IL-12、TNF-α及其受体在AIDP、AMAN中的作用
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摘要
本文以研究IL-12、TNF-α及其相应受体在AIDP和AMAN发病中的作用为目的,探讨其可能的发病机制,为抗炎症细胞因子药物治疗GBS提供理论依据。依据GBS患者电生理的改变将患者分为AIDP组和AMAN组,根据患者是否接受了IVIg治疗,将患者分为未经IVIg治疗AIDP组、未经IVIg治疗AMAN组、IVIg治疗AIDP组、IVIg治疗AMAN组,应用FACS检测各组患者体内淋巴细胞、单核细胞表面IL-12Rβ1、IL-12Rβ2、TNFR1、TNFR2及细胞内部IL-12和TNF-α表达量的经时变化,并应用ELISA方法同时检测各组患者血浆中IL-12P40、IL-12P70、TNF-α及其可溶性受体sTNFR1、sTNFR2含量。分析炎症细胞因子及其受体表达与临床症状及IVIg治疗之间的关系。FACS检测结果发现,未经IVIg治疗AIDP患者在急性期IL-12、IL-12Rβ1水平增高,恢复期TNF-α和TNFR1水平增高,未经IVIg治疗AMAN患者急性期TNF-α水平增高;IVIg治疗AIDP组患者TNFR1及IL-12Rβ1表达量下降,IVIg治疗AMAN组患者TNF-α和TNFR2表达量增加;ELISA检测结果发现,IVIg治疗后AIDP组患者血浆中可溶性受体sTNFR1和IL-12P70含量下降。研究结果提示IL-12及IL-12Rβ1参与了AIDP的发病,在疾病发展中起促进作用,而AMAN组没发现类似的变化。TNF-α通过与不同的受体结合对GBS发挥着双向调节作用,在AIDP急性期TNF-α主要通过与TNFR1结合来实现其破坏性作用,在AMAN恢复期,TNF-α主要通过与TNFR2结合来发挥其保护性作用。IVIg通过下调TNFR1和IL-12Rβ1促进了AIDP的恢复,通过上调TNF-α和TNFR2促进了AMAN的恢复。
Guillain-Barrésyndrome (GBS) is an immune-mediated disease of the peripheral nerves involving both the myelin sheath and axons. Among its four subtypes of acute peripheral neuropathy, the most common is acute inflammatory demyelinating polyradiculoneuropathy (AIDP); another common subtype is acute motor axonal neuropathy (AMAN). GBS is generally accepted as a post-infectious autoimmune disease and is involved in molecular mimicry trigged by many antecedent pathogens. Numerous inflammatory cytokines and chemokines are thought to play pivotal roles in initiating, enhancing and perpetuating pathphysiological procedure in GBS.
Interleukin 12 (IL-12) is an important candidate cytokine for the study of autoimmune disease because of its proinflammatory role with potent immune-regulatory activities and pivotal place in determining the differentiation and generation of Th1 cell. In previous studies, we reported that up-regulated IL-12 mRNA expression was found at the height of experimental autoimmune neuritis (EAN) course and IL-12p40 deficient mice showed significantly less severity of EAN, a widely accepted animal model for GBS in humans. However, whether IL-12 is implicated in the pathogenesis of GBS and its main subtypes (AIDP and AMAN) is still not clear.
As another key mediator of regulatory processes in autoimmune demyelinating diseases, tumour necrosis factor-α(TNF-α) is considered crucial in the pathogenesis of GBS.The function of TNF-αwas initially characterized as inflammatory activity; however it was later found to be pleiotropic, exemplified by its anti-inflammatory effect. The contradictory biological activities of TNF-αare due to binding to its two receptors (TNFR1 and TNFR2) with distinct effects.
In addition, as an effective immune-modulating therapy, intravenous high dose immunoglobulin (IVIg) is replacing corticosteroids in GBS. Hughes and his colleagues reported IVIg improved the disability grade scale in five trials with altogether 582 participants. The efficiency of immunoglobulin may at least partially be explained by the participation of modulating cytokines and their receptors in immunoglobulin therapy; however, the exact mechanism of IVIg remains unclear.
In this study, we hypothesized that TNF-αand IL-12 molecules, as well as their receptors might play the different roles in the subtypes of GBS since AIDP and AMAN differ with regard to clinical pattern, electrophysiological testing, pathology and pathogenesis. We also observed the effects of IVIg on expression of TNF-αand IL-12 molecules, as well as their receptors in AIDP and AMAN.
Materials and Methods
Patients and controls
We recruited 28 patients fulfilling international diagnostic criteria for GBS or its variants from the Department of Neurology, the First Hospital, Jilin University, Changchun, China, and 13 healthy controls between December 2006 and August 2007. All patients were classified neurophysiologically as AMAN (n=18) and AIDP (n=10), using motor nerve conduction criteria. Severity of GBS was scored by the use of Hughes degree (a functional disability scale). The pre-treatment patients were defined as absent of any immune-modulating drugs within 3 months and other treatments within 3 months and the post-treatment patients were treated with IVIg at a dose of 0.4g/kg body weight per day for 5 days consecutively. Blood was sampled two times to observe the different course of GBS, at acute phase (1-14 days from onset day) and at plateau phase (15-32 days from onset day). Patients with chronic inflammatory demyelinating polyneuropathy were excluded. The clinical characteristics of all subjects are shown in Table 1. Thirteen healthy donors (7 females and 6 males, age 21-58 years) were included. The present study was approved by the Human Ethics Committee of Jilin Province, China and informed consent was obtained from all patients and healthy controls.
Peripheral blood mononuclear cells preparation and flow cytometric analysis
Blood samples were taken at 15:00 pm each day. Lymphoprep (Axis-Shield PoC AS, Oslo, Norway) gradient centrifugation was used to separate peripheral blood mononuclear cells (PBMCs). Mononuclear cells were washed twice in PBS and cell viability measured by Trypan blue exclusion was confirmed to exceed 95%. Serum samples were also collected and cryopreserved at -80°C for further ELISA performance. An amount of 1000 units of protease inhibitor (Aprotinin, Sigma, London, UK) were used to prevent protein degradation.
Three-colour flow cytometric technique was used in the analysis of surface phenotypes of PBMCs and cytokine as well as their receptor expression. Briefly, 106 cells/ml were incubated with the following PE- or FITC-conjugated anti-human monoclonal antibodies (mAbs): anti-CD3 (marker for T cells) and anti-CD14 (marker for monocytes, Caltag Laboratories, Burlingame, California, USA); anti-TNF-αreceptor 1 (TNFR1, CD120a; Serotec, Oxford, UK), anti-TNFR2 (CD120b; Caltag), anti-IL-12RΒ1 and IL-12R2 (BD Biosciences Pharmingen, San Diego, CA); moreover APC-conjugated mAb anti-TNF-αand anti-IL-12 (p40/p70) (BD) were used with the corresponding isotype controls. Cells were incubated for 20 min at room temperature and subsequently fixed in 2% paraformaldehyded PBS and stored at 4℃until flow cytometric analysis by an FACSCalibur cytometer using CellQuest software (Becton Dickinson, San Jose, California, USA). The molecule expression was assessed by determining of the positive percentage of the PBMCs labelled with fluorescent mAbs directed against the respective molecules.
ELISA measurements of soluble TNF-αand its receptors, as well as IL-12p40/70
To measure the levels of serum TNF-α, soluble TNFR1 and TNFR2, IL-12p40 and IL-12p70 ELISA was performed according to the manufacturer’s instructions. The serum samples were all diluted 1:10 for TNF-α(Diaclon, Becancon, France), TNFRs (Bender MedSystem Inc., Vienna, Austria) and IL-12p40/70 (BD) detection. The assays were carried out in 96-well plates, measured spectrophotometrically at 450 nm (Molecular Devices Spectra MAX 250). All assays were done in duplicate. Statistical analysis
Data were expressed as the mean±SD. For statistical analysis, differences of mean values were tested with one way analysis of variance (ANOVA) test for multiple comparisons and the student-t test for two groups, using SPSS software (version 11.5). Reported P-values are two-tailed and considered statistically significant at P < 0.05. Spearman rank test was used for correlation analysis.
Results
Clinical profiles
The clinical features of 28 patients with GBS are shown in Table 1. In total 21 patients had the antecedent infection; namely, 7 with gastrointestinal infection, 9 with upper respiratory tract infection, 4 with gastrointestinal and upper respiratory tract infection and 1 with chickenpox infection. After intravenous immunoglobulin therapy, based on the Hughes degree during acute (named T1) and plateau phases (named T2), the clinical severity remitted during plateau phase in 7 out of 11 (63.6%) patients with AIDP and 4 out of 10 (40%) patients with AMAN. On the other hand, only 1 out of 4 untreated patients with AIDP and none with
AMAN were found remitted during plateau phase.
Increased IL-12, IL-12Rβ1 in AIDP and TNF-αin AMAN during the acute phase, and increased TNF-αand TNFR1 during the plateau phase of AIDP
To explore the role of TNF-αand IL-12 as well as their receptors in the pathogenesis of AIDP and AMAN, we examined these molecules’expression on circulating T cells (CD3) and monocytes (CD14) of AIDP and AMAN without any treatment at the acute and plateau phases, respectively. Our data showed that in acute phase of AIDP, the expressions of IL-12Rβ1 clearly increased on T cells when compared with health controls (P< 0.05). A higher level of IL-12 was found in acute phase of AIDP than in plateau (P< 0.05). The levels of TNF-α(P< 0.01) and TNFR1 (P< 0.05) were also found markedly up-regulated during plateau phase in AIDP compared with health controls. Thus, increased levels of IL-12 and IL-12Rβ1 correlated directly with disease severity of AIDP and reduced their expression in parallel with clinical recovery in AIDP patients. However, the role of TNF-αin AIDP seems the reverse compared to IL-12 at the plateau phase of disease. Interestingly in AMAN, a higher level of TNF-αwas observed on both T cells and monocytes (compared with health controls) in acute phase (P< 0.05). This suggests that TNF-αappears to contribute AMAN development due to an inherent biological activity change of TNF-αin AMAN. IVIg therapy altered the profiles of TNF-αand its receptors, as well as IL-12RΒ1 expression, on cells
To explore the mechanisms of the therapeutic efficiency of IVIg in GBS, we observed the profiles of TNF-α, IL-12 and their receptors’expression on circulating immune cells before and after IVIg treatment at acute and plateau phases of the patients by FACS. The results of FACS were estimated as the positive percentage, i.e. the above molecules’expression on T cells and monocytes in patients.
In plateau phase of AIDP group, there was significant decrease in the percentage of TNFR1 (P< 0.05) and IL-12Rβ1 (P< 0.05) expression on monocytes between before and after treatment with IVIg. Interestingly, when compared with healthy controls, the level of IL-12Rβ1 on the circulating pre-treated monocytes was much higher (P< 0.05); whereas after treatment, IL-12Rβ1 expression decreased at a low level, dramatically less than healthy controls. Additionally, IVIg treatment did not alter markedly the expression of other molecules in AIDP either at acute or plateau phases.
For confirming our findings in AIDP, the correlations between these molecules expression and clinical severity as well as courses were analyzed according to the full neurological assessment (Hughes RA, 1978). Our results indicated that the clinical severity in the nine patients with AIDP was associated significantly with high expression of IL-12Rβ1 in the acute phase (P< 0.05) and TNFR1 in the plateau phase (P< 0.05) on T cells. There were no significant correlations between expression of other molecules and clinical profile.
