligomers, i

73 Properdin could be represented by seven TSR domains, not

74 ly with apoptotic T cells, they suggest that properdin could play a similar role during apoptosis of

75 xposes binding sites for factors B, H and I, properdin, decay accelerating factor (DAF, CD55), membra

76 count for the effect of mutations that cause properdin deficiencies, and suggest that the biologicall

77 Properdin deficiency rescued mice from AP complement-med

78 Properdin-deficient mice and wild-type littermates compa

79 ed by sublethal cecal ligation and puncture, properdin-deficient mice appear immunocompromised, becau

80 We have generated a fully backcrossed properdin-deficient mouse line by conventional gene-spec

81 Properdin-deficient patients are susceptible to lethal m

82 nderstanding the selective predisposition of properdin-deficient patients to meningococcal infection.

83 In vitro, properdin-deficient serum is impaired in alternative pat

84 measured by factor B binding, occurred in a properdin-dependent manner.

85 ition than when bacteria were incubated with properdin-depleted serum alone.

86 Finally, properdin-depleted serum could not control Chlamydia pne

87 native properdin followed by the addition of properdin-depleted serum did not cause detectable increa

88 ver, after addition of native properdin, the properdin-depleted serum recovered the ability to contro

89 nated properdin, followed by the addition of properdin-depleted serum resulted in higher C3 depositio

90 to zymosan or E. coli, but when incubated in properdin-depleted serum this form of properdin bound ef

91 However, reconstituting properdin-depleted serum with native properdin a priori

92 pstatin on these substrates, indicating that properdin deposition depended on initial C3b deposition

93 Properdin did not bind wild-type Escherichia coli, but i

94 Properdin-directed complement activation occurred on yea

95 The properdin-directed model is consistent with a proposal m

96 standard model and one that proceeds by the properdin-directed model.

97 In conclusion, the physiological forms of properdin do not bind directly to either N. meningitidis

98 We monitored properdin during AP activation and in complement-deficie

99 These outcomes position properdin early in the response to an infectious challen

100 Inhibition of endogenous properdin, either circulating in the blood or produced l

101 Cumulatively, our data indicate that properdin enhances PGA formation via increased productio

102 Properdin exists as either a dimer, trimer or tetramer.

103 Moreover, we found that properdin factor B, an alternative pathway complement ac

104 This review examines the new properdin findings and their implications.

105 isseriae, preincubating bacteria with native properdin followed by the addition of properdin-depleted

106 reincubation of bacteria with unfractionated properdin, followed by the addition of properdin-deplete

107 A rationale for such a means to supply properdin for immune reactions is proposed.

108 se gonococcal strains that bind C4BP require properdin for killing by 2C7, whereas strains that do no

109 All physiological properdin forms increase PGA formation, but properdin te

110 Properdin (FP) is an essential positive regulator of the

111 tors including C3, C4, factor B (fB), factor properdin (fP), mannose-binding lectin, C3aR, C5aR, or I

112 ent factor B protein that produces a stable, properdin-free AP C3 convertase, we show that properdin

113 Salp20 directly bound to and displaced properdin from the C3 convertase.

114 Previous reports suggest that properdin function depends on multiple interactions betw

115 ed production of C5a, and that inhibition of properdin function has therapeutic potential to limit th

116 The current understanding of properdin function is that it facilitates AP complement

117 osition on Neisseria decreased markedly when properdin function was blocked using an anti-properdin m

118 e have localized about 6.5kb upstream of the properdin gene on the X chromosome.

119 t properdin localizes to mast cells and that properdin has the ability to directly associate with E.

120 um have complicated studies of its function, properdin has, regardless, emerged as a key player in va

121 factor H interaction and clearly differ from properdin-heparinoid interaction.

122 Principles governing properdin homeostasis are unknown.

123 us C3 activation via AP tickover to maintain properdin homeostasis.

124 pended on initial C3b deposition followed by properdin in a second step.

125 We therefore studied the role of properdin in activation of complement in normal human se

126 We examined the role of properdin in AP activation on diverse strains of Neisser

127 These results reveal a novel role of properdin in AP complement initiation and have implicati

128 e role of AP recruitment and, in particular, properdin in assisting killing of gonococci by specific

129 Here, we demonstrate a critical role for properdin in autologous tissue injury mediated by AP com

130 The role of properdin in complement activation on stimulated platele

131 y, these data point to an important role for properdin in facilitating immune Ab-mediated complement-

132 In the present study, we found that properdin in human serum bound dose-dependently to solid

133 New studies are now focusing on a role for properdin in inflammatory and autoimmune diseases.

134 Markedly reduced properdin in mice deficient in an AP component and its p

135 in normal renal tissues and colocalized with properdin in proteinuric kidneys.

