• Users Online: 416
  • Home
  • Print this page
  • Email this page
Home About us Editorial board Search Ahead of print Current issue Archives Submit article Instructions Subscribe Contacts Login 

 Table of Contents  
ORIGINAL ARTICLE
Year : 2012  |  Volume : 37  |  Issue : 3  |  Page : 166-171

Expression of B-cell activating factor and its receptor in idiopathic thrombocytopenic purpura


1 Department of Clinical and Chemical Pathology, Faculty of Medicine, Cairo University, Cairo, Egypt
2 Department of Internal Medicine, Faculty of Medicine, Cairo University, Cairo, Egypt
3 Department of Pediatrics, Faculty of Medicine, Beni-Suef University, Beni-Suef, Egypt

Date of Submission12-Dec-2011
Date of Acceptance15-Jan-2012
Date of Web Publication21-Jun-2014

Correspondence Address:
Dalia Gamil Amin
MD, Department of Clinical and Chemical Pathology, Faculty of Medicine, Cairo University, 11559 Cairo
Egypt
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.7123/01.EJH.0000416547.99666.65

Rights and Permissions
  Abstract 

Background

B-cell activating factor (BAFF) plays a crucial role in B-cell development, survival, and immunoglobulin production. Excess BAFF results in the rescue of self-reactive B cells from anergy and the rescue of autoreactive T cells from the suppressing effect of dendritic cells, thus implicating a role in the development of autoimmunity.

Aim

The aim of this study was to evaluate BAFF and its receptor (BAFF-R) mRNA expression in patients with idiopathic thrombocytopenic purpura (ITP) and also to study the potential association of their expression with variations in disease severity, chronicity, and response to treatment.

Patients and methods

Evaluation of BAFF and BAFF-R expression was carried out using a quantitative real-time PCR, in 79 ITP patients as well as 20 age-matched and sex-matched control volunteers.

Results

The median expression level of BAFF and BAFF-R in ITP patients was significantly higher compared with that in the control group. Children had a significantly lower mean BAFF expression level compared with adults with ITP. Female patients had a significantly higher mean BAFF-R expression level compared with male patients. Patients with active ITP had a significantly higher BAFF expression compared with those in remission and those of the control group. The mean expression level of BAFF-R was significantly higher in patients with active ITP and in those in remission when it was compared with that of the control group. BAFF-R expression was significantly higher in steroid-treated patients compared with untreated patients. A significant positive correlation was found between BAFF and BAFF-R mRNA expression levels. BAFF expression was correlated positively with the median age of patients at the time of sampling and diagnosis.

Conclusion

Elevated BAFF expression in patients with active ITP indicates its possible role in the pathogenesis of ITP. Hence, selective antagonistic targeting of BAFF or BAFF-R in ITP patients with high levels of BAFF expression might be considered as a novel therapeutic strategy.

Keywords: B-cell activating factor, B-cell activating factor-receptor, idiopathic thrombocytopenic purpura, quantitative real-time polymerase chain reaction


How to cite this article:
Eiada TK, Amin DG, Amin ES, Morgan DS, El Kareem MG. Expression of B-cell activating factor and its receptor in idiopathic thrombocytopenic purpura. Egypt J Haematol 2012;37:166-71

How to cite this URL:
Eiada TK, Amin DG, Amin ES, Morgan DS, El Kareem MG. Expression of B-cell activating factor and its receptor in idiopathic thrombocytopenic purpura. Egypt J Haematol [serial online] 2012 [cited 2019 Dec 14];37:166-71. Available from: http://www.ehj.eg.net/text.asp?2012/37/3/166/135054


  Introduction Top


Idiopathic thrombocytopenic purpura (ITP) is an autoimmune disorder in which platelets are opsonized by autoantibodies and destroyed by macrophages 1. The autoantibodies produced by autoreactive B cells against self-antigens, specifically immunoglobulin G (IgG) antibodies against glycoprotein IIb (GPIIb)/IIIa and/or GPIb/IX, are considered to play a crucial role in the pathogenesis of ITP 2. Therefore, ITP represents a prototype of a B-cell-mediated autoimmune disorder and B-cell depletion has become a feasible option for ITP patients by decreasing the formation of autoantibody 3.

