Influence of IFN-β1b (Betaferon) on cytokine mRNA profiles in blood mononuclear cells and plasma levels of soluble VCAM-1 in multiple sclerosis

Inflammatory cell infiltration within the central nervous system (CNS) and upregulation of both pro- and anti-inflammatory cytokines are characteristic for multiple sclerosis (MS). Treatment with interferon-β1b (IFN-β1b) reduces the number and severity of MS relapses. To examine whether treatment with IFN-β1b affects levels of cytokine mRNA expressing blood mononuclear cells (MNC) we employed in-sit hybridization with synthetic oligonucleotide probes to detect and enumerate IFN-γ, TNF-α, IL-10, TGF-β and perforin mRNA expressing cells in MS patients before treatment with IFN-β1b and during tretmetn for 3–6 weeks and for 3–6 monts. Numbers of blood MNC spontaneously expressing TNF-α and IL-10 mRNA were lower after 3–6 months of treatment, while numbers of IFN-γ, TGF-β and perforin mRNA expressing MNC were not affected by treatment. IFN-β1b had no influence on levels of MBP-reactive IFN-γ, TNF-α, TGF-β, IL-10 or perforin mRNA expressing blood MNC determined after 3–6 weeks 3–6 months of treatment. Parallel measurements of plasma concentrations of soluble vascular cell adhesion molecule-1 (sVCAM-1) revealed elevated levels after 3–6 weeks of treatment and these levels remained higher after 3–6 months of treatment. The results suggest that IFN-β1b treatment upregulates plasma levels of sVCAM-1, but has little effects on numbers of blood MNC expressing mRNA of the pro- and anti-inflammatory cytokines under study.     

Linomide (roquinimex) affects the balance between pro- and anti-inflammatory cytokines in vitro in multiple sclerosis

Objectives - Multiple sclerosis (MS) is characterized by high levels of circulating mononuclear cells (MNC) that respond to myelin proteins like myelin basic protein (MBP) in vitro by expressing mRNA of both pro-inflammatory cytokines, e.g. interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α) and lymphotoxin (LT) that may make MS worse, and anti-inflammatory cytokines like IL-4, IL-10 and transforming growth factor-β (TGF-β) that may act beneficially. Substances that down-regulate cytokines such as TNF-α or promote IL-10 or TGF-β can be anticipated to affect MS beneficially. Material and methods - In situ hybridization to detect and enumerate IFN-γ, TNF-α, LT, IL-4, IL-10 and TGF-β mRNA expressing blood MNC after stimulation with myelin basic protein (MBP), control antigens and without antigen in presence and absence of Linomide (roquinimex, LS-2616) was employed. In parallel, ELISPOT assay to detect MBP- and PHA-reactive IFN-γ secreting blood MNCLinomide was used. Results - Here we report that Linomide, a synthetic immunomodulator, at concentrations effective in vivo reduces the number of MBP-reactive TNF-a and increases MBP-reactive IL-10 and TGF-β mRNA expressing MNC from MS patients'blood when analysed in vitro. Compared to dexamethasone, Linomide up-regulated levels of blood MNC expressing mRNA of TGF-β after culture in presence of MBP. Conclusions - Changes of cytokine balance towards a production of anti-inflammatory cytokines could be a desirable effect to be evaluated in future drug studies of Linomide-like substances. At present, Linomide is not evaluable in MS clinical trials due to side-effects.     

Local expression of cytokines in idiopathic inflammatory myopathies

H. Lepidi, V. Frances, D. Figarella-Branger, C. Bartoli, A. Machado-Baeta & J-F. Pellissier (1998) Neuropathology and Applied Biology , 24, 73–79
Local expression of cytokines in idiopathic inflammatory myopathies
The idiopathic inflammatory myopathies (IIM), including dermatomyositis (DM), polymyositis (PM), and inclusion body myositis (IBM), are regarded as autoimmune diseases. They are characterized by chronic lymphocytic and macrophagic infiltration in muscle tissue. Of particular importance in understanding the immune response to IIM is the specific pattern of locally produced cytokines. Frozen muscle tissues from IIM (5 DM, 3 PM, and 1 IBM) were used to investigate the cytokine responses. The RT-PCR technique was instrumental to determine the pattern of expression of pro-inflammatory (IL-1β, IL-6, TNF-α), Th1 (IFN-γ IL-2), and Th2 (IL-4) cytokines. Immunohistochemistry was also used to localize morphologically IFN-γ and IL-4. Our results show that pro-inflammatory cytokines and Th1 cytokines are mainly expressed in IIM. The accumulation of mononuclear inflammatory cells and the inflammatory syndrome in IIM are probably related in part to the production of pro-inflammatory cytokines. Moreover, the pattern of local cytokine expression is consistent with a Th1 immune response related to autoimmune diseases.     