136 Collectively, these data indicate that properdin in serum as well as polymorphonuclear-released

137 rnover in the maintenance of basal levels of properdin in the blood.

138 There was a >90% reduction of properdin in the Crry single-knockout mice (Crry SKO).

139 lomerular basement membrane, but the role of properdin in the pathophysiology is unknown.

140 tic T cells, whereas the binding activity of properdin in the serum appeared to be inhibited.

141 dition, we elaborate on an emerging role for properdin in thromboinflammation and discuss the potenti

142 Ab neutralization of properdin in WT mice similarly ameliorated arthritis dev

143 d at the level of initiating molecules (MBL, properdin) in the lectin/alternative pathways or C4b in

144 a complement profile observed in humans with properdin-independent C3 nephritic factors.

145 ion of C3 driven by complete CFH deficiency, properdin influences the intraglomerular localization of

146 mmation and discuss the potential utility of properdin inhibitors as long-term therapeutic options to

147 n preparations and the presence of potential properdin inhibitors in serum have complicated studies o

148 In conclusion, factor H and properdin interact with different HS epitopes of PTECs.

149 surface plasmon resonance assays to examine properdin interactions with C3b and factor B.

150 Properdin is a natural, positive regulator of the altern

151 Altogether, our data suggest that properdin is a pattern recognition molecule that plays a

152 Properdin is a plasma protein and is also released from

153 Properdin is a positive regulator of alternative pathway

154 Properdin is a positive regulator of AP complement activ

155 Properdin is a positive regulator of complement activati

156 Properdin is a positive regulator of complement activati

157 Recently, it has been shown that properdin is also a pattern-recognition molecule that bi

158 in C3-depleted human serum, or when purified properdin is applied in buffer.

159 Properdin is composed of multiple identical protein subu

160 ne targeting in the mouse, we show here that properdin is essential for AP complement activation indu

161 e pathway on activated platelets occurs when properdin is on the surface and recruits C3b or C3(H2O)

162 Properdin is produced by many different leukocyte subset

163 roperdin-free AP C3 convertase, we show that properdin is required for the development of elastase-in

164 f the alternative pathway of complement, and properdin is the sole positive regulator.

165 serum as well as polymorphonuclear-released properdin is unable to bind and initiate direct alternat

166 Properdin is well known as an enhancer of the alternativ

167 Following infection, properdin knockout (P(KO)) mice had increased diarrhea a

168 lity of CFHR4-bound C3b to bind factor B and properdin, leading to an active convertase that generate

169 n one ligand at a time, forming a lattice of properdin: ligand interactions bound to a surface scaffo

170 sidue peptide derived from the second type 1 properdin-like repeat of the antiangiogenic protein thro

171 tion involves CSVTCG sequences in the type 1 properdin-like repeats of TSP1, the known binding site f

172 th the thrombospondins 1 (TSP1) and 2 (TSP2) properdin-like type 1 repeats (TSR).

173 ivity of TSP-1 is mediated by the binding of properdin-like type I repeats to the receptor CD36.

174 We further show that properdin localizes to mast cells and that properdin has

175 Using a properdin loss of function mutation in mice and a mutant

176 properdin function was blocked using an anti-properdin mAb or when properdin was depleted from serum.

177 The role of the other TSR domains in properdin may be to act as spacers to make TSR-4, TSR-5

178 Here we studied whether properdin-mediated complement activation occurs on the s

179 n of C5a with its cellular receptor prevents properdin-mediated increases in PGA formation.

180 Our model explains how properdin mediates the assembly of stabilized C3/C5-conv

181 s abolished in properdin-/- mouse serum, and properdin-/- mice were unable to clear Crry-deficient er

182 were only partially or minimally affected in properdin-/- mice.

183 modules more exactly, we expressed the first properdin module (P1); the third properdin module (P3);

184 d the first properdin module (P1); the third properdin module (P3); the first and second properdin mo

185 gen module with the first, second, and third properdin modules (CP123) in the GELEX expression vector

186 properdin module (P3); the first and second properdin modules (P12); the first, second, and third pr

187 modules (P12); the first, second, and third properdin modules (P123); and the procollagen module wit

188 These results indicate that the properdin modules of TSP1 specifically interact with fib

189 tore LPS-dependent AP complement activity in properdin-/- mouse serum correlated with the human prope

190 ed AP complement activation was abolished in properdin-/- mouse serum, and properdin-/- mice were una