In addition, several abnormalities involving the cellular mechanisms of immune modulation, such as the T-helper 1 bias 4, the decreased number or defective suppressive function of regulatory T cells 5, and the platelet destruction by cytotoxic T cells 6, have been described.

B-cell activating factor (BAFF) (also known as B-lymphocyte stimulator) is a survival factor for most B cells; it belongs to the tumor necrosis factor family. BAFF is produced by macrophages, monocytes, dendritic cells, T cells, and neutrophils 7,8. BAFF, as an essential component of B-cell homeostasis, plays an important role in B-cell proliferation and functions as a costimulator 9.

Excess BAFF rescues autoreactive B cells from rapid competitive elimination and promotes the survival of autoreactive B cells that normally die. Therefore, BAFF overexpression alters immune tolerance in the periphery and predisposes to the development of autoimmune disease 10. BAFF overexpression impairs self-tolerance not only by promoting autoreactive B cells but also by suppressing the protective effects of dendritic cells against the emergence of autoreactive T cells 11.

BAFF binds to three different receptors: B-cell maturation antigen (BCMA), transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI) and BAFF-receptor (BAFF-R), whose expression is restricted to B cells and a small subset of T cells 12,13. A proliferation-inducing ligand, a cytokine homologous to BAFF, can bind to B-cell maturation antigen and TACI, but not BAFF-R, which makes BAFF-R a specific receptor for BAFF 14.

Elevated serum levels of BAFF have been reported in patients with autoimmune diseases including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjögren’s syndrome, and myasthenia gravis 15. BAFF-R was often found to be increased in autoantibody-related diseases 16. Few studies have shown that serum BAFF level and BAFF mRNA are significantly increased in ITP, which provides important new insights into the pathogenesis of ITP 17,18.

Moreover, the treatment regimens for ITP including glucocorticosteroids, intravenous immunoglobulin G, anti-D, and splenectomy are not always effective, and only one-third of adult patients achieve long-term remission. Therefore, BAFF might serve as a new rational therapeutic target for ITP.

Taken together, these evidences have led us to hypothesize that BAFF and BAFF-R may play an important role in the pathogenesis of ITP. Hypothesizing that variations in BAFF and/or BAFF-R expression levels might be associated with variations in disease severity, chronicity, and response to treatment, we decided on a short follow-up period (3–12 months) for a number of patients among the ITP group studied according to availability.

Aim

The aim of this study was to evaluate BAFF and BAFF-R mRNA expression in patients with ITP and also to study the potential association of their expression with variations in disease severity, chronicity, and response to treatment.


  Patients and methods Top


The present study was carried out on 79 patients with ITP as well as 20 age-matched and sex-matched control volunteers after informed consent was obtained from each participant or his/her guardians. These patients attended Kasr Al Aini Hospital, Cairo University, to be diagnosed in the clinical pathology department between February 2010 and August 2011. All cases were subjected to careful history-taking and a comprehensive clinical examination. ITP was diagnosed on the basis of the guidelines of the American Society of Hematology 19. Thrombocytopenia was defined as platelet count less than 100×109/l. The mean age of the patients in the study was 20.4±18.1 years. Among the 79 patients, 57 were women (72%) and 22 were men (28%). The clinical and laboratory data of the patient group are summarized in [Table 1].
Table 1: Clinical and laboratory data of the ITP patients studied