In acute phase of AMAN group, unexpectedly, the patients had a significantly increased percentage of TNFR2 (P<0.01)and intracellular TNF-α(P< 0.01) expression on circulating monocytes after IVIg therapy. The level of TNFR2 on monocytes was increased dramatically (P< 0.05) before IVIg. After the immunomodulator intervention, the high level of TNFR2 was further up-regulated significantly(P< 0.01) compared with normal standard (healthy controls). Contrarily, the intracellular TNF-αpercentage of circulating monocytes was increased significantly (P< 0.01) only in the patients after IVIg treatment, but not pre-treatment. IVIg therapy down-regulated soluble Il-12p70 and TNFR1 in AIDP
To further investigate the role of IL-12 and TNF-αin GBS and to determine the levels of IL-12 and TNF-α, as well as their receptors in sera, the enzyme linked immunosorbent assays (ELISA) of serous forms were performed in the GBS patients with AIDP, AMAN and healthy controls. The intravenous immunoglobulin therapy down-regulated the levels of soluble TNFR1 (P < 0.05 at T2) and IL-12p70 (P < 0.05 at T1, P < 0.01 at T2) into the normal standard (healthy controls). There were no significant results found in the AMAN group. Discussion
Inflammatory cytokines plays an important role in initiating, enhancing and perpetuating pathogenic events in GBS. Our results showed that TNF-αand IL-12 molecules as well as their receptors are involved in the pathogenesis of GBS. Our results suggest TNF-αand IL-12p70 may play an inflammatory role in the pathogenesis of AIDP by increasing the expression of their receptor 1. In addition, TNF-αmay have an anti-inflammatory effect through a TNFR2-dependent mechanism in AMAN.
TNF-αplays a complex and different role in AIDP and AMAN as it does in other autoimmune diseases. Because of its macrophage-stimulating capacity and inflammatory cell accumulation, TNF-αcan be classified as a Th1-type, pro-inflammatory cytokine that binds to its specific cell surface receptor, TNFR1. In patients with GBS it was found that TNF-αlevels correlate with clinical severity and serum concentration regression of TNF-αwas found correlated with the improvement of clinical features. However, recent studies have suggested anti-inflammatory and neuroprotective role of TNFR2, of which serum level assessment may serve as a prognostic factor of GBS. Similar to another study, our data demonstrated that the level of TNF-αand TNFR1 in AIDP was not increased in acute phase but in plateau phase, which was subsequently down-regulated by IVIg during plateau phase. On the other hand, TNF-αand TNFR2 were significantly up-regulated by the treatment of IVIg in AMAN during acute phase. Therefore, two conflicting mechanisms of TNF-αmay be involved in the pathogenesis of immunoglobulin therapy: a down-regulated TNFR1 dependent pathway in AIDP during plateau phase and an up-regulated TNFR2 dependent pathway in AMAN during acute phase.
IL-12, or natural killer (NK) stimulatory factor, is a pleiotropic cytokine with Th1-promoting activity and acts as a proinflammatory stimulus, inducing consequent activation of NK cells and production of IFN-γin immune response. Administration of IL-12 exacerbated chronic EAN in Lewis rats and was associated with increased IFN-γproduction in the PNS. Paralleled with its inflammatory role, our data demonstrated that IL-12 and one of its receptors, IL-12Rβ1, were found to be increased in AIDP during acute phase, and then decreased during plateau phase after IVIg. The correlation analysis reconfirms the possible therapeutic mechanism in AIDP, i.e., that IVIg reduces the inflammatory activity of IL-12 by down-modulating the IL-12Rβ1 dependent pathway. Considering the Th1-promoting role of IL-12, our data indicated cellular immunity may be involved in pathogenesis of AIDP rather than in AMAN. There was no IL-12Rβ2 relative data were found significantly in our study; it deserves further investigation to delineate the role of it in GBS.