191 ritis development, whereas reconstitution of properdin-null mice with exogenous properdin restored ar

192 and C-terminal ends of adjacent monomers in properdin oligomers conform a curly vertex that holds to

193 complement exclusively via association with properdin on A. fumigatus as validated by detection of C

194 The full stabilizing effect of properdin on C3bBb would be attained as properdin binds

195 Finally, we demonstrate that the effects of properdin on PGA formation are tightly regulated by Fact

196 henotypic change to a differential effect of properdin on the dynamics of alternative pathway complem

197 a von Willebrand factor type C module, three properdin or thrombospondin type 1 repeat (TSR) modules,

198 nd the other is required for blocking C5 and properdin (P) binding to C3.

199 In this study, we investigated the role of properdin (P), a positive alternative pathway complement

200 We conclude properdin participates in two distinct complement activa

201 How properdin performs this function is, however, unclear.

202 We conclude that properdin plays a significant role in the outcome of pol

203 complement component, a recombinant form of properdin (Pn), with significantly higher activity than

204 e of nonphysiological aggregates in purified properdin preparations and experimental models that do n

205 of non-physiological aggregates in purified properdin preparations and the presence of potential pro

206 lement; however, fH inhibits activation, and properdin promotes activation of the alternative pathway

207 I demonstrated that properdin promotes the association of C3b with factor B

208 This enhanced surface binding and properdin recruitment was further evidenced in the mesan

209 Properdin regulates the alternative pathway of the compl

210 Finally, properdin released by activated neutrophils binds to act

211 Properdin released by activated neutrophils was particul

212 Properdin released from human polymorphonuclear cells st

213 tution of properdin-null mice with exogenous properdin restored arthritis sensitivity.

214 n this study, we sought to determine whether properdin serves as a focal point for the initiation of

215 Moreover, properdin:single-chain Ab constructs were used to direct

216 Two functions have been assigned to properdin; stabilization of the alternative convertase,

217 rum was not due in part to its effect on the properdin-stabilized C3 convertase, C3b,Bb,P.

218 On pathogen surfaces, properdin stabilizes C3/C5 convertases to efficiently fi

219 Enhanced properdin staining correlated with local complement acti

220 he C3-convertase complex (C3bBb) formed on a properdin surface and inhibits the convertase activity o

221 "Properdin tagging" of apoptotic T cells also induced the

222 Moreover, the study suggests that properdin-targeting strategies may halt aneurysmal growt

223 properdin forms increase PGA formation, but properdin tetramers are the most efficient at increasing

224 Adding either properdin tetramers or C5a to whole blood increases CD11

225 maged human endothelial cell surfaces and to properdin, the human complement activator.

226 However, after addition of native properdin, the properdin-depleted serum recovered the ab

227 peptide also had no effect on the binding of properdin to C3, demonstrating that the observed inhibit

228 ut not gC-2, inhibited the binding of C5 and properdin to C3b and also inhibited the alternative path

229 at gC-1 sterically hindered access of C5 and properdin to C3b.

230 antigonococcal antiserum required functional properdin to kill C4BP-binding strains, but not C4BP-non

231 IgM, C1q, mannose-binding lectin (MBL), and properdin to LDL and acLDL were investigated by ELISA.

232 onse was reversed by administering exogenous properdin to P(KO) mice.

233 We further show that the ability of human properdin to restore LPS-dependent AP complement activit

234 Similarly, binding of properdin to the surface of human umbilical vein endothe

235 The complement protein properdin, traditionally viewed as a positive regulator

236 es have been assigned to the procollagen and properdin (Type I) modules of thrombospondin-1 (TSP1) ba

237 However, and unexpectedly, properdin was also deficient in C3(-/-), fB(-/-), and fD

238 blocked using an anti-properdin mAb or when properdin was depleted from serum.

239 Within 10 min, properdin was partially restored in fB(-/-) but not in C

240 ently, commercially available unfractionated properdin was shown to bind to certain biological surfac

241 molecular structures of dimeric and trimeric properdin were studied by X-ray scattering and analytica

242 Properdin, which lacks the structural homology shared by

243 th significantly higher activity than native properdin, which promotes complement activation via the

244 ither genetic or pharmacological blockade of properdin, which we expected to be therapeutic, converte

245 c, and by blocking the interaction of C5 and properdin with C3b.

246 CFHR5, bound damaged human cell surfaces and properdin with greater intensity and exacerbated local c

247 uman kidney diseases, but whether inhibiting properdin would be beneficial in these diseases is unkno

248 3, suggesting that therapeutic inhibition of properdin would be detrimental in this setting.