Cytokines Regulate L-Arginine-Dependent Cyclic GMP Production in Rat Glial Cells

We have previously demonstrated that primary astrocyte cultures from neonatal rat cortex and C6 glioma cells express a calcium-independent nitric oxide synthase (NOS) on induction with bacterial endotoxin (lipopolysaccharide, LPS). One hypothesis regarding the mechanism of the LPS induction is that it causes release of cytokines from these cells which then induce the enzyme directly. Such cytokine induction of NOS has been demonstrated in many extraneural cell types. l -Arginine-dependent increases in cyclic GMP correlate with smaller increases in accumulation of nitrite, the major oxidation product of nitric oxide, and hence can serve as a more sensitive measure of nitric oxide production. Here we provide evidence that interferon-γ (IFN-γ), interleukin (IL)-1β and tumour necrosis factor-α induce l -arginine-dependent cyclic GMP synthesis in C6 cells and that a combination of IFN-γ and IL-1β induce l -arginine-dependent cyclic GMP synthesis in astrocyte cultures, indicating that these cytokines induce NOS. In both cell types the induction by cytokines was less sensitive to inhibition by dexamethasone, IL-10 and IL-4 than was induction by LPS. These data suggest that cytokines can also induce a NOS in glial cells and that the mechanism of this induction may be more direct than that of LPS, since it is less sensitive to modulation by immunosuppressors. Due to the close associations of astrocytes with neurons and microvasculature, cytokine-induced NOS could have potentially important pathophysiological effects in the central nervous system.     

Cytokine production by peripheral blood monocytes/macrophages in the patients with multiple sclerosis and its suppression by methylprednisolone]

The production of tumor necrosis factor alpha (TNF alpha), interleukin-1 alpha (IL-1 alpha), interleukin-1 beta (IL-1 beta) and interleukin-6 (IL-6) by stimulated peripheral blood monocytes/macrophages (PBM) was assessed in patients with multiple sclerosis (MS), other neurological diseases (OND) or normal controls (NC) using enzyme-linked immunosorbent assay (ELISA). PBM obtained from acute phase of MS produced significantly higher amount of all these cytokines than those from chronic stable MS, OND or NC (TNF alpha, IL-1 alpha, IL-6: p less than 0.01, IL-1 beta: p less than 0.05). Methylprednisolone (MP) inhibited the lipopolysaccharide-induced cytokine production in a dose-dependent manner. These results suggest the possible roles of activated monocytes/macrophages in the acute exacervation of MS and suppressive effect of MP on cytokine production by activated monocytes/macrophages.     

Recombinant erythropoietin down-regulates IL-6 and CXCR4 genes in TNF-α-treated primary cultures of human microvascular endothelial cells

In multiple sclerosis (MS), disruption of the blood-brain barrier might lead to new gadolinium-enhanced lesion formation in the brain and cause acute relapses. Current therapeutic options for acute relapses in MS are limited. The effect of recombinant erythropoietin (rEPO) on cytokine gene expression in TNF-α-treated human brain microvascular endothelial cells was studied. The cells were controls (untreated), exposed for either 6 or 24 h to TNF-α or TNF-α/rEPO. Of the 96 genes studied, interleukin-6 (IL-6), IL-1β, CXCR4, and IL-1α genes were down-regulated when treated with TNF-α/rEPO for 6 h as compared with TNF-α alone. At 24 h, IL-6 and CXCR4 gene expression was 4.24 and 2.98, respectively. Quantitative RT-PCR analysis showed down-regulation by 3.86 and 1.9 for IL-6 and CXCR4 genes, respectively. Our findings suggest that further studies are warranted to evaluate the use of EPO in minimizing acute relapses in MS.     

Immunocompetence of human microvascular brain endothelial cells: cytokine regulation of IL-1β, MCP-1, IL-10, sICAM-1 and sVCAM-1

Endothelia from the brains of four patients undergoing neurosurgery, including one multiple sclerosis (MS) patient, were studied in vitro to determine cytokine and chemokine production; the release of soluble adhesion molecules was also investigated. The same procedure was repeated on human umbilical vein endothelial cells (HUVECs) in order to detect possible district-specific differences. After isolation, the endothelium was cultured and stimulated with γ-interferon (IFN), tumour necrosis factor alpha (TNF-α) and LPS. The results showed that brain endothelium, in our experimental conditions, does not produce interleukin (IL)-10 and produces lower amounts of IL-1β and soluble intercellular adhesion molecule-1 (sICAM-1) than HUVECs do; no differences were detected in soluble vascular cell adhesion molecule-1 (sVCAM-1) production. MCP-1 mRNA was detected both without and after stimulation with TNF-α and γ-IFN in HUVECs and MS human brain endothelial cells (HBECs), while in non-MS-HBECs it was found only after γ-IFN stimulation. Received: 24 June 1997 Received in revised form: 20 February 1998 Accepted: 5 March 1988     

Effect of treatment with methylprednisolone on the serum levels of IL-12, IL-10 and CCL2 chemokine in patients with multiple sclerosis in relapse

Objectives

Interleukin-12 (IL-12), a proinflammatory cytokine produced by Th1 cells, and interleukin-10 (IL-10), a product of Th2 cells, are involved in the pathogenetic mechanisms of multiple sclerosis (MS). CCL2 chemokine expression is induced by Th2 cytokines and is decreased in MS relapse. The mechanisms responsible for the beneficial effects of IVmethylprednisolone in attacks are not clearly established and the duration of the effect of this treatment remains controversial.