Click here to view


Evaluation of BAFF and BAFF-R expression was carried out using a quantitative real-time PCR. RNA extraction from peripheral blood samples was carried out using the QIAamp RNA Blood Mini Kit (catalog number 52304; Qiagen, Hilden, Germany). RNA conversion into complementary DNA (cDNA) was carried out using the QIAGEN LongRange 2Step RT-PCR Kit (catalog number 205922; Qiagen) according to the manufacturer’s instructions. Synthesized cDNA was stored at −70°C until use. Quantitative real-time PCR was performed for BAFF and BAFF-R and the endogenous control (β-actin) on an Applied Biosystems 7300 thermocycler (Qiagen, Foster City, California, USA) using the SYBR Green PCR Master Mix (catalog number 4309155; Applied Biosystems, Warrington, UK) as a double-strand DNA-specific binding dye as described previously 17. In brief, the 25 µl reaction mixture contained 12.5 µl SYBR Green qPCR Mix (2×), 0.5 µl DNA, and 1 µl primer pair mix (5 pmol/µl each primer). The primers used for amplification were β-actin internal control forward: 5′-ggcacccagcacaatgaag-3′, reverse: 5′-cgtcatactcctgcttgctg-3′. BAFF mRNA forward: 5′-ggggaagtgccctagaag-3′, reverse: 5′-acatcgaaacaaagtcaccaga-3′; and BAFF-R mRNA- forward: 5′-tcctggtgggtctggtgagc-3′, reverse: 5′-ggtggttcctgggtcttcc-3′ 17. A PCR control without reverse transcriptase was used routinely as a negative control. The PCR parameters were as follows: 95°C, 15 min, followed by 40 cycles of PCR reaction at 94°C for 15 s; 60°C for 30 s; and then 72°C for 35 s. Plates were read after each cycle, and a melting curve was generated after amplification. The quantity of BAFF and BAFF-R mRNA expression was determined using the &Dgr;&Dgr;Ct method, where the amount of target was normalized to the endogenous reference (β-actin) and relative to the calibrator. The formula was used as follows: target amount= 2−&Dgr;&Dgr;Ct, where &Dgr;&Dgr;Ct={[Ct (BAFF or BAFF-R sample)−Ct (β-actin sample)]−[Ct (BAFF or BAFF-R calibrator)−Ct (β-actin calibrator)]}, where the Ct value (cycle threshold) is defined as the number of cycles required for the fluorescent signal to cross the threshold.

Statistical analysis

Data were analyzed using the SPSS win statistical package version 17 (SPSS Inc., Chicago, Illinois, USA). Numerical data were expressed as the mean and SD or median and range as appropriate. Qualitative data were expressed as frequency and percentage. The χ2-test was used to examine the relation between qualitative variables. For quantitative data, comparison between two groups was carried out using the Mann–Whitney U-test (non-parametric t-test). Comparison between three groups was carried out using the Kruskal–Wallis test (nonparametric analysis of variance), followed by a post-hoc ‘Scheffe’s test’ on the rank of variables for a pair-wise comparison. A P value less than 0.05 was considered significant. The correlation between various variables was determined using the Spearman rank correlation equation for non-normal variables.


  Results Top


The BAFF expression level in ITP patients ranged from 0.018 to 45.705, with a median of 2.387, whereas in the control group, it ranged from 0.376 to 10.656, with a median of 0.811. The median expression level of BAFF in ITP patients was significantly higher compared with that in the control group (P=0.008). ITP patients had a BAFF-R median expression level of 38.640 (range 2.487–699.291); control individuals had a BAFF-R median expression level of 1.748 (range 0.259–8.748). ITP patients had a significantly higher median BAFF-R expression level compared with the control group (P<0.001) [Table 2], [Figure 1].
Figure 1: BAFF and BAFF-R mRNA expression in the control group as well as in different classified ITP patient groups. *P<0.05 (significant difference). BAFF, B-cell activating factor; BAFF-R, B-cell activating factor-receptor; ITP, idiopathic thrombocytopenic purpura.

Click here to view
Table 2: Comparison of BAFF and BAFF-R expression levels in different groups of the ITP patients studied

Click here to view


This study included 37 children (⩽12 years) with ITP (47%); these children had a significantly lower mean BAFF expression level (3.954±8.063) compared with adults with ITP (5.101±5.593) (P=0.017). No significant difference was found when children’s mean BAFF-R expression level (99.237±149.259) was compared with those of the adults (74.580±76.391) (P>0.05) [Table 2], [Figure 1].

The mean BAFF expression level was 3.107±4.283 in ITP male patients and 5.126±7.558 in female patients, with no statistically significant difference (P>0.05). Female patients had a significantly higher mean BAFF-R expression level (102.310±130.515) compared with male patients (44.202±46.661) (P=0.048) [Table 2], [Figure 1].

Defining the disease state at the time of sampling according to Zhou et al. 17, 68 of our patients (86%) were in activity (platelet count <100×109/l) and 11 patients (14%) were in remission (platelet count ≥100×109/l). Patients with active ITP had a significantly higher BAFF expression (8.182±8.154) compared with those in remission (4.097±6.562, P=0.015) and those of the control group (P=0.002). However, BAFF expression was not significantly different in ITP patients in remission in comparison with the control group (P>0.05). For BAFF-R, despite the tendency toward a higher expression of BAFF-R in patients with active ITP (86.869±123.180) compared with those in remission (70.114±49.399), this variability did not reach statistical significance (P>0.05). The mean expression level of BAFF-R was significantly higher in patients with active ITP and in those in remission compared with the control group (P<0.001) [Table 2], [Figure 1].

This study included 50 patients (63%) classified as acute ITP patients (disease duration <6 months) and 29 patients (37%) classified as chronic ITP patients; this classification was carried out at the time of sampling and according to the guidelines of the British Society for Hematology 20. The mean BAFF expression level was 4.868±7.448 and 4.041±5.725 in acute and chronic ITP patients, respectively, whereas the mean BAFF-R expression level was 73.631±87.001 and 107.676±153.655 for the same ordered groups. No statistically significant difference was found between acute and chronic ITP patients when they were compared in terms of BAFF or BAFF-R expression level (P>0.05) [Table 2], [Figure 1].

Bleeding, as an indicator of clinical severity, was manifested in 21 ITP patients (27%) at the time of sampling. The bleeder group had a median BAFF expression of 2.193 (range 0.034–8.365) and BAFF-R expression of 33.708 (range 2.940–144.101); the nonbleeder group had a median BAFF expression of 2.554 (range 0.018–45.705) and BAFF-R expression of 40.676 (range 2.487–699.291). No statistically significant difference was found between the two groups in BAFF or BAFF-R expression level (P>0.05) [Table 2].

At the time of sampling, 48 of the ITP patients included (61%) were receiving steroid therapy; among these steroid-treated patients, 11 (14%) were receiving a combination of steroids and imuran. BAFF expression tends to be lower in steroid-treated patients (4.535±5.388) compared with untreated patients (4.608±8.726); however, this did not reach statistical significance (P>0.05). BAFF-R expression was significantly higher in steroid-treated patients (104.087±133.519) compared with untreated patients (58.322±76.573) (P=0.024) [Table 2], [Figure 1]. No statistically significant difference was found when BAFF or BAFF-R expression levels were compared in steroid-treated versus combined steroid and imuran-treated patient groups (P>0.05). It is noteworthy that among the 48 patients who were on steroid therapy, other lines of treatment were concomitantly followed in some patients (intravenous Ig in two patients, cyclosporine in one patient, and splenectomy in two patients); however, these subgroups were too small to be analyzed statistically.

Assessment of response in patients who were eligible for follow-up (62/79, 78%) was carried out according to Francesco et al. 21; nonresponders (platelet count <30×109/l or less than double the baseline count, 7/62, 11%), partial responders (platelet count between 30 and 100×109/l, 10/62, 16.5%), and complete responders (platelet count ≥100×109/l, 45/62, 72.5%) had a mean BAFF expression of 2.318±2.053, 8.942±14.037, and 3.109±3.679, respectively. BAFF-R expression was 50.773±58.814, 115.394±78.432, and 87.701±142.270 in the same ordered groups. No statistically significant difference was found when these classified groups were compared for BAFF or BAFF-R expression level (P>0.05) [Table 2], [Figure 1].

A significant positive correlation was found between BAFF and BAFF-R mRNA expression levels. BAFF expression was positively correlated with the median age of patients at time of sampling and at diagnosis. No other significant correlation was found between BAFF or BAFF-R expression and different clinical or hematological variables, for example hemoglobin concentration, total leukocytic count, or platelet count.


  Discussion Top


The pathogenetic mechanisms of ITP remain unclear. Many pathways may be involved in the pathogenesis of ITP such as failure of immune tolerance, autoreactive B and T cells, and abnormality of cytokines 22.

BAFF plays a crucial role in B-cell development, survival, and production of Igs. However, excess BAFF results in the rescue of self-reactive B cells from anergy and the rescue of autoreactive T cells from the suppressing effect of dendritic cells, thus implicating a role in the development of autoimmunity 10.

