research paper

Reduced tumour necrosis factor receptor superfamily 13C inversely correlated with tumour necrosis factor superfamily 13B in patients with immune thrombocytopenia

Xiao-juan Zhu,1* Yan Shi,2,3* Feng Zhang,1 Qing-min Yao,1 Yan-xia Liu,1 Ning-ning Shan,1 Dan Wang,4 Jun Peng,2,3 Jian Xu1 and Ming Hou2,3 1

Department of Haematology, Provincial Hospi-

tal affiliated to Shandong University, 2Department of Haematology, Qilu Hospital, Shandong University, 3The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, and 4Department of Research, Provincial Hospital affiliated to Shandong University, Jinan, China Received 18 January 2014; accepted for publication 1 April 2014 Correspondence: Professor Ming Hou, Department of Haematology, Qilu Hospital, Shandong University, Jinan 250012, China. E-mail: [email protected]. *These authors contributed equally to this study

Summary To investigate the expression of tumour necrosis factor superfamily 13B (TNFSF13B) receptors in immune thrombocytopenia (ITP) and their correlation with disease activity, we investigated the protein and mRNA levels of TNFSF13B, tumour necrosis factor receptor superfamily 13C (TNFRSF13C), TNFRSF13B and TNFRSF17 by flow cytometry, enzymelinked immunosorbent assay and real time quantitative polymerase chain reaction. All CD19+B lymphocytes expressed TNFRSF13C by flow cytometry, but the mean fluorescence intensity (MFI) was decreased in patients with active disease compared to patients in remission and healthy controls, while no significant difference of TNFRSF13C mRNA was found between ITP patients and controls. The mRNA and plasma TNFSF13B were elevated in active ITP patients, and TNFRSF13C MFI level was inversely correlated with plasma TNFSF13B in active patients. In vitro assays showed that TNFRSF13C MFI was decreased after long exposure to TNFSF13B. No significant difference for TNFRSF13B or TNFRSF17 was found between ITP patients and controls. In conclusion, TNFRSF13C expression is reduced on CD19+ cells in active ITP patients. This down-regulation occurs through a post-transcriptional mechanism and could be a consequence of chronic increase of TNFSF13B. Keywords: Tumour necrosis factor superfamily 13B, tumour necrosis factor receptor superfamily 13C, immune thrombocytopenia.

Immune thrombocytopenia (ITP) is an autoimmune disorder in which the patient’s immune system reacts with a platelet autoantigen(s) resulting in thrombocytopenia due to immune-mediated platelet destruction and/or suppression of platelet production (McMillan, 2007). The autoantibodies produced by autoreactive B lymphocytes against self-antigens are considered to play a crucial role (Cines & Blanchette, 2002). However, the exact mechanism remains to be elucidated. The treatment regimens for ITP include corticosteroids, intravenous immunoglobulin (IVIg), intravenous antiD immunoglobulin, splenectomy, danazol, thrombopoietin (TPO) and TPO-receptor agonists (Bussel, 2000; Stasi & Provan, 2004; Cines & McMillan, 2005; Basciano & Bussel, 2012), although these treatments are still unsuitable for 15–20% patients. The tumour necrosis factor (TNF) superfamily of ligands and receptors are known to play a crucial role in the regulation ª 2014 John Wiley & Sons Ltd British Journal of Haematology, 2014, 166, 783–791

of inflammation and immune responses (Locksley et al, 2001). Tumour necrosis factor superfamily 13B (TNFSF13B) (Schneider et al, 1999), (also known as BAFF, BlyS, TALL-1, THANK and zTNF4) (Shu et al, 1999; Moore et al, 1999; Mukhopadhyay et al, 1999; Tribouley et al, 1999; Gross et al, 2000) is critical for the maintainance of normal B-cell development and homeostasis (Moore et al, 1999; Schneider et al, 1999), T cell costimulation (Huard et al, 2001, 2004; Ye et al, 2004), and certain T cell helper type 1 (Th1)-associated inflammatory responses (Sutherland et al, 2005). Expression of TNFSF13B is highly restricted to myeloid lineage cells (e.g.monocytes, macrophages, neutrophils, dendritic cells) and activated T cells (Ng et al, 2005; Dillon et al, 2006). TNFSF13B binds to three TNF receptor superfamily (TNFRSF) members: TNFRSF17 also known as BCMA), TNFRSF13B and TNFRSF13C (also known as BR3 and BAFF-R) (Gross et al, 2000; Thompson et al, 2001). All three receptors are primarily First published online 30 May 2014 doi:10.1111/bjh.12958