Patients and methods

We measured by enzyme-like immunosorbent assay (ELISA) serum levels of IL-12, IL-10 and CCL2 before, 5 days and 1 month after the initiation of treatment with IVMP in 20 patients with MS in relapse.

Results

A significant increase of IL-10 and decrease of CCL2 serum levels was observed (p = 0.0028 and 0.045 respectively) five days after the onset of steroid treatment but not after one month. Steroid treatment had no influence in serum levels of IL-12.

Conclusions

The clinical improvement of our MS patients with relapse following the treatment with methylprednisolone may be associated with an immediate but not a long-term modification of serum levels of IL-10 and CCL2. IL-12 may not be influenced by steroid treatment.     

Immune deviation following pulse cyclophosphamide/methylprednisolone treatment of multiple sclerosis: Increased interleukin-4 production and associated eosinophilia

Multiple sclerosis (MS) is postulated to be a Th1-type cell-mediateds autiommune disease. Thus therapies that decrease T cell interferon (IFN)-γ production or increase interleukin (IL)-4 production would be expected to have an ameliorating effect on MS. Some progressive MS patients receiving pulse cyclophosphamide therapy developed periheral blood eosinophilia. We investigated whether cyclophosphamide-treated patients had immune deviation toward Th2 responses. We measured cytokine production in patients receiving either monthly intravenous methylprednisolone (MP), intravenous cyclophosphamide plus methylprednisolone (CY/MP), methotrexate, IFN-β1b, in untreated MS patients, and in healthy controls. Minimal IL-4 was secreted in untreated patients (129 · 62 pg/ml), methotrexate-treated patients (99 · 79 pg/ml), and healthy controls (50 · 13 pg/ml). A marked increase in IL-4 was observed in CY/MP patients (1,503 · 291 pg/ml). Patients treated with MP (418 · 160 pg/ml) or IFN-β1b (425 · 167 pg/ml) showed small increases. Eosinophilia in CY/MP-treated patients (6.0 · 0.7%) correlated with increased IL-4. IL-10 production was also increased in CY/MP-treated patients. Both CY/MP- and MP-treated groups had decreased production of IFN-γ compared with untreated MS. These findings demonstrate pronounced immune deviation favoring Th2-type responses after pulse cyclophosphamide therapy.     

Interleukin-6 is elevated in plasma in multiple sclerosis

Levels of interleukin-6 (IL-6)--a cytokine which induces immunoglobulin production of activated B cells--were measured in cerebrospinal fluid (CSF) and plasma of patients with multiple sclerosis (MS), acute meningo-encephalitis (AM) and muscular tension headache (TH). MS patients had in repeated samples higher levels of IL-6 in plasma compared to patients with AM and TH. IL-6 concentrations in MS plasma were about 17 times higher than MS CSF, while in AM 20-fold higher levels were found in CSF compared to plasma during the acute stage. IL-6 in AM CSF decreased rapidly during clinical recovery. No correlation was found between IL-6 in MS patients' plasma or CSF and disease activity. The functional significance of elevated IL-6 concentrations in MS plasma is unknown, although the findings support the hypothesis of a systemic B cell response in MS.     

No eidence for increased frequency of autoantibodies during interferon-βlb treatment of multiple sclerosis

Interferon-β_lb (IFN-β_lb) is a widespread therapy of multiple sclerosis (MS), reducing the numbers and severity of exacerbations and the total lesion load measured by magnetic resonance imaging of the brain. Since IFN-β_lb has potent immunomodulatory properties, a potential side-effect of IFN-β_lb treatment could be the development of autoimmune responses. The frequencies of antinuclear and smooth muscle antibodies, antibodies against microsomal antigen of thyroid epithelial cells as well as a group of heterophilic antibodies were determined in 26 MS patients treated with IFN-β_lb for 3-20 months. No elevation of antibody titres was found for any of the antibodies studied when compared with paired samples obtained from most of the patients before the initiation of treatment. Although examined on a rather small group of patients, the results show no evidence of increased frequency of autoantibodies during interferon-β_lb treatment of multiple sclerosis.     