The current study showed that the expression levels of BAFF and BAFF-R mRNA were significantly higher in ITP patients compared with the normal controls. In agreement, Zhou et al. 17 reported higher BAFF expression in ITP patients not only at the mRNA expression level but also at the protein level in plasma, whereas for BAFF-R, Zhou et al. 17 reported that the mRNA level of BAFF-R in ITP was not statistically different from that of the normal controls. Debates on the expression of BAFF-R in ITP and other autoimmune diseases, are evident in the literature. Ju et al. 23 and Warnatz et al. 16 reported significant elevation in the BAFF-R mRNA expression in PBMNC of SLE and in autoantibody-related diseases. Yang et al. 24 reported a significant increase of BAFF-R on peripheral B cells in ITP mice. However, some studies have reported that the expression of BAFF-R did not change or even decrease in autoimmune diseases including SLE, Sjogren's syndrome, multiple sclerosis, and RA 25–28. Further research on BAFF-R expression in B or T cells may help elucidate its actual roles in ITP.

The present study reported significantly higher BAFF mRNA expression in patients with active ITP compared with those in remission and those of the control group, with no significant difference between the latter groups. In terms of BAFF-R expression, we found no significant difference between patients in activity and those in remission. In agreement, elevated levels of plasma BAFF and BAFF mRNA were reported in active ITP patients in comparison with those in remission and controls, with no significant difference between the latter groups 1, 29, 30. Although Zhou et al. 17 reported a tendency of higher BAFF serum levels in the active ITP group compared with the remission group, this was not statistically significant. A review of their study indicated that only six ITP patients were in remission; this small sample number could partially be responsible for this statistical insignificance. To the best of our knowledge, analysis of BAFF-R expression according to different disease phases (activity vs. remission) has not been reported before in the literature.

This study showed that children had a significantly lower mean BAFF expression level compared with adults with ITP. No significant difference was found when children’s mean BAFF-R expression level was compared with adults’ level. On review of the literature, we could not find reports that were in agreement with or in contrast to our results as the majority of studies that analyzed BAFF and/or BAFF-R expression in ITP were carried out on adult patients, and even when children were included, as in Zhou et al. 17, they were not compared with adults in terms of the BAFF or BAFF-R expression level.

We found a tendency for BAFF expression to be lower in steroid-treated patients compared with untreated patients; however, this was not statistically significant. Emmerich et al. 1 and Zhu et al. 31 reported that BAFF serum and mRNA levels in patients with untreated ITP were significantly higher than those in patients receiving immune-suppressive treatment and in healthy individuals. Reviewing their studies, Emmerich et al. 1 reported that BAFF suppression was secondary to a treatment strategy that involved the administration of glucocorticoids, methotrexate, and azathioprine, and proposed that the transcriptional downregulation of BAFF represents a novel mechanism by which these substances exert their therapeutic effects. Zhu et al. 31 evaluated BAFF expression at the end of the second week after the administration of high-dose dexamethasone (HD-DXM, 40 mg/day). It is worth noting here that HD-DXM has been reported to have a higher response rate than conventional prednisone doses in the treatment of ITP patients 32,33. To our knowledge, multiagent therapy and the HD-DXM protocol might be responsible for the potentiated effect on downregulation of BAFF in treated ITP patients included in these studies. Unexpectedly, we found a significantly higher BAFF-R expression in steroid-treated patients compared with the untreated patient group; no data were found in the literature in terms of this. We propose that the expression of BAFF-R on a subset of lymphocytes may confer these cells with resistance to the well-established steroid-induced lymphopenia; further researches are required to elucidate the mechanism of BAFF-R resistance to the downregulatory effect of steroid administration.

We found no statistically significant difference between acute and chronic ITP patients or between nonresponders, partial responders, and complete responders of ITP groups (after a follow-up period) when these groups were compared in terms of BAFF or BAFF-R expression levels. Zhou et al. 17 reported the same finding for acute and chronic ITP groups.

We found a significant positive correlation between BAFF and BAFF-R mRNA expression levels in ITP patients. However, Zhou et al. 17 found this positive correlation between BAFF and BAFF-R in splenic mononuclear cells, but not in peripheral blood mononuclear cells of untreated ITP patients. In disagreement with Zhou et al. 17, this study found a positive correlation between BAFF expression and the median age of patients at the time of sampling and at diagnosis. The current study found no association between BAFF or BAFF-R expression level and different clinical or hematological variables including the platelet count in any phase of the study. In agreement, no significant correlation was found between BAFF expression and platelet count as reported by several studies 17, 30, 31, 34. Zhou et al. 17 found the same for BAFF-R.

