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IVIG regulates BAFF expression in patients with chronic inflammatory demyelinating polyneuropathy (CIDP)
Journal of Neuroimmunology 274 (2014) 225–229
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IVIG regulates BAFF expression in patients with chronic inflammatory demyelinating polyneuropathy (CIDP) Christian Ritter a,c, Dominik Förster b, Philipp Albrecht b, Hans-Peter Hartung b, Bernd C. Kieseier b, Helmar C. Lehmann a,⁎ a b c
Dept. of Neurology and Center of Molecular Medicine Cologne, University of Cologne, Kerpenerstr. 62, D-50937 Cologne, Germany Department of Neurology, Medical Faculty, Heinrich-Heine University Düsseldorf, D-40225 Düsseldorf, Germany Institut for Neuroscience und Medicin (INM-3), Forschungszentrum Jülich, Wilhelm-Johnen-Str., D-52428 Jülich, Germany
a r t i c l e
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Article history: Received 26 February 2014 Received in revised form 10 June 2014 Accepted 12 June 2014 Keywords: B-cell activating factor CIDP Immune neuropathy Cytokine Therapy Treatment
a b s t r a c t Recent studies indicate that the cytokine B-cell activating factor (BAFF) is involved in the pathogenesis of chronic inflammatory demyelinating polyneuropathy (CIDP). Intravenous immunoglobulin (IVIg) is standard treatment for CIDP and is known to rapidly modulate increased serum levels of pro-inflammatory cytokines. We evaluated the expression profile of BAFF and its corresponding BAFF-receptor in samples from CIDP patients, focusing on rapid changes before and after IVIg treatment. In CIDP patients BAFF serum concentrations were elevated compared to controls. Treatment with high-dose IVIg restored those elevated BAFF serum levels. Whereas treatment with IVIg did not affect BAFF production in monocytes, antibodies against BAFF could be detected in IVIg preparations, which may explain the short-term decrease of BAFF levels after IVIg treatment. Our data suggest that BAFF plays an important role in the pathogenesis of CIDP and may serve as marker for IVIg treatment response. © 2014 Elsevier B.V. All rights reserved.
1. Introduction Chronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired inflammatory peripheral neuropathy characterized by endoneural inflammation, demyelination and secondary axonal loss (Lewis, 2005; Vallat et al., 2010; Kieseier et al., 2012). Current pathogenetic concepts assume that CIDP is caused by an aberrant immune response involving autoreactive T-cells and B-cells, macrophages and soluble factors including autoantibodies, inflammatory cytokines and chemokines (Koller et al., 2005; Nobile-Orazio et al., 2010; Dalakas, 2011). Intravenous immunoglobulin (IVIg) is a mainstay in the treatment of CIDP and several studies demonstrated short- and long-term efficacy of this treatment (Hughes et al., 2008; Eftimov et al., 2013; Lehmann et al., 2013). IVIg has various modes of action. Generally, Fc-dependent mechanisms, e.g. Fc-receptor blockage or modulation of Fcy receptor expression, can be distinguished from F(ab)2-dependent mechanisms including regulation of T-cell and B-cell activation, binding of
⁎ Corresponding author at: Department of Neurology and Center of Molecular Medicine Cologne, University Hospital Cologne, Germany. Tel.: +49 221 478 087091; fax: +49 221 487 87306. E-mail address: [email protected] (H.C. Lehmann).
http://dx.doi.org/10.1016/j.jneuroim.2014.06.007 0165-5728/© 2014 Elsevier B.V. All rights reserved.
pathological autoantibodies by anti-idiotypic antibodies and neutralization of complement (Creange et al., 2003; Mata et al., 2006; Hartung, 2008; Nimmerjahn and Ravetch, 2008; Lehmann and Hartung, 2011; Buttmann et al., 2013). IVIg lowers also substantially increased levels of inflammatory cytokines either by modulating their expression in circulating mononuclear cells or via naturally occurring antibodies that are present in IVIg (Vani et al., 2008; Lehmann and Hartung, 2011; Kaveri, 2012). Apart from long-term modulation there is also evidence that IVIg has immediate effects on cytokine expression. These lead to measurable changes in cytokine levels in serum from patients with autoimmune diseases immediately after infusion of IVIg (Ling et al., 1993; Sewell et al., 1999; Reinhold et al., 2004; Rissmann et al., 2009). The cytokine B-cell activating factor (BAFF) plays an important role in the survival and maturation of B-cells and T-cells (Moore et al., 1999; Schneider et al., 1999; Ng et al., 2004; Mackay and Leung, 2006; Yoshimoto et al., 2006; Dalakas, 2008). An excess of BAFF production results in prolonged survival of autoreactive B-cells and subsequent breakdown of B-cell tolerance in animal models (Mackay et al., 1999; Schneider et al., 1999; Groom et al., 2002; Thien et al., 2004). In humans, elevated BAFF levels have been found in a variety of autoimmune disorders, including systemic lupus erythematosus, Kawasaki disease, myasthenia gravis and idiopathic inflammatory myopathies (Zhang et al., 2001; Thangarajh et al., 2006; Kim et al., 2008; Fuhlhuber et al., 2009;
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Krystufkova et al., 2009; Vincent et al., 2011; Baek et al., 2012). Recently it was also reported that in CIDP, serum BAFF levels are elevated and treatment with IVIg resulted in a decrease of BAFF production in monocytes from CIDP patients (Bick et al., 2013). Because of the broad implications of those findings for the pathogenesis and for the further development of potential biomarkers for diagnosis and treatment response in CIDP, we reassessed the expression profile of BAFF and its corresponding receptor (BAFF receptor, BAFF-R) in a cohort of CIDP patients focusing on short-term changes during IVIg maintenance treatment.
measured using a commercially available sandwich-enzyme-linked immunoassay kit (Quantikine BAFF ELISA; R&D Systems) according to the manufacturer's protocol. Briefly, sera and standards were incubated in the antibody-coated microtiter plate for 2 h at room temperature (RT). BAFF/BLyS (or APRIL, respectively) conjugate was added and incubated for 2 h at RT. After washing, the substrate solution was added and incubated for 30 min at RT in the dark. The reaction was stopped with sulfuric acid. Optical density (OD) was measured within 30 min at 450 nm with 650 nm as reference. All measurements were performed in duplicate.
2. Patients & methods
2.3. Flow cytometry
2.1. Patients
PBMCs of a subset of patients (n = 14) were isolated using BD Vacutainer CPT (BD Bioscience). According to the manufacturer's protocol, blood samples were centrifuged (1500 g, 20 min) and mononuclear cell layer was collected. PBMCs were stored immediately at − 80 °C until further use. For flow cytometry analysis, PMBCs were washed with PBS. For intracellular and membrane-bound BAFF staining, cells were permeabilized using Cytofix/Cytoperm (Becton Dickinson) and stained with anti-BAFF and anti-BAFF-R (eBioscience) for 20 min at 4 °C in the dark. Then, cells were stained with anti-CD3, anti-CD14 and anti-CD20 antibodies (eBioscience). Staining of PBMC was analyzed using a FACSCalibur using CellQuest® software (BD Biosciences). Flow cytometry experiments were conducted with isotype controls for cell type, time point and stimulus to exclude unspecific binding effects of IVIg to Fc receptors. Data analysis was performed with the FlowJo software (Tree Star, Ashland, OR). All values were given as delta geometric means.
Twenty-three patients with CIDP (mean age 64.4 ± 11.8, 11 females, 12 males) were included in the study (Table 1). All patients were diagnosed according to diagnostic criteria developed by the Peripheral Nerve Society (PNS, 2005). All patients were on maintenance therapy with IVIg without additional immunosuppressant medication and received a standard dose of either 1 g/kg (n = 18) or 0.4 g/kg (n = 5) bodyweight (BW) IVIg with an infusion rate of around 15 g per hour. Blood was obtained immediately before and 30 min after IVIg infusion. All patients underwent a detailed clinical workup prior to the IVIg infusion which also included assessment of the MRC sum score and the INCAT disability score as previously described (Hughes, 2001). In addition serum was measured from 14 control patients (mean age 64.7 ± 12.7, 6 females, 8 males). These included patients with neurological diseases other than CIDP, myasthenia gravis and idiopathic inflammatory myopathies (mild cognitive impairment; peripheral facial nerve paralysis; multiple sclerosis; subarachnoid hemorrhage; radiculopathy; normal pressure hydrocephalus). The study was approved by the local ethics committee and all patients gave written informed consent. 2.2. Detection of soluble BAFF and APRIL by ELISA Blood samples of patients were centrifuged (2000 g, 15 min) and the serum was stored at − 80 °C until further use. The concentration of the cytokines BAFF and APRIL (a proliferation-inducing ligand) was Table 1 Clinical characteristics from CIDP patients with the INCAT disability score, MRC sum score, and duration of IVIg treatment. Pat
Sex
Age
MRC-SS
INCAT score
IVIg doses (g/kg BW)
IVIg treatment duration (month)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
F F M F F F M F F M M F M M M M M M M F F M F
71 53 72 69 63 65 61 67 74 80 41 76 75 65 67 61 76 51 62 78 77 68 73
60 56 59 60 56 60 42 60 58 60 56 60 60 60 54 58 58 52 58 58 53 58 58
0 2 0 0 1 1 6 1 1 1 2 1 1 1 1 1 2 2 1 1 2 0 1
1 1 1 1 1 0.4 1 1 1 1 1 0.4 1 1 1 1 0.4 0.4 1 1 1 1 0.4
2 12 4 8 9 4 3 4 30 4 4 15 7 16 3 36 23 18 3 3 10 3 25
2.4. Detection of anti-BAFF IgG by ELISA Commercial ELISA plates (Sigma Aldrich) were coated with human recombinant BAFF (Millipore). BAFF coated microtiter plates were blocked with 1%-BSA solution for 2 h at 4 °C. After clearing the BSAsolution, IVIg was added at different concentrations and incubated overnight at 4 °C. After washing with TWEEN-20 washing buffer, peroxidase conjugated anti-human IgG was added and incubated for 2 h at 4 °C. After another washing OPD-solution (Sigma Aldrich) was added according to the manufacturer's instructions and incubated for 30 min at RT. Finally, the stop solution was added and optical density (OD) was measured within 30 min at 492 nm. Measurements were performed in duplicate. 2.5. Statistical analysis Differences between serum samples and cell samples before and after treatment were analyzed by a t-test (two groups) and data were checked for normality using the Kolmogorov–Smirnov test. The nonparametric Spearman correlation test (Graph Pad Prism Software) was used for correlation with the ordinal scaled clinical parameters. A p b 0.05 was considered to be statistically significant. Given the exploratory approach of our study we did not perform a correction for multiple testing of the different cellular fractions during the primary data analysis. 3. Results 3.1. Elevated BAFF serum levels in CIDP patients We analyzed BAFF serum levels in 23 CIDP patients compared to 14 controls. Serum levels of BAFF were significantly elevated in CIDP patients (mean BAFF serum concentration: CIDP: 1381.0 ± 134.5 pg/ml; HC: 761.3 ± 201.3 pg/ml, Fig. 1A) and correlated with disease severity as measured by the INCAT disability score and the MRC sum score (Fig. 1B–C). One CIDP patient (number 7) who suffered from a severe
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Fig. 1. BAFF serum levels in CIDP patients and controls. (A) BAFF serum levels are significantly increased in CIDP patients (n = 23) compared to controls group (n = 14). (B) BAFF serum levels are correlated to CIDP disease severity measured via the INCAT disability score and the MRC sum score (C). (D) BAFF serum levels significantly decrease immediately after IVIg treatment (95% CI for 1 g/kg BW IVIg: −495.8 to −180.8). (E) APRIL serum levels significantly increase after IVIg application. Data is presented as mean values (*p b 0.05; **p b 0.01; ***p b 0.001).
disease course, showed excessive BAFF serum levels. Excluding the patient's values from statistical analysis annihilates the significant correlation of BAFF serum levels and disease severity (rs correlation coefficient: INCATds: 0.022; MRC-SS: 0.01; p-value: INCATds: 0.4758; MRC-SS: 0.9772). CIDP patients receiving 1 g/kg BW showed a significant decrease of BAFF serum levels comparing pre- and post-IVIg treatment whereas patients receiving 0.4 g/kg BW showed a non significant decrease of BAFF serum levels (Fig. 1D). To exclude dilution effects we also measured serum levels of the B cell stimulating cytokine APRIL. As shown in Fig. 1E APRIL serum levels were elevated after IVIg infusion.
p b 0.05). No changes were observed on CD20+ cells (dGMean, pre-, post-IVIg: CD20+: 220.5 ± 134.6, 218.5 ± 128.4) (Fig. 2D–E). 3.3. IVIg contains anti-BAFF IgG Since our flow cytometry analyses indicate that the short-term decrease of serum BAFF levels could not be explained by reduced BAFF production on CD14+ monocytes, we investigated the presence of antibodies against BAFF in the IVIg preparations. As shown in Fig. 3, IVIg contained anti-BAFF antibodies as detected with ELISA against BAFF (Fig. 3).
3.2. Short-term BAFF and BAFF-R modulation after IVIg treatment
4. Discussion
Because elevated BAFF serum levels significantly decreased after high dose IVIg treatment in CIPD patients, we further analyzed the production of BAFF and the expression of its corresponding receptor in PBMC before and after IVIg infusion. Intracellular and membranebound BAFF remained unchanged in CD3+ T-cells, CD20+ B-cells and CD14+ monocytes (dGMean, pre-, post-IVIg: CD3+: 1.4 ± 1.2, 1.1 ± 1.1; CD20+: 71.3 ± 126.9, 76.3 ± 140.7; CD14+: 14.2 ± 13.3, 21.4 ± 20.4) (Fig. 2A–C). In contrast, a significant decrease of membrane BAFF-R expression on CD3+ cells could be detected immediately after IVIg treatment (dGMean, pre-, post-IVIg: 0.24 ± 0.11, 0.16 ± 0.13,
Our study demonstrates that BAFF levels are increased in serum from CIDP patients. In humans, BAFF is considered to be a master regulatory cytokine for B-cell homeostasis and BAFF serum levels are increased in a variety of B-cell related autoimmune disorders including systemic lupus erythematosus (Zhang et al., 2001; Pers et al., 2005; Vincent et al., 2011, 2012), rheumatoid arthritis (Cheema et al., 2001; Leandro and Cambridge, 2013), myasthenia gravis (Thangarajh et al., 2006; Kim et al., 2008) and idiopathic inflammatory myopathies (Fuhlhuber et al., 2009; Krystufkova et al., 2009; Baek et al., 2012). More recently,
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Fig. 2. Effects of IVIg treatment on PBMCs (n = 14). No short-term changes of intracellular and membrane-bound BAFF expression in CD3+ T cells (A), CD20+ B cells (B) and CD14+ monocytes (C). Significant decrease of BAFF-R on CD3+ T cells (D) and no effect of IVIg on BAFF-R expression on CD20+ B cells (E). Data is indicated as means ± SD (p b 0.05; **p b 0.01; ***p b 0.001).
Bick and colleagues also reported increased BAFF serum levels in a cohort of ten patients with newly diagnosed CIDP, compared to patients with non-inflammatory polyneuropathy and healthy controls (Bick et al., 2013). In our study we could reproduce this finding in a larger cohort of CIDP patients. In addition our observation of the association of higher BAFF serum levels with more severe neurological deficits as assessed by INCAT and MRC sum scores may indicate that BAFF serum levels could serve as a surrogate parameter for disease activity in CIDP
Fig. 3. IgG from commercial IVIg preparation binds to BAFF. Data is indicated as means ± SD of optical density (OD).
patients. However, since the statistical significance of this correlation depends on a considerably outlying value of one patient, larger studies with more severely affected patients are warranted to validate this finding. The slightly higher absolute values for BAFF measured in our study can be explained by methodological differences or higher disease activity in our cohort compared to the CIDP patients examined in the study by Bick and colleagues. We further observed that treatment of CIDP patients with IVIg resulted in a rapid decrease of BAFF serum levels. Our data thereby complement previous observations that BAFF is modulated by IVIg treatment in CIDP patients (Bick et al., 2013). In contrast to the aforementioned study that determined changes of BAFF serum levels after five days of IVIg treatment, we focused on rapid alterations of BAFF serum levels immediately before and after IVIg infusion. We chose this paradigm because IVIg is known to alter the expression of cytokines such as TNF-α, IL-2, IL-6, IL-8 and TGF-β over very short time periods, i.e. several hours after infusion (Ling et al., 1993; Sewell et al., 1999; Reinhold et al., 2004; Rissmann et al., 2009). Decreased BAFF levels after IVIg infusion could be explained either by altered BAFF production or by anti-BAFF-antibodies that are present in IVIg preparations. Our finding that IVIg binds to recombinant BAFF antigen suggests that IVIg contains anti-BAFF antibodies. It is in line with previous studies characterizing the nature of anti-BAFF antibodies in IVIg preparations in greater detail (Le Pottier et al., 2007). In contrast, we did not observe short-term effects of IVIg on intracellular and
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membrane bound BAFF on CD14+ monocytes, the predominant cellular source of BAFF (Nardelli et al., 2001; Vincent et al., 2013), which argues against substantial alteration of cellular BAFF production during the short time interval of IVIg infusion. Further analysis of PBMC before and after IVIg infusion did not reveal significant differences regarding expression of BAFF and BAFF-R, except for CD3+ T-cells that displayed less BAFF-R upon IVIg infusion. It may point to an additional immunomodulatory effect of IVIg on T-cells, since BAFF also influences T-cell survival through binding to BAFF-R (Ng et al., 2004). In summary our study provides further evidence that CIDP is associated with increased levels of BAFF. Furthermore, treatment with IVIg may rapidly restore those pathologically elevated BAFF serum levels. 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IVIG regulates BAFF expression in patients with chronic inflammatory demyelinating polyneuropathy (CIDP) Christian Ritter a,c, Dominik Förster b, Philipp Albrecht b, Hans-Peter Hartung b, Bernd C. Kieseier b, Helmar C. Lehmann a,⁎ a b c
Dept. of Neurology and Center of Molecular Medicine Cologne, University of Cologne, Kerpenerstr. 62, D-50937 Cologne, Germany Department of Neurology, Medical Faculty, Heinrich-Heine University Düsseldorf, D-40225 Düsseldorf, Germany Institut for Neuroscience und Medicin (INM-3), Forschungszentrum Jülich, Wilhelm-Johnen-Str., D-52428 Jülich, Germany
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Article history: Received 26 February 2014 Received in revised form 10 June 2014 Accepted 12 June 2014 Keywords: B-cell activating factor CIDP Immune neuropathy Cytokine Therapy Treatment
a b s t r a c t Recent studies indicate that the cytokine B-cell activating factor (BAFF) is involved in the pathogenesis of chronic inflammatory demyelinating polyneuropathy (CIDP). Intravenous immunoglobulin (IVIg) is standard treatment for CIDP and is known to rapidly modulate increased serum levels of pro-inflammatory cytokines. We evaluated the expression profile of BAFF and its corresponding BAFF-receptor in samples from CIDP patients, focusing on rapid changes before and after IVIg treatment. In CIDP patients BAFF serum concentrations were elevated compared to controls. Treatment with high-dose IVIg restored those elevated BAFF serum levels. Whereas treatment with IVIg did not affect BAFF production in monocytes, antibodies against BAFF could be detected in IVIg preparations, which may explain the short-term decrease of BAFF levels after IVIg treatment. Our data suggest that BAFF plays an important role in the pathogenesis of CIDP and may serve as marker for IVIg treatment response. © 2014 Elsevier B.V. All rights reserved.
1. Introduction Chronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired inflammatory peripheral neuropathy characterized by endoneural inflammation, demyelination and secondary axonal loss (Lewis, 2005; Vallat et al., 2010; Kieseier et al., 2012). Current pathogenetic concepts assume that CIDP is caused by an aberrant immune response involving autoreactive T-cells and B-cells, macrophages and soluble factors including autoantibodies, inflammatory cytokines and chemokines (Koller et al., 2005; Nobile-Orazio et al., 2010; Dalakas, 2011). Intravenous immunoglobulin (IVIg) is a mainstay in the treatment of CIDP and several studies demonstrated short- and long-term efficacy of this treatment (Hughes et al., 2008; Eftimov et al., 2013; Lehmann et al., 2013). IVIg has various modes of action. Generally, Fc-dependent mechanisms, e.g. Fc-receptor blockage or modulation of Fcy receptor expression, can be distinguished from F(ab)2-dependent mechanisms including regulation of T-cell and B-cell activation, binding of
⁎ Corresponding author at: Department of Neurology and Center of Molecular Medicine Cologne, University Hospital Cologne, Germany. Tel.: +49 221 478 087091; fax: +49 221 487 87306. E-mail address: [email protected] (H.C. Lehmann).
http://dx.doi.org/10.1016/j.jneuroim.2014.06.007 0165-5728/© 2014 Elsevier B.V. All rights reserved.
pathological autoantibodies by anti-idiotypic antibodies and neutralization of complement (Creange et al., 2003; Mata et al., 2006; Hartung, 2008; Nimmerjahn and Ravetch, 2008; Lehmann and Hartung, 2011; Buttmann et al., 2013). IVIg lowers also substantially increased levels of inflammatory cytokines either by modulating their expression in circulating mononuclear cells or via naturally occurring antibodies that are present in IVIg (Vani et al., 2008; Lehmann and Hartung, 2011; Kaveri, 2012). Apart from long-term modulation there is also evidence that IVIg has immediate effects on cytokine expression. These lead to measurable changes in cytokine levels in serum from patients with autoimmune diseases immediately after infusion of IVIg (Ling et al., 1993; Sewell et al., 1999; Reinhold et al., 2004; Rissmann et al., 2009). The cytokine B-cell activating factor (BAFF) plays an important role in the survival and maturation of B-cells and T-cells (Moore et al., 1999; Schneider et al., 1999; Ng et al., 2004; Mackay and Leung, 2006; Yoshimoto et al., 2006; Dalakas, 2008). An excess of BAFF production results in prolonged survival of autoreactive B-cells and subsequent breakdown of B-cell tolerance in animal models (Mackay et al., 1999; Schneider et al., 1999; Groom et al., 2002; Thien et al., 2004). In humans, elevated BAFF levels have been found in a variety of autoimmune disorders, including systemic lupus erythematosus, Kawasaki disease, myasthenia gravis and idiopathic inflammatory myopathies (Zhang et al., 2001; Thangarajh et al., 2006; Kim et al., 2008; Fuhlhuber et al., 2009;
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Krystufkova et al., 2009; Vincent et al., 2011; Baek et al., 2012). Recently it was also reported that in CIDP, serum BAFF levels are elevated and treatment with IVIg resulted in a decrease of BAFF production in monocytes from CIDP patients (Bick et al., 2013). Because of the broad implications of those findings for the pathogenesis and for the further development of potential biomarkers for diagnosis and treatment response in CIDP, we reassessed the expression profile of BAFF and its corresponding receptor (BAFF receptor, BAFF-R) in a cohort of CIDP patients focusing on short-term changes during IVIg maintenance treatment.
measured using a commercially available sandwich-enzyme-linked immunoassay kit (Quantikine BAFF ELISA; R&D Systems) according to the manufacturer's protocol. Briefly, sera and standards were incubated in the antibody-coated microtiter plate for 2 h at room temperature (RT). BAFF/BLyS (or APRIL, respectively) conjugate was added and incubated for 2 h at RT. After washing, the substrate solution was added and incubated for 30 min at RT in the dark. The reaction was stopped with sulfuric acid. Optical density (OD) was measured within 30 min at 450 nm with 650 nm as reference. All measurements were performed in duplicate.
2. Patients & methods
2.3. Flow cytometry
2.1. Patients
PBMCs of a subset of patients (n = 14) were isolated using BD Vacutainer CPT (BD Bioscience). According to the manufacturer's protocol, blood samples were centrifuged (1500 g, 20 min) and mononuclear cell layer was collected. PBMCs were stored immediately at − 80 °C until further use. For flow cytometry analysis, PMBCs were washed with PBS. For intracellular and membrane-bound BAFF staining, cells were permeabilized using Cytofix/Cytoperm (Becton Dickinson) and stained with anti-BAFF and anti-BAFF-R (eBioscience) for 20 min at 4 °C in the dark. Then, cells were stained with anti-CD3, anti-CD14 and anti-CD20 antibodies (eBioscience). Staining of PBMC was analyzed using a FACSCalibur using CellQuest® software (BD Biosciences). Flow cytometry experiments were conducted with isotype controls for cell type, time point and stimulus to exclude unspecific binding effects of IVIg to Fc receptors. Data analysis was performed with the FlowJo software (Tree Star, Ashland, OR). All values were given as delta geometric means.
Twenty-three patients with CIDP (mean age 64.4 ± 11.8, 11 females, 12 males) were included in the study (Table 1). All patients were diagnosed according to diagnostic criteria developed by the Peripheral Nerve Society (PNS, 2005). All patients were on maintenance therapy with IVIg without additional immunosuppressant medication and received a standard dose of either 1 g/kg (n = 18) or 0.4 g/kg (n = 5) bodyweight (BW) IVIg with an infusion rate of around 15 g per hour. Blood was obtained immediately before and 30 min after IVIg infusion. All patients underwent a detailed clinical workup prior to the IVIg infusion which also included assessment of the MRC sum score and the INCAT disability score as previously described (Hughes, 2001). In addition serum was measured from 14 control patients (mean age 64.7 ± 12.7, 6 females, 8 males). These included patients with neurological diseases other than CIDP, myasthenia gravis and idiopathic inflammatory myopathies (mild cognitive impairment; peripheral facial nerve paralysis; multiple sclerosis; subarachnoid hemorrhage; radiculopathy; normal pressure hydrocephalus). The study was approved by the local ethics committee and all patients gave written informed consent. 2.2. Detection of soluble BAFF and APRIL by ELISA Blood samples of patients were centrifuged (2000 g, 15 min) and the serum was stored at − 80 °C until further use. The concentration of the cytokines BAFF and APRIL (a proliferation-inducing ligand) was Table 1 Clinical characteristics from CIDP patients with the INCAT disability score, MRC sum score, and duration of IVIg treatment. Pat
Sex
Age
MRC-SS
INCAT score
IVIg doses (g/kg BW)
IVIg treatment duration (month)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
F F M F F F M F F M M F M M M M M M M F F M F
71 53 72 69 63 65 61 67 74 80 41 76 75 65 67 61 76 51 62 78 77 68 73
60 56 59 60 56 60 42 60 58 60 56 60 60 60 54 58 58 52 58 58 53 58 58
0 2 0 0 1 1 6 1 1 1 2 1 1 1 1 1 2 2 1 1 2 0 1
1 1 1 1 1 0.4 1 1 1 1 1 0.4 1 1 1 1 0.4 0.4 1 1 1 1 0.4
2 12 4 8 9 4 3 4 30 4 4 15 7 16 3 36 23 18 3 3 10 3 25
2.4. Detection of anti-BAFF IgG by ELISA Commercial ELISA plates (Sigma Aldrich) were coated with human recombinant BAFF (Millipore). BAFF coated microtiter plates were blocked with 1%-BSA solution for 2 h at 4 °C. After clearing the BSAsolution, IVIg was added at different concentrations and incubated overnight at 4 °C. After washing with TWEEN-20 washing buffer, peroxidase conjugated anti-human IgG was added and incubated for 2 h at 4 °C. After another washing OPD-solution (Sigma Aldrich) was added according to the manufacturer's instructions and incubated for 30 min at RT. Finally, the stop solution was added and optical density (OD) was measured within 30 min at 492 nm. Measurements were performed in duplicate. 2.5. Statistical analysis Differences between serum samples and cell samples before and after treatment were analyzed by a t-test (two groups) and data were checked for normality using the Kolmogorov–Smirnov test. The nonparametric Spearman correlation test (Graph Pad Prism Software) was used for correlation with the ordinal scaled clinical parameters. A p b 0.05 was considered to be statistically significant. Given the exploratory approach of our study we did not perform a correction for multiple testing of the different cellular fractions during the primary data analysis. 3. Results 3.1. Elevated BAFF serum levels in CIDP patients We analyzed BAFF serum levels in 23 CIDP patients compared to 14 controls. Serum levels of BAFF were significantly elevated in CIDP patients (mean BAFF serum concentration: CIDP: 1381.0 ± 134.5 pg/ml; HC: 761.3 ± 201.3 pg/ml, Fig. 1A) and correlated with disease severity as measured by the INCAT disability score and the MRC sum score (Fig. 1B–C). One CIDP patient (number 7) who suffered from a severe
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Fig. 1. BAFF serum levels in CIDP patients and controls. (A) BAFF serum levels are significantly increased in CIDP patients (n = 23) compared to controls group (n = 14). (B) BAFF serum levels are correlated to CIDP disease severity measured via the INCAT disability score and the MRC sum score (C). (D) BAFF serum levels significantly decrease immediately after IVIg treatment (95% CI for 1 g/kg BW IVIg: −495.8 to −180.8). (E) APRIL serum levels significantly increase after IVIg application. Data is presented as mean values (*p b 0.05; **p b 0.01; ***p b 0.001).
disease course, showed excessive BAFF serum levels. Excluding the patient's values from statistical analysis annihilates the significant correlation of BAFF serum levels and disease severity (rs correlation coefficient: INCATds: 0.022; MRC-SS: 0.01; p-value: INCATds: 0.4758; MRC-SS: 0.9772). CIDP patients receiving 1 g/kg BW showed a significant decrease of BAFF serum levels comparing pre- and post-IVIg treatment whereas patients receiving 0.4 g/kg BW showed a non significant decrease of BAFF serum levels (Fig. 1D). To exclude dilution effects we also measured serum levels of the B cell stimulating cytokine APRIL. As shown in Fig. 1E APRIL serum levels were elevated after IVIg infusion.
p b 0.05). No changes were observed on CD20+ cells (dGMean, pre-, post-IVIg: CD20+: 220.5 ± 134.6, 218.5 ± 128.4) (Fig. 2D–E). 3.3. IVIg contains anti-BAFF IgG Since our flow cytometry analyses indicate that the short-term decrease of serum BAFF levels could not be explained by reduced BAFF production on CD14+ monocytes, we investigated the presence of antibodies against BAFF in the IVIg preparations. As shown in Fig. 3, IVIg contained anti-BAFF antibodies as detected with ELISA against BAFF (Fig. 3).
3.2. Short-term BAFF and BAFF-R modulation after IVIg treatment
4. Discussion
Because elevated BAFF serum levels significantly decreased after high dose IVIg treatment in CIPD patients, we further analyzed the production of BAFF and the expression of its corresponding receptor in PBMC before and after IVIg infusion. Intracellular and membranebound BAFF remained unchanged in CD3+ T-cells, CD20+ B-cells and CD14+ monocytes (dGMean, pre-, post-IVIg: CD3+: 1.4 ± 1.2, 1.1 ± 1.1; CD20+: 71.3 ± 126.9, 76.3 ± 140.7; CD14+: 14.2 ± 13.3, 21.4 ± 20.4) (Fig. 2A–C). In contrast, a significant decrease of membrane BAFF-R expression on CD3+ cells could be detected immediately after IVIg treatment (dGMean, pre-, post-IVIg: 0.24 ± 0.11, 0.16 ± 0.13,
Our study demonstrates that BAFF levels are increased in serum from CIDP patients. In humans, BAFF is considered to be a master regulatory cytokine for B-cell homeostasis and BAFF serum levels are increased in a variety of B-cell related autoimmune disorders including systemic lupus erythematosus (Zhang et al., 2001; Pers et al., 2005; Vincent et al., 2011, 2012), rheumatoid arthritis (Cheema et al., 2001; Leandro and Cambridge, 2013), myasthenia gravis (Thangarajh et al., 2006; Kim et al., 2008) and idiopathic inflammatory myopathies (Fuhlhuber et al., 2009; Krystufkova et al., 2009; Baek et al., 2012). More recently,
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Fig. 2. Effects of IVIg treatment on PBMCs (n = 14). No short-term changes of intracellular and membrane-bound BAFF expression in CD3+ T cells (A), CD20+ B cells (B) and CD14+ monocytes (C). Significant decrease of BAFF-R on CD3+ T cells (D) and no effect of IVIg on BAFF-R expression on CD20+ B cells (E). Data is indicated as means ± SD (p b 0.05; **p b 0.01; ***p b 0.001).
Bick and colleagues also reported increased BAFF serum levels in a cohort of ten patients with newly diagnosed CIDP, compared to patients with non-inflammatory polyneuropathy and healthy controls (Bick et al., 2013). In our study we could reproduce this finding in a larger cohort of CIDP patients. In addition our observation of the association of higher BAFF serum levels with more severe neurological deficits as assessed by INCAT and MRC sum scores may indicate that BAFF serum levels could serve as a surrogate parameter for disease activity in CIDP
Fig. 3. IgG from commercial IVIg preparation binds to BAFF. Data is indicated as means ± SD of optical density (OD).
patients. However, since the statistical significance of this correlation depends on a considerably outlying value of one patient, larger studies with more severely affected patients are warranted to validate this finding. The slightly higher absolute values for BAFF measured in our study can be explained by methodological differences or higher disease activity in our cohort compared to the CIDP patients examined in the study by Bick and colleagues. We further observed that treatment of CIDP patients with IVIg resulted in a rapid decrease of BAFF serum levels. Our data thereby complement previous observations that BAFF is modulated by IVIg treatment in CIDP patients (Bick et al., 2013). In contrast to the aforementioned study that determined changes of BAFF serum levels after five days of IVIg treatment, we focused on rapid alterations of BAFF serum levels immediately before and after IVIg infusion. We chose this paradigm because IVIg is known to alter the expression of cytokines such as TNF-α, IL-2, IL-6, IL-8 and TGF-β over very short time periods, i.e. several hours after infusion (Ling et al., 1993; Sewell et al., 1999; Reinhold et al., 2004; Rissmann et al., 2009). Decreased BAFF levels after IVIg infusion could be explained either by altered BAFF production or by anti-BAFF-antibodies that are present in IVIg preparations. Our finding that IVIg binds to recombinant BAFF antigen suggests that IVIg contains anti-BAFF antibodies. It is in line with previous studies characterizing the nature of anti-BAFF antibodies in IVIg preparations in greater detail (Le Pottier et al., 2007). In contrast, we did not observe short-term effects of IVIg on intracellular and
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membrane bound BAFF on CD14+ monocytes, the predominant cellular source of BAFF (Nardelli et al., 2001; Vincent et al., 2013), which argues against substantial alteration of cellular BAFF production during the short time interval of IVIg infusion. Further analysis of PBMC before and after IVIg infusion did not reveal significant differences regarding expression of BAFF and BAFF-R, except for CD3+ T-cells that displayed less BAFF-R upon IVIg infusion. It may point to an additional immunomodulatory effect of IVIg on T-cells, since BAFF also influences T-cell survival through binding to BAFF-R (Ng et al., 2004). In summary our study provides further evidence that CIDP is associated with increased levels of BAFF. Furthermore, treatment with IVIg may rapidly restore those pathologically elevated BAFF serum levels. 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