甲基强的松龙对多发性硬化患者外周血IL-12和CXCL13的影响

目的通过检测多发性硬化(MS)患者用甲基强的松龙(MP)治疗前后外周血中的白介素-12(IL-12)和趋化因子CXC配体13(CXCL13)水平的变化情况,探讨活化的T细胞和活化的B细胞分泌的细胞因子在发病机制中的作用。方法以酶联免疫吸附(ELISA)方法检测对照组及MP治疗组在治疗前后的IL-12和CXCL13水平。结果MP治疗前,MS患者的IL-12和CXCL13水平显著高于对照组(IL-12p<0.05;CXCL13p<0.01),MP治疗后与治疗前相比,MS患者的IL-12水平显著下降(p<0.05),而CXCL13水平显著升高(p<0.05)。结论MP治疗使IL-12水平降低;使CXCL13水平升高。     

Serial analysis of cytokine mRNA profiles in whole blood samples from patients with early multiple sclerosis

In this pilot study, we serially determined the cytokine messenger RNA (mRNA) expression pattern in whole blood samples from 12 patients with clinical isolated syndrome suggestive of early multiple sclerosis (MS) using a new sensitive quantitative polymerase chain reaction (PCR) method. Significantly higher levels of tumor necrosis factor- (TNF-; ×5.1), interferon-γ (IFN-γ; ×4.8) and interleukin-10 (IL-10; ×5.6) mRNA were detected in MS patients at the time of a relapse compared to healthy controls. Treatment with i.v. methylprednisolone (MP) led to an increase of IL-4 mRNA and a significant decrease of IFN-γ and TNF- mRNA expression. In this cohort of clinically stable patients, proinflammatory cytokines remained low during the 1-year follow-up period. As several indications point to a cytokine dysregulation in MS, quantitative analysis of cytokine mRNA profiles in whole blood samples by real time PCR may be a useful immunological marker to monitor disease activity in future therapeutic trials in MS.     

Neuronal Control of MHC Class II Inducibility in Rat Astrocytes and Microglia

We analysed the inducibility of major histocompatibility complex (MHC) class II molecules of astrocytes and microglia in organotypic hippocampus slice cultures of Lewis rats. Treatment with interferon-γ (IFN-γ) resulted in the induction of MHC class II molecules on microglia preferentially in the injured marginal zones of the slice culture, but only sporadically in areas containing intact neuronal architecture. In astrocytes, inducibility of MHC class II molecules was even more strictly controlled. IFN-γ treatment induced MHC class II expression only in the slice culture zones containing degenerated neurons, and not in the presence of functional neurons. After suppression of spontaneous neuronal activity of the slice culture by the sodium channel blocker tetrodotoxin, MHC class II molecules on astrocytes could be induced by IFN-γ in areas with intact neuronal architecture, and microglia cells exhibited a higher level of expression. These data suggest that loss of neurons could result in MHC class II inducibility of glial cells, and thus in increased immune reactivity of nervous tissue.     

Expression of tumor necrosis factor-alpha and interferon-gamma mRNA in blood cells correlates with depression scores during an acute attack in patients with multiple sclerosis

Depression is a common problem in multiple sclerosis (MS) and affects about 50% of MS patients. Since a dysregulation of cytokine levels has been implicated in the pathogenesis of MS and alterations in cytokine serum levels have been found in depressive illness, we examined the relationship between depressive symptoms, cytokine mRNA expression levels of Th1-type and Th2-type cytokines and neurological disability among early diagnosed MS patients in a prospective study. Sixteen patients with clinically or laboratory supported MS were assessed using the Beck Depression Inventory (BDI) and the Kurtzke Expanded Disability Status Scale (EDSS). Cytokine mRNA in whole blood was serially determined by a new quantitative polymerase chain reaction (PCR) method. BDI sum scores (2,9 fold) and the expression levels of tumor necrosis factor-alpha (TNF-alpha; 4 fold), interferon-gamma (IFN-gamma; 4,6 fold) and interleukin-10 (IL-10; 6,1 fold) mRNA were increased in MS patients during an acute attack compared to age and sex matched healthy controls. We detected a significant positive correlation between TNF-alpha (r=0.55) and interferon-gamma (r=0.54) mRNA expression and the BDI sum scores during an acute attack in MS patients. At follow-up after 3-6 months, only TNF-alpha mRNA expression was correlated with BDI sum scores (r=0.62 resp. r=0.31). No correlation of the BDI sum scores with Th2-type cytokine mRNA expression for interleukin-4 (IL-4) and interleukin-10 (IL-10) or with the extent of neurological disability was observed. The possible contribution of Th1-type cytokines to the development of depression in MS is discussed.     

MxA protein assay for optimal monitoring of IFN-beta bioactivity in the treatment of MS patients

Objectives –  Myxovirus resistance protein A (MxA) can be used as a marker of the bioactivity of interferon-beta (IFN-β) