Pathway of Toll-Like Receptor 7/B Cell Activating Factor/B Cell Activating Factor Receptor Plays a Role in Immune Thrombocytopenia In Vivo

PLOS ONE, Jul 2011

Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by anti-platelet autoantibody-mediated platelet destruction. Antigen-presenting cell (APC) dysfunction is considered to play crucial roles in ITP. However, how APC affects autoreactive B cells in ITP is still unknown. Using a mouse model of immune thrombocytopenia, we demonstrated an increase in levels of TLR7 in splenic mononuclear cells (SMCs). Using both TLR7 agonist and TLR7 silencing lentivirus, we found stimulation of TLR7 decreased platelet counts and increased levels of platelet-associated IgG (PAIgG) in ITP mice, which correlates TLR7 with platelet destruction by autoantibodies. Levels of serum BAFF increased significantly in ITP mice and stimulation of TLR7 promoted secretion of BAFF. Among the three BAFF receptors, only BAFF receptor (BAFF-R) increased in ITP mice. However, activation of TLR7 showed no effect on the expression of BAFF receptors. These findings indicate that upregulation of TLR7 may augment BAFF secretion by APC and through ligation of BAFF-R promote autoreactive B cell survival and thus anti-platelet autoantibody production. The pathway of TLR7/BAFF/BAFF-R provides us with an explanation of how activation of APC affects autoantibody production by B cells in ITP and thus might provide a reasonable therapeutic strategy for ITP.

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Pathway of Toll-Like Receptor 7/B Cell Activating Factor/B Cell Activating Factor Receptor Plays a Role in Immune Thrombocytopenia In Vivo

et al. (2011) Pathway of Toll-Like Receptor 7/B Cell Activating Factor/B Cell Activating Factor Receptor Plays a Role in Immune Thrombocytopenia In Vivo. PLoS ONE 6(7): e22708. doi:10.1371/journal.pone.0022708 Pathway of Toll-Like Receptor 7/B Cell Activating Factor/ B Cell Activating Factor Receptor Plays a Role in Immune Thrombocytopenia In Vivo Qing Yang 0 Shuqian Xu 0 Xiaofang Li 0 Bo Wang 0 Xuping Wang 0 Daoxin Ma 0 Lei Yang 0 Jun Peng 0 Ming Hou 0 Clive M. Gray, University of Cape Town, South Africa 0 1 Department of Parasitology, Shandong University School of Medicine , Jinan , China , 2 Haematology Oncology Centre, Qilu Hospital, Shandong University , Jinan , China , 3 Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Qilu Hospital, Shandong University , Jinan , China , 4 Hematology Department, Nanfang Hospital, Southern Medical University , Guangzhou , China , 5 Department of Traditional Chinese Medicine, Qilu Hospital, Shandong University , Jinan , China Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by anti-platelet autoantibody-mediated platelet destruction. Antigen-presenting cell (APC) dysfunction is considered to play crucial roles in ITP. However, how APC affects autoreactive B cells in ITP is still unknown. Using a mouse model of immune thrombocytopenia, we demonstrated an increase in levels of TLR7 in splenic mononuclear cells (SMCs). Using both TLR7 agonist and TLR7 silencing lentivirus, we found stimulation of TLR7 decreased platelet counts and increased levels of platelet-associated IgG (PAIgG) in ITP mice, which correlates TLR7 with platelet destruction by autoantibodies. Levels of serum BAFF increased significantly in ITP mice and stimulation of TLR7 promoted secretion of BAFF. Among the three BAFF receptors, only BAFF receptor (BAFF-R) increased in ITP mice. However, activation of TLR7 showed no effect on the expression of BAFF receptors. These findings indicate that upregulation of TLR7 may augment BAFF secretion by APC and through ligation of BAFF-R promote autoreactive B cell survival and thus anti-platelet autoantibody production. The pathway of TLR7/BAFF/BAFF-R provides us with an explanation of how activation of APC affects autoantibody production by B cells in ITP and thus might provide a reasonable therapeutic strategy for ITP. - Funding: This work was supported by grants from Tai Shan Scholar Foundation, National Natural Science Foundation of China (No. 81070396, No. 81070408, No. 81070407 and No. 81070411), 973 Program (No. 2011 CB 503906), Foundation for the Author of National Excellent Doctoral Dissertation of PR China (No. 200561), Program for New Century Excellent Talents in University (NCET-07-0514), Key Project of Chinese Ministry of Education (109097), Key Clinical Research Project of Public Health Ministry of China 20102012, the 43rd China Postdoctoral Science Foundation (20080431205), the Second China Postdoctoral Special Foundation (200902566), Postdoctoral Innovation Program of Shandong Province, China in 2008 (200803074), Natural Science Foundation of Shandong Province (ZR2009CM001), Clinical Medicine Center Foundation of Shandong Province, Leading Medical Professionals Foundation of Shandong Province, Outstanding Young Scientist Research Award Foundation of Shandong Province (2008BSO3009, BS2010YY039), Independent Innovation Foundation of Shandong University (No. 2009TS053) and State Program of National Natural Science Foundation of China for Innovative Research Group 20112013 (81021001). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. . These authors contributed equally to this work. Immune thrombocytopenia (ITP) is an autoimmune disease manifested by immune-mediated platelet destruction and suppression of platelet production. Although several abnormalities involving the cellular mechanisms of immune modulation have been identified, development of autoantibodies against platelet glycoproteins remains central in the pathogenesis of ITP [1]. Increasing evidence suggests an important role of deviant APC in the pathophysiology of autoimmune diseases [2]. Targeting APC shows promising therapeutic effects in an animal model of rheumatoid arthritis (RA) [3]. In ITP patients, changes in number and function of APC have also been indicated [4]. Activation of APC is found to play a critical role in the pathogenic anti-platelet autoantibody response [4,5]. However, how activation of APC affects autoantibody producing B cells is not well elucidated. Toll-like receptors (TLRs) are type I transmembrane patternrecognition receptors (PPRs) that have long been known to recognize highly conserved, pathogen-associated molecular patterns (PAMPs) [6]. TLRs are expressed on many cell types, especially APC [7] (...truncated)


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Qing Yang, Shuqian Xu, Xiaofang Li, Bo Wang, Xuping Wang, Daoxin Ma, Lei Yang, Jun Peng, Ming Hou. Pathway of Toll-Like Receptor 7/B Cell Activating Factor/B Cell Activating Factor Receptor Plays a Role in Immune Thrombocytopenia In Vivo, PLOS ONE, 2011, Volume 6, Issue 7, DOI: 10.1371/journal.pone.0022708