X.-j. Zhu et al expressed by B cells (Mackay & Browning, 2002), with TNFRSF13C expressed on all peripheral blood B cells (Thompson et al, 2001; Ng et al, 2004), TNFRSF13B on B cells and a subset of activated T cells (von Bulow & Bram, 1997) and TNFRSF17 on B cells, particularly plasmablasts (Gross et al, 2000; Schiemann et al, 2001; Avery et al, 2003). The expression of TNFSF13B is elevated in several human autoimmune diseases such as systemic lupus erythematosus (SLE) (Zhang et al, 2001; Stohl et al, 2003; Vallerskog et al, 2006; Carter et al, 2013), rheumatoid arthritis (RA) (Pers et al, 2005a; Seyler et al, 2005; Vallerskog et al, 2006), Sj€ ogren’s syndrome (SS)(Jonsson et al, 2005; Pers et al, 2005b; Szodoray & Jonsson, 2005), multiple sclerosis (MS) (Thangarajh et al, 2004), including ITP (Emmerich et al, 2007; Zhou et al, 2009; Zhu et al, 2009). Abnormal expression of TNFSF13B receptors have been reported in many autoimmune diseases, including RA (de la Torre et al, 2010), SLE (Zhao et al, 2010; Kim et al, 2011), MS (Thangarajh et al, 2004, 2007) and myasthenia gravis (MG) (Thangarajh et al, 2007). To date, articles about TNFSF13B receptors are few, although normal or increased expression of TNFSF13B receptors in ITP patients have been reported (Wang et al, 2008; Zhou et al, 2009). Here we studied the expression of TNFSF13B receptors in ITP patients to investigate the possible role of TNFSF13B receptors in ITP.

Materials and methods Patients Twenty-three active ITP patients with platelet counts 5 ng/ml), which were not achieved in ITP in our experiment. To determine whether the decrease of TNFRSF13C MFI in ITP could be explained by chronic TNFSF13B exposure, we incubated PBMCs from the same controls and patients with rhTNFSF13B at different concentrations for various times. BAFF-R MFI was reduced when incubated for 24 h or longer. Figure 4 shows effects of rhTNFSF13B at different concentrations (0 ng/ml, 1 ng/ml, 5 ng/ml and 10 ng/ml)

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Fig 4. Effects of rhTNFSF13B at different concentrations and times on TNFRSF13C expression on CD19+ B lymphocytes by flow cytometry. The results are from a representative patient following incubation of peripheral blood mononuclear cells with rhTNFSF13B at different concentration [(A) 0 ng/ml; (B) 1 ng/ml; (C) 5 ng/ml; (D)10 ng/ml] for 30 min, 24 h and 48 h. ª 2014 John Wiley & Sons Ltd British Journal of Haematology, 2014, 166, 783–791

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X.-j. Zhu et al and for different time (30 min, 24 h and 48 h) on TNFRSF13C expression on CD19+ B lymphocytes by flow cytometry.

No significant differences of TNFRSF13B or TNFRSF17 betwenn ITP patients and controls The protein and mRNA levels of TNFRSF13B and TNFRSF17 were measured by flow cytometry and real-time PCR, there was no significant difference between different groups of ITP patients and healthy controls (P > 005).

No correlation between plasma TNFSF13B and its receptors to anti-platelet GPIIb/IIIa and/or GPIb/IX autoantibodies and platelet counts We assessed the expression of anti-platelet GPIIb/IIIa and/or GPIb/IX autoantibodies by MAIPA, and investigated the correlation between TNFSF13B/TNFRSF13C and anti-platelet autoantibodies, no correlation was found. Plasma TNFSF13B, TNFSF13B mRNA and TNFRSF13C MFI were then correlated to platelet counts; no significant correlation was found.

Discussion The TNFSF13B/TNFRSF13C system is crucial for B cell survival and maturation (Moore et al, 1999; Mukhopadhyay et al, 1999; Schneider et al, 1999; Tribouley et al, 1999; Gross et al, 2000). Excessive TNFSF13B promotes the survival of immature B cells, which contribute to the emergence and maturation of autoreactive B cells (Batten et al, 2000). TNFRSF13C, identified as the crucial receptor for B-cell survival, is expressed on a wide range of B-cell subsets, including immature, transitional, mature, memory and germinal centre B cells, as well as on plasma cells (Mackay & Browning, 2002). Several articles have reported elevated TNFSF13B expression and their correlation to disease activity in autoimmune diseases, such as SLE, RA, MS, MG and SS including ITP (Zhang et al, 2001; Stohl et al, 2003; Thangarajh et al, 2004; Jonsson et al, 2005; Pers et al, 2005a,b; Seyler et al, 2005; Szodoray & Jonsson, 2005; Vallerskog et al, 2006). There is conflicting data concerning TNFSF13B receptor expression in human autoimmune diseases. Some reported elevated TNFSF13B receptors (Thangarajh et al, 2004; Matsushita et al, 2006; Li et al, 2008; Zhou et al, 2009; Zhao et al, 2010; Kim et al, 2011) while others reported similar or reduced expression of TNFSF13B receptors (Carter et al, 2005; Sellam et al, 2007; Thangarajh et al, 2007; de la Torre et al, 2010; Zhao et al, 2010; Kim et al, 2011). In accordance with our previous experiment and others, elevated level of plasma TNFSF13B and TNFSF13B mRNA was found in active ITP patients (Emmerich et al, 2007; Zhou et al, 2009; Zhu et al, 2009). Moreover, we found TNFRSF13C was expressed by all CD19+ B lymphocytes, and TNFRSF13C 788

MFI was reduced in active ITP patients by flow cytometry. The decrease of TNFRSF13C was inversely correlated with plasma TNFSF13B level and correlated with disease activity. Similar TNFRSF13C mRNA between ITP patients and controls indicated the down-regulation of TNFRSF13C was a post-transcriptional event. Similar to Carter et al (2005) and Sellam et al (2007), we found TNFRSF13C MFI reduced only at very high rhTNFSF13B concentrations (≥5 ng/ml) which was much higher than that of ITP patients, indicating no spatial competition between anti-TNFRSF13C mAb from the clone 11C1 and endogenous TNFSF13B already bound to memberanous TNFRSF13C. Receptor internalization may be another possible explanation for the decreased expression of TNFRSF13C MFI similar to the rapid internalization of TNF receptor 10– 30 min after the binding of TNF or shedding of this complex from the membrane (Schneider-Brachert et al, 2004). The absence of downregulation of TNFRSF13C after 30 min of incubation with rhTNFSF13B at 1 or 25 ng/ml (similar to or a little higher than plasma TNFSF13B level in ITP patients in our experiment) does not support this hypothesis. However, when we incubated PBMCs with rhTNFSF13B at concentrations corresponding to plasma TNFSF13B level for 24 h or more, we found a down-regulation of TNFRSF13C MFI, suggesting an internalization or shedding of TNFRSF13C in vivo after long-term exposure to TNFSF13B. To investigate whether TNFRSF13C level decrease resulted from TNFRSF13C mRNA downregulation, we assessed TNFRSF13C mRNA levels in PBMCs. TNFRSF13C mRNA levels were similar between patients and controls, thus the down-regulation of TNFRSF13C took place at the post-transcriptional level and the long exposure of elevated plasma TNFSF13B level may contribute to this, although the exact mechanism needs to be elucidated. Activation of nuclear factor (NF)-jB is fundamental to signal transduction by members of the TNFRSF family (Smith & Cancro, 2003). TNFSF13B/TNFRSF13C signalling was also biochemically linked to both the classical and alternative NF-jB pathways (Senftleben et al, 2001; Claudio et al, 2002). In addition, Reports also demonstrate cross-talk between BCR and TNFRSF13C singalling (Khan, 2009). Further study on TNFSF13B/TNFRSF13C signal needs to be undertaken to investigate the mechanism of TNFSF13B/TNFRSF13C in ITP. The abnormal expression of TNFSF13B/TNFRSF13C in active ITP patients indicated the possible role of the TNFSF13B/TNFRSF13C axis in the pathogenesis of ITP. As the increased destruction of platelets in ITP patients is partly caused by increased autoantibodies particularly IgG antibodies against GPIIb/IIIa and/or GPIb/IX, and anti-platelet GPIIb⁄IIIa and GPIb/IX autoantibodies are elevated in most patients, we further investigated the possible effect of TNFSF13B/TNFRSF13C on autoantibodies, however, no correlation was found between TNFSF13B or TNFRSF13C and anti-platelet autoantibodies. We have previously shown addiª 2014 John Wiley & Sons Ltd British Journal of Haematology, 2014, 166, 783–791