Finally, although different explanations are involved, TNF-αand IL-12 molecules, as well as their receptors, participate in the pathogenesis of immunoglobulin therapy in GBS. Because inflammatory cytokines, IL-12 and TNF-αand their receptors may participate in AIDP, immune-modulating therapy may decrease their disease-promoting effect by reducing TNFR1 and IL-12Rβ1. Additionally, the anti-inflammatory role of TNF-αrealized through TNFR2 in AMAN is possibly a therapeutic mechanism in the IVIg treatment of AMAN.
In summary, both TNF-αand IL-12 may play an inflammatory role in AIDP and AMAN. Moreover TNF-αmay also be an anti-inflammatory factor in AMAN by combining with TNFR2. The immunoglobulin therapy probably exerts its protective effect by down-modulating bioactivity of IL-12 through an IL-12Rβ1 dependent mechanism in AIDP and up-modulating the anti-inflammatory activity of TNF-αthrough a TNFR2 pathway in AMAN.
Guillain-Barrésyndrome (GBS) is an immune-mediated disease of the peripheral nerves involving both the myelin sheath and axons. Among its four subtypes of acute peripheral neuropathy, the most common is acute inflammatory demyelinating polyradiculoneuropathy (AIDP); another common subtype is acute motor axonal neuropathy (AMAN). GBS is generally accepted as a post-infectious autoimmune disease and is involved in molecular mimicry trigged by many antecedent pathogens. Numerous inflammatory cytokines and chemokines are thought to play pivotal roles in initiating, enhancing and perpetuating pathphysiological procedure in GBS.
Interleukin 12 (IL-12) is an important candidate cytokine for the study of autoimmune disease because of its proinflammatory role with potent immune-regulatory activities and pivotal place in determining the differentiation and generation of Th1 cell. In previous studies, we reported that up-regulated IL-12 mRNA expression was found at the height of experimental autoimmune neuritis (EAN) course and IL-12p40 deficient mice showed significantly less severity of EAN, a widely accepted animal model for GBS in humans. However, whether IL-12 is implicated in the pathogenesis of GBS and its main subtypes (AIDP and AMAN) is still not clear.
As another key mediator of regulatory processes in autoimmune demyelinating diseases, tumour necrosis factor-α(TNF-α) is considered crucial in the pathogenesis of GBS.The function of TNF-αwas initially characterized as inflammatory activity; however it was later found to be pleiotropic, exemplified by its anti-inflammatory effect. The contradictory biological activities of TNF-αare due to binding to its two receptors (TNFR1 and TNFR2) with distinct effects.
In addition, as an effective immune-modulating therapy, intravenous high dose immunoglobulin (IVIg) is replacing corticosteroids in GBS. Hughes and his colleagues reported IVIg improved the disability grade scale in five trials with altogether 582 participants. The efficiency of immunoglobulin may at least partially be explained by the participation of modulating cytokines and their receptors in immunoglobulin therapy; however, the exact mechanism of IVIg remains unclear.
In this study, we hypothesized that TNF-αand IL-12 molecules, as well as their receptors might play the different roles in the subtypes of GBS since AIDP and AMAN differ with regard to clinical pattern, electrophysiological testing, pathology and pathogenesis. We also observed the effects of IVIg on expression of TNF-αand IL-12 molecules, as well as their receptors in AIDP and AMAN.
