1、C-reactive protein and rheumatoid arthritis OutlineC-reactive protein (CRP)IdentificationStructure of proteinFunctional CRP pathwaysFactors affecting CRP levelRheumatoid arthritis (RA)CharacteristicsCRP and RAInfluence on formal clinical algorithmCRP and cardiovascular risk of RACRP and osteoclastog

2、enesis in RAPerspectiveReferenceIdentification1930Tillet and FrancisIn plasma of patients with Streptococcus pneumoniae infectionLigandPhosphorylcholine (PC)Endogenous ligand exposed after cell damage or deathStructure of protein Pentraxin protein familyCyclic homo-pentameric Structure of proteinA s

3、urface: binding site for C1q and FcRB surface: binding site for calcium molecule and phosphorylcholineFunctional CRP pathwaysRhodes, B., Frnrohr, B. G., & Vyse, T. J. (2011). Nature Reviews Rheumatology, 7(5), 282-289.Factors affecting CRP levelInfection,inflammation and tissue injuryNormal 500mg/LC

4、orrelated with severity of inflammationGeneticsHeritability of basal CRP expressionBasal CRP levelAcute-phase CRP levelGenetics of CRPRhodes, B., Frnrohr, B. G., & Vyse, T. J. (2011). Nature Reviews Rheumatology, 7(5), 282-289.1q23Rheumatoid ArthritisAutoimmune disorderCharacteristicsSynovitis of pe

5、ripheral jointsSubsequent joint destructionInvolving lungs and kidneysMarkedly increased cardiovascular riskInfluence on formal clinical algorithm Evaluation of RA activity: DAS28-CRPDAS28-CRP=(0.56TJC)+(0.28SJC)+(0.36lnCRP+1)+(0.014global disease activity score)+0.96.80 Influence on formal clinical

6、 algorithm CRP and cardiovascular risk of RA48% increased risk of incident CVD in patients with RARisk of myocardial infraction increased by 68%RA-related systemic inflammation plays a role in determining cardiovascular riskCRP10mg/L significantly increased MI riskCRP inhibits eNOS activationCRP-ind

7、uced declines in NO production promote monocytes adhesion.CRP modulates prostanoid(前列腺素類) balance and activity花生四烯酸環加氧酶血栓烷A2前列環素C-reactive protein (CRP) small interfering RNA (siRNA) reduces CRP and thromboxane receptor (TP) expression. Etty Grad et al. Arterioscler Thromb Vasc Biol. 2012;32:2468-24

8、74Copyright American Heart Association, Inc. All rights reserved.Human platelet adhesion to murine heart endothelial cells (MHECs) derived from wild-type, CRP transgenic (CRPtg), TP-deficient (TP/), and CRPtgTP/ mice. Etty Grad et al. Arterioscler Thromb Vasc Biol. 2012;32:2468-2474Copyright America

9、n Heart Association, Inc. All rights reserved.CRP and osteoclastogenesis in RAKim K W, Kim B M, Moon H W, et al. Arthritis Research & Therapy, 2015, 17(1):26-30.RANKL: receptor activator for nuclear factor-B ligand 核因子B受體活化因子配體CRP and osteoclastogenesis in RAKim K W, Kim B M, Moon H W, et al. Arthri

10、tis Research & Therapy, 2015, 17(1):26-30.PerspectivePathogenesis of rheumatoid arthritisPotential drug targetClinical evaluationReferenceKim, K. W., Kim, B. M., Moon, H. W., Lee, S. H., & Kim, H. R. (2015). Role of c-reactive protein in osteoclastogenesis in rheumatoid arthritis. Arthritis Research

11、 & Therapy, 17(1), 26-30.McInnes, I. B., Buckley, C. D., & Isaacs, J. D. (2015). Cytokines in rheumatoid arthritis mdash shaping the immunological landscape. Nature Reviews Rheumatology.Danila, M. I., Westfall, A. O., Raman, K., Chen, L., Reynolds, R. J., Hughes, L. B., . & Conn, D. (2015). The role

12、 of genetic variants in CRP in radiographic severity in African Americans with early and established rheumatoid arthritis. Genes and immunity, 16(7), 446-451.Zhang, J., Chen, L., Delzell, E., Muntner, P., Hillegass, W. B., Safford, M. M., . & Curtis, J. R. (2014). The association between inflammator

13、y markers, serum lipids and the risk of cardiovascular events in patients with rheumatoid arthritis. Annals of the rheumatic diseases, 73(7), 1301-1308.Grad, E., & Danenberg, H. D. (2013). C-reactive protein and atherothrombosis: Cause or effect?. Blood reviews, 27(1), 23-29.ReferenceGrad, E., Pachi

14、no, R. M., FitzGerald, G. A., & Danenberg, H. D. (2012). Role of Thromboxane Receptor in C-Reactive ProteinInduced Thrombosis. Arteriosclerosis, thrombosis, and vascular biology, 32(10), 2468-2474.Avina-Zubieta, J. A., Thomas, J., Sadatsafavi, M., Lehman, A. J., & Lacaille, D. (2012). Risk of incide

15、nt cardiovascular events in patients with rheumatoid arthritis: a meta-analysis of observational studies. Annals of the rheumatic diseases, 71(9), 1524-1529.Rhodes, B., Frnrohr, B. G., & Vyse, T. J. (2011). C-reactive protein in rheumatology: biology and genetics. Nature Reviews Rheumatology, 7(5),

16、282-289.Nurmohamed, M. T. (2009). Cardiovascular risk in rheumatoid arthritis. Autoimmunity reviews, 8(8), 663-667.Suk Danik, J., Chasman, D. I., Cannon, C. P., Miller, D. T., Zee, R. Y. L., Kozlowski, P., . & Ridker, P. M. (2006). Influence of Genetic Variation in the CReactive Protein Gene on the Inflammatory Response During and After Acute Coronary Ischemia. Annals of human