The cellular source of excess BAFF remains unknown. A local production was suggested by the observation of accumulated BAFF in the synovial fluid of patients with RA 15. BAFF was found to be highly expressed in the salivary glands of SLE patients 35. In accordance with this, Zhou et al. 17 reported upregulated BAFF expression in splenic mononuclear cells of ITP patients, and as ITP can be treated effectively by splenectomy, it is tempting to speculate that BAFF is primarily produced by a cell population homing in the spleen.

Approximately 60% of adult ITP patients develop therapy-refractory chronic disease within 12 months 36. This indicates the need for the development of novel therapeutic strategies. It is now believed that inhibition of BAFF signaling is a potential therapeutic option for the treatment of B-cell-mediated autoimmune conditions. For example, belimumab (Benlysta) is a monoclonal antibody that specifically inhibits the biologic activity of BAFF and is currently being used in clinical trials to treat patients with SLE 37. Alternatively, clinical trials have suggested that the blockade of BAFF by blocking reagents such as TACI-Ig or BAFF-RIg may be an effective therapeutic approach for autoimmune diseases 38. In vivo, the administration of soluble decoy receptors for BAFF effectively decreases disease progression in some autoimmune diseases mouse models, such as SLE 39, RA 40, and Sjögren’s syndrome 41. These evidences show that BAFF may be a potentially new therapeutic target for ITP and other autoimmune diseases.


  Conclusion Top


The current study confirms previous studies indicating that the expressions of BAFF and BAFF-R are elevated in ITP patients. Elevated BAFF expression in patients with active ITP patients indicates its possible role in the pathogenesis of ITP. Hence, selective antagonistic targeting of BAFF or BAFF-R in ITP patients with high levels of BAFF expression might be considered as a novel therapeutic strategy. Still further researches on the BAFF and BAFF-R expression in B and T cells that could be applied on a larger cohort of patients may help elucidate their actual roles in the pathogenesis of ITP.[41]

 
  References Top

1.Emmerich F, Bal G, Barakat A, Milz J, Mühle C, Martinez-Gamboa L, et al. High-level serum B cell activating factor and promoter polymorphisms in patients with idiopathic thrombocytopenic purpura. Br J Haematol. 2007;136:309–314  Back to cited text no. 1
    
2.Cines DB, Blanchette VS. Immune thrombocytopenic purpura. N Engl J Med. 2002;346:995–1008  Back to cited text no. 2
    
3.Koene HR. Critical issues of current and future developments in the treatment of immune thrombocytopenic purpura. Pediatr Blood Cancer. 2006;47:703–705  Back to cited text no. 3
    
4.Semple JW, Milev Y, Cosgrave D, Mody M, Hornstein A, Blanchette V, Freedman J. Differences in serum cytokine levels in acute and chronic autoimmune thrombocytopenic purpura: relationship to platelet phenotype and antiplatelet T-cell reactivity. Blood. 1996;87:4245–4254  Back to cited text no. 4
    
5.Stasi R, Cooper N, Del Poeta G, Stipa E, Laura Evangelista M, Abruzzese E, Amadori S. Analysis of regulatory T-cell changes in patients with idiopathic thrombocytopenic purpura receiving B cell depleting therapy with rituximab. Blood. 2008;112:1147–1150  Back to cited text no. 5
    
6.Zhao CH, Li XF, Zhang F, Wang L, Peng J, Hou M. Increased cytotoxic T-lymphocyte-mediated cytotoxicity predominant in patients with idiopathic thrombocytopenic purpura without platelet autoantibodies. Haematologica. 2008;93:1428–1430  Back to cited text no. 6
    
7.Bossen C, Schneider P. BAFF, APRIL and their receptors: structure, function and signaling. Semin Immunol. 2006;18:263–275  Back to cited text no. 7
    
8.Sutherland AP, Mackay F, Mackay CR. Targeting BAFF: immunomodulation for autoimmune diseases and lymphomas. Pharmacol Ther. 2007;112:774–786  Back to cited text no. 8
    
9.Schiemann B, Gommerman JL, Vora K, Cachero TG, Shulga-Morskaya S, Dobles M, et al. An essential role for BAFF in the normal development of B cells through a BCMA-independent pathway. Science. 2001;293:2111–2114  Back to cited text no. 9
    
10.Thien M, Phan TG, Gardam S, Amesbury M, Basten A, Mackay F, Brink R. Excess BAFF rescues self-reactive B cells from peripheral deletion and allows them to enter forbidden follicular and marginal zone niches. Immunity. 2004;20:785–798  Back to cited text no. 10
    
11.Mackay F, Woodcock SA, Lawton P, Ambrose C, Baetscher M, Schneider P, et al. Mice transgenic for BAFF develop lymphocytic disorders along with autoimmune manifestations. J Exp Med. 1999;190:1697–1710  Back to cited text no. 11
    
12.Yu H, Liu Y, Hou M. BAFF – an essential survival factor for B cells: links to genesis of ITP and may be of therapeutic target. Med Hypotheses. 2008;70:40–42  Back to cited text no. 12
    
13.Rodig SJ, Shahsafaei A, Li B, Mackay CR, Dorfman DM. BAFF-R, the major B-cell-activating factor receptor, is expressed on most mature B cells and B-cell lymphoproliferative disorders. Hum Pathol. 2005;36:1113–1119  Back to cited text no. 13
    
14.Treml JF, Hao Y, Stadanlick JE, Cancro MP. The BLyS family: toward a molecular understanding of B cell homeostasis. Cell Biochem Biophys. 2009;53:1–16  Back to cited text no. 14
    
15.Cheema GS, Roschke V, Hilbert DM, Stohl W. Elevated serum B lymphocyte stimulator levels in patients with systemic immune-based rheumatic diseases. Arthritis Rheum. 2001;44:1313–1319  Back to cited text no. 15
    
16.Warnatz K, Salzer U, Rizzi M, Fischer B, Gutenberger S, Böhm J, et al. B-cell activating factor receptor deficiency is associated with an adult-onset antibody deficiency syndrome in humans. Proc Natl Acad Sci USA. 2009;106:13945–13950  Back to cited text no. 16
    
17.Zhou Z, Chen Z, Li H, Chen X, Xu J, Gu D, et al. BAFF and BAFF-R of peripheral blood and spleen mononuclear cells in idiopathic thrombocytopenic purpura. Autoimmunity. 2009;42:112–119  Back to cited text no. 17
    
18.Zhou Z, Li X, Li J, Su C, Zhuang L, Luo S, Zhang L. Direct B-cell stimulation by peripheral blood monocyte-derived dendritic cells in idiopathic thrombocytopenic purpura patients. J Clin Immunol. 2010;30:814–822  Back to cited text no. 18
    
19.Neunert C, Lim W, Crowther M, Cohen A, Solberg L, Crowther M. The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. Blood. 2011;117:4190–4207  Back to cited text no. 19
    
20.. Guidelines for the investigation and management of idiopathic thrombocytopenic purpura in adults, children and in pregnancy. Br J Haematol. 2003;120:574–596  Back to cited text no. 20
    
21.Rodeghiero F, Stasi R, Gernsheimer T, Michel M, Provan D, Arnold D, et al. Standardization of terminology, definitions and outcome criteria immune thrombocytopenic purpura of adults and children: report from in an international working group. Blood. 2009;113:2386–2393  Back to cited text no. 21
    
22.Zhou B, Zhao H, Yang RC, Han ZC. Multi-dysfunctional pathophysiology in ITP. Crit Rev Oncol Hematol. 2005;54:107–116  Back to cited text no. 22
    
23.Ju S, Zhang D, Wang Y, Ni H, Kong X, Zhong R. Correlation of the expression levels of BLyS and its receptors mRNA in patients with systemic lupus erythematosus. Clin Biochem. 2006;39:1131–1137  Back to cited text no. 23
    
24.Yang Q, Xu S, Li X, et al. 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;6:e22708  Back to cited text no. 24
    
25.Nakajima K, Itoh K, Nagatani K, et al. Expression of BAFF and BAFF-R in the synovial tissue of patients with rheumatoid arthritis. Scand J Rheumatol. 2007;36:365–372  Back to cited text no. 25
    
26.Carter RH, Zhao H, Liu X, et al. Expression and occupancy of BAFF-R on B cells in systemic lupus erythematosus. Arthritis Rheum. 2005;52:3943–3954  Back to cited text no. 26
    
27.Sellam J, Miceli-Richard C, Gottenberg JE, Ittah M, Lavie F, Lacabaratz C, et al. Decreased B cell activating factor receptor expression on peripheral lymphocytes associated with increased disease activity in primary Sjögren’s syndrome and systemic lupus erythematosus. Ann Rheum Dis. 2007;66:790–797  Back to cited text no. 27
    