Materials and Methods
Patients and controls
We recruited 28 patients fulfilling international diagnostic criteria for GBS or its variants from the Department of Neurology, the First Hospital, Jilin University, Changchun, China, and 13 healthy controls between December 2006 and August 2007. All patients were classified neurophysiologically as AMAN (n=18) and AIDP (n=10), using motor nerve conduction criteria. Severity of GBS was scored by the use of Hughes degree (a functional disability scale). The pre-treatment patients were defined as absent of any immune-modulating drugs within 3 months and other treatments within 3 months and the post-treatment patients were treated with IVIg at a dose of 0.4g/kg body weight per day for 5 days consecutively. Blood was sampled two times to observe the different course of GBS, at acute phase (1-14 days from onset day) and at plateau phase (15-32 days from onset day). Patients with chronic inflammatory demyelinating polyneuropathy were excluded. The clinical characteristics of all subjects are shown in Table 1. Thirteen healthy donors (7 females and 6 males, age 21-58 years) were included. The present study was approved by the Human Ethics Committee of Jilin Province, China and informed consent was obtained from all patients and healthy controls.
Peripheral blood mononuclear cells preparation and flow cytometric analysis
Blood samples were taken at 15:00 pm each day. Lymphoprep (Axis-Shield PoC AS, Oslo, Norway) gradient centrifugation was used to separate peripheral blood mononuclear cells (PBMCs). Mononuclear cells were washed twice in PBS and cell viability measured by Trypan blue exclusion was confirmed to exceed 95%. Serum samples were also collected and cryopreserved at -80°C for further ELISA performance. An amount of 1000 units of protease inhibitor (Aprotinin, Sigma, London, UK) were used to prevent protein degradation.
Three-colour flow cytometric technique was used in the analysis of surface phenotypes of PBMCs and cytokine as well as their receptor expression. Briefly, 106 cells/ml were incubated with the following PE- or FITC-conjugated anti-human monoclonal antibodies (mAbs): anti-CD3 (marker for T cells) and anti-CD14 (marker for monocytes, Caltag Laboratories, Burlingame, California, USA); anti-TNF-αreceptor 1 (TNFR1, CD120a; Serotec, Oxford, UK), anti-TNFR2 (CD120b; Caltag), anti-IL-12RΒ1 and IL-12R2 (BD Biosciences Pharmingen, San Diego, CA); moreover APC-conjugated mAb anti-TNF-αand anti-IL-12 (p40/p70) (BD) were used with the corresponding isotype controls. Cells were incubated for 20 min at room temperature and subsequently fixed in 2% paraformaldehyded PBS and stored at 4℃until flow cytometric analysis by an FACSCalibur cytometer using CellQuest software (Becton Dickinson, San Jose, California, USA). The molecule expression was assessed by determining of the positive percentage of the PBMCs labelled with fluorescent mAbs directed against the respective molecules.
ELISA measurements of soluble TNF-αand its receptors, as well as IL-12p40/70
To measure the levels of serum TNF-α, soluble TNFR1 and TNFR2, IL-12p40 and IL-12p70 ELISA was performed according to the manufacturer’s instructions. The serum samples were all diluted 1:10 for TNF-α(Diaclon, Becancon, France), TNFRs (Bender MedSystem Inc., Vienna, Austria) and IL-12p40/70 (BD) detection. The assays were carried out in 96-well plates, measured spectrophotometrically at 450 nm (Molecular Devices Spectra MAX 250). All assays were done in duplicate. Statistical analysis
Data were expressed as the mean±SD. For statistical analysis, differences of mean values were tested with one way analysis of variance (ANOVA) test for multiple comparisons and the student-t test for two groups, using SPSS software (version 11.5). Reported P-values are two-tailed and considered statistically significant at P < 0.05. Spearman rank test was used for correlation analysis.
Results
Clinical profiles
The clinical features of 28 patients with GBS are shown in Table 1. In total 21 patients had the antecedent infection; namely, 7 with gastrointestinal infection, 9 with upper respiratory tract infection, 4 with gastrointestinal and upper respiratory tract infection and 1 with chickenpox infection. After intravenous immunoglobulin therapy, based on the Hughes degree during acute (named T1) and plateau phases (named T2), the clinical severity remitted during plateau phase in 7 out of 11 (63.6%) patients with AIDP and 4 out of 10 (40%) patients with AMAN. On the other hand, only 1 out of 4 untreated patients with AIDP and none with
AMAN were found remitted during plateau phase.
Increased IL-12, IL-12Rβ1 in AIDP and TNF-αin AMAN during the acute phase, and increased TNF-αand TNFR1 during the plateau phase of AIDP
To explore the role of TNF-αand IL-12 as well as their receptors in the pathogenesis of AIDP and AMAN, we examined these molecules’expression on circulating T cells (CD3) and monocytes (CD14) of AIDP and AMAN without any treatment at the acute and plateau phases, respectively. Our data showed that in acute phase of AIDP, the expressions of IL-12Rβ1 clearly increased on T cells when compared with health controls (P< 0.05). A higher level of IL-12 was found in acute phase of AIDP than in plateau (P< 0.05). The levels of TNF-α(P< 0.01) and TNFR1 (P< 0.05) were also found markedly up-regulated during plateau phase in AIDP compared with health controls. Thus, increased levels of IL-12 and IL-12Rβ1 correlated directly with disease severity of AIDP and reduced their expression in parallel with clinical recovery in AIDP patients. However, the role of TNF-αin AIDP seems the reverse compared to IL-12 at the plateau phase of disease. Interestingly in AMAN, a higher level of TNF-αwas observed on both T cells and monocytes (compared with health controls) in acute phase (P< 0.05). This suggests that TNF-αappears to contribute AMAN development due to an inherent biological activity change of TNF-αin AMAN. IVIg therapy altered the profiles of TNF-αand its receptors, as well as IL-12RΒ1 expression, on cells
To explore the mechanisms of the therapeutic efficiency of IVIg in GBS, we observed the profiles of TNF-α, IL-12 and their receptors’expression on circulating immune cells before and after IVIg treatment at acute and plateau phases of the patients by FACS. The results of FACS were estimated as the positive percentage, i.e. the above molecules’expression on T cells and monocytes in patients.
In plateau phase of AIDP group, there was significant decrease in the percentage of TNFR1 (P< 0.05) and IL-12Rβ1 (P< 0.05) expression on monocytes between before and after treatment with IVIg. Interestingly, when compared with healthy controls, the level of IL-12Rβ1 on the circulating pre-treated monocytes was much higher (P< 0.05); whereas after treatment, IL-12Rβ1 expression decreased at a low level, dramatically less than healthy controls. Additionally, IVIg treatment did not alter markedly the expression of other molecules in AIDP either at acute or plateau phases.
For confirming our findings in AIDP, the correlations between these molecules expression and clinical severity as well as courses were analyzed according to the full neurological assessment (Hughes RA, 1978). Our results indicated that the clinical severity in the nine patients with AIDP was associated significantly with high expression of IL-12Rβ1 in the acute phase (P< 0.05) and TNFR1 in the plateau phase (P< 0.05) on T cells. There were no significant correlations between expression of other molecules and clinical profile.
In acute phase of AMAN group, unexpectedly, the patients had a significantly increased percentage of TNFR2 (P<0.01)and intracellular TNF-α(P< 0.01) expression on circulating monocytes after IVIg therapy. The level of TNFR2 on monocytes was increased dramatically (P< 0.05) before IVIg. After the immunomodulator intervention, the high level of TNFR2 was further up-regulated significantly(P< 0.01) compared with normal standard (healthy controls). Contrarily, the intracellular TNF-αpercentage of circulating monocytes was increased significantly (P< 0.01) only in the patients after IVIg treatment, but not pre-treatment. IVIg therapy down-regulated soluble Il-12p70 and TNFR1 in AIDP
To further investigate the role of IL-12 and TNF-αin GBS and to determine the levels of IL-12 and TNF-α, as well as their receptors in sera, the enzyme linked immunosorbent assays (ELISA) of serous forms were performed in the GBS patients with AIDP, AMAN and healthy controls. The intravenous immunoglobulin therapy down-regulated the levels of soluble TNFR1 (P < 0.05 at T2) and IL-12p70 (P < 0.05 at T1, P < 0.01 at T2) into the normal standard (healthy controls). There were no significant results found in the AMAN group. Discussion
Inflammatory cytokines plays an important role in initiating, enhancing and perpetuating pathogenic events in GBS. Our results showed that TNF-αand IL-12 molecules as well as their receptors are involved in the pathogenesis of GBS. Our results suggest TNF-αand IL-12p70 may play an inflammatory role in the pathogenesis of AIDP by increasing the expression of their receptor 1. In addition, TNF-αmay have an anti-inflammatory effect through a TNFR2-dependent mechanism in AMAN.
TNF-αplays a complex and different role in AIDP and AMAN as it does in other autoimmune diseases. Because of its macrophage-stimulating capacity and inflammatory cell accumulation, TNF-αcan be classified as a Th1-type, pro-inflammatory cytokine that binds to its specific cell surface receptor, TNFR1. In patients with GBS it was found that TNF-αlevels correlate with clinical severity and serum concentration regression of TNF-αwas found correlated with the improvement of clinical features. However, recent studies have suggested anti-inflammatory and neuroprotective role of TNFR2, of which serum level assessment may serve as a prognostic factor of GBS. Similar to another study, our data demonstrated that the level of TNF-αand TNFR1 in AIDP was not increased in acute phase but in plateau phase, which was subsequently down-regulated by IVIg during plateau phase. On the other hand, TNF-αand TNFR2 were significantly up-regulated by the treatment of IVIg in AMAN during acute phase. Therefore, two conflicting mechanisms of TNF-αmay be involved in the pathogenesis of immunoglobulin therapy: a down-regulated TNFR1 dependent pathway in AIDP during plateau phase and an up-regulated TNFR2 dependent pathway in AMAN during acute phase.
IL-12, or natural killer (NK) stimulatory factor, is a pleiotropic cytokine with Th1-promoting activity and acts as a proinflammatory stimulus, inducing consequent activation of NK cells and production of IFN-γin immune response. Administration of IL-12 exacerbated chronic EAN in Lewis rats and was associated with increased IFN-γproduction in the PNS. Paralleled with its inflammatory role, our data demonstrated that IL-12 and one of its receptors, IL-12Rβ1, were found to be increased in AIDP during acute phase, and then decreased during plateau phase after IVIg. The correlation analysis reconfirms the possible therapeutic mechanism in AIDP, i.e., that IVIg reduces the inflammatory activity of IL-12 by down-modulating the IL-12Rβ1 dependent pathway. Considering the Th1-promoting role of IL-12, our data indicated cellular immunity may be involved in pathogenesis of AIDP rather than in AMAN. There was no IL-12Rβ2 relative data were found significantly in our study; it deserves further investigation to delineate the role of it in GBS.
Finally, although different explanations are involved, TNF-αand IL-12 molecules, as well as their receptors, participate in the pathogenesis of immunoglobulin therapy in GBS. Because inflammatory cytokines, IL-12 and TNF-αand their receptors may participate in AIDP, immune-modulating therapy may decrease their disease-promoting effect by reducing TNFR1 and IL-12Rβ1. Additionally, the anti-inflammatory role of TNF-αrealized through TNFR2 in AMAN is possibly a therapeutic mechanism in the IVIg treatment of AMAN.
In summary, both TNF-αand IL-12 may play an inflammatory role in AIDP and AMAN. Moreover TNF-αmay also be an anti-inflammatory factor in AMAN by combining with TNFR2. The immunoglobulin therapy probably exerts its protective effect by down-modulating bioactivity of IL-12 through an IL-12Rβ1 dependent mechanism in AIDP and up-modulating the anti-inflammatory activity of TNF-αthrough a TNFR2 pathway in AMAN.
引文
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