TNFRSF13C in ITP tion of rhTNFSF13B did not promote the production of autoantibodies in vitro. The excessive TNFSF13B may rescue autoreactive B and T cells from apoptosis and increased survival of CD8+ T cells may promote the apoptosis of platelets through cytotoxic T cell lysis (CTL)-mediated platelet lysis (Zhu et al, 2009). These findings suggested that the abnormal expression of the TNFSF13B/TNFRSF13C axis may not directly promote the production of anti-platelet autoantibodies but may play a role in other mechanisms than autoantibody production in ITP patients. Inhibition of TNFSF13B/TNFRSF13C signalling is a potentially therapeutic option for treatment of B cell-mediated autoimmune conditions. Blockade of TNFSF13B has been used successfully in murine models of several autoimmune diseases including SLE, RA and MS (Gross et al, 2001; Huntington et al, 2006; Ramanujam et al, 2010). Data from clinical trials had proved that blockade of TNFSF13B by blocking reagents was an effective therapeutic approach for some autoimmune diseases. The most exciting findings have been the positive results of two large Phase III studies of belimumab in SLE (Furie et al, 2009; Wallace et al, 2009). The anti-TNFSF13B mAb, belimumab, was recently approved by the US Food and Drug Administration for the treatment of adult SLE patients, and three additional TNFSF13B antagonists (atacicept, blisibimod, tabalumab) are presently being evaluated in SLE Phase-III trials. Reports on the blockade of TNFSF13B in ITP are few; in our previous study, we demonstrated that TNFRSF13C-Fc could successfully correct the effects of rhTNFSF13B by promoting the apoptosis of CD19+ and CD8+ cells and inhibiting secretion of IFN-c in vitro in ITP (Zhu et al, 2009). Blockade of TNFSF13B/TNFRSF13C may be a promising therapeutic approach for ITP, especially for those patients with active disease. In summary, the expression of TNFSF13B is elevated and TNFRSF13C is reduced in active ITP patients. This downregulation of TNFRSF13C occurs through a post-transcriptional mechanism and could be a reflection of chronic TNFSF13B overproduction over time.

Acknowledgements This work was supported by grants from Tai Shan Scholar Foundation, Clinical Medicine Centre Foundation of Shandong Province, Leading Medical Professionals Foundation of Shandong Province, National Natural Science Foundation of China (No. 81070396, No. 81100334, No. 81100335, No. 81100336, No. 81100348, No. 81101869, No. 81170475, No. 81200344, No. 81202307, No. 81270578, No. 81300383, No. 81370623, No. 81370616, No. 81300384), National Natural Science Funds for Distinguished Young Scholar (No. 81125002), State Programme of National Natural Science Foundation of China for Innovative Research Group (81321061), Outstanding Young Scientist Research Award Foundation of Shandong Province (No. 2008BS03025, No. BS2010YY024, No. BS2010YY039, No. BS2011SW013, No. BS2011YY021), National Basic Research Programme of China (973 Programme, No. 2009CB521904, No. 2011CB503906), State Key Clinical Specialty of China for Blood Disorders, the Research Fund for the Doctoral Programme of Higher Education of China (No. 20100131120058), National Public Health Grand Research Foundation (No. 201202017), National High Technology Research and Development Programme of China (863 Program, No. 2012AA02A505), and Independent Innovation Foundation of Shandong University (No. 2082012TS134).

Author contributions Z.X. performed the research, analysed data and wrote the paper, S.Y. contributed vital new reagents, designed the research study and wrote the paper, Z.F., Y.Q and L.Y. performed the research, S.N. and W.D. analysed data, X.J. and P.J. designed the research and wrote the paper, H.M. designed the research and wrote the paper.

Conflict of interest None of the authors have competing financial interests.

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Reduced tumour necrosis factor receptor superfamily 13C inversely correlated with tumour necrosis factor superfamily 13B in patients with immune thrombocytopenia.

To investigate the expression of tumour necrosis factor superfamily 13B (TNFSF13B) receptors in immune thrombocytopenia (ITP) and their correlation wi...
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