28.Thangarajh M, Kisiswa L, Pirskanen R, Hillert J. The expression of BAFF-binding receptors is not altered in multiple sclerosis or myasthenia gravis. Scand J Immunol. 2007;65:461–466  Back to cited text no. 28
    
29.Zhu XJ, Shi Y, Peng J, Guo CS, Shan NN, Qin P, et al. The effects of BAFF and BAFF-R-Fc fusion protein in immune thrombocytopenia. Blood. 2009a;114:5362–5367  Back to cited text no. 29
    
30. The effects of B cell activating factor in immune thrombocytopenia. Available at: http://www.Medical Research. [Accessed 10 December 2011]  Back to cited text no. 30
    
31.Zhu XJ, Shi Y, Sun JZ, Shan NN, Peng J, Guo CS, et al. High-Dose Dexamethasone inhibits BAFF expression in patients with immune thrombocytopenia. J Clin Immunol. 2009b;29:603–610  Back to cited text no. 31
    
32.Cheng Y, Wong R, Soo Y, Chui C, Lau F, Chan N, et al. Initial treatment of immune thrombocytopenic purpura with high dose dexamethasone. N Engl J Med. 2003;349:831–836  Back to cited text no. 32
    
33.Mazzucconi MG, Fazi P, Bernasconi S, De Rossi G, Leone G, Gugliotta L, et al. Therapy with high-dose dexamethasone (HDDXM) in previously untreated patients affected by idiopathic thrombocytopenic purpura: a GIMEMA experience. Blood. 2007;109:1402–1407  Back to cited text no. 33
    
34.Yujiri T, Tanaka Y, Tanaka M, Takahashi T, Tanizawa Y. Alteration in serum B cell-activating factor levels in patients with idiopathic thrombocytopenic purpura after Helicobacter pylori eradication therapy. Br J Haematol. 2010;152:492–502  Back to cited text no. 34
    
35.Groom J, Kalled SL, Cutler AH, Olson C, Woodcock SA, Schneider P, et al. Association of BAFF/BLyS overexpression and altered B cell differentiation with Sjogren’s syndrome. J Clin Invest. 2002;109:59–68  Back to cited text no. 35
    
36.Godeau B, Chevret S, Varet B, Lefrère F, Zini JM, Bassompierre F, et al. Intravenous immunoglobulin or high-dose methylprednisolone, with or without oral prednisone, for adults with untreated severe autoimmune thrombocytopenic purpura: a randomised, multicentre trial. Lancet. 2002;359:23–29  Back to cited text no. 36
    
37. HGSI and GSK Joint Press Release. Human Genome Sciences and GlaxoSmithKline announce full presentation at ACR of positive phase 3 study results for BENLYSTA in systemic lupus erythematosus. 2009. Available at: http://www.pressreleasepoint.com/human-genome-sciences-and-glaxosmithklineannounce-positive-results-second-two-phase-3-trials-benlys [Accessed 10 December 2011]  Back to cited text no. 37
    
38.Mackay F, Browning JL. BAFF: a fundamental survival factor for B cells. Nat Rev Immunol. 2002;2:465–475  Back to cited text no. 38
    
39.Sabahi R, Anolik JH. B-cell-targeted therapy for systemic lupus erythematosus. Drugs. 2006;66:1933–1948  Back to cited text no. 39
    
40.Bosello S, Pers JO, Rochas C, Devauchelle V, De Santis M, Daridon C, et al. BAFF and rheumatic autoimmune disorders: implications for disease management and therapy. Int J Immunopathol Pharmacol. 2007;20:1–8  Back to cited text no. 40
    
41.Szodoray P, Jonsson R. The BAFF/APRIL system in systemic autoimmune diseases with a special emphasis on Sjogren’s syndrome. Scand J Immunol. 2005;62:421–428  Back to cited text no. 41
    


    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2]



 

Top
 
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

 
  In this article
Abstract
Introduction
Patients and methods
Results
Discussion
Conclusion
Introduction
Patients and methods
Results
Discussion
Conclusion
References
Article Figures
Article Tables

 Article Access Statistics
    Viewed892    
    Printed30    
    Emailed0    
    PDF Downloaded93    
    Comments [Add]    

Recommend this journal


[TAG2]
[TAG3]
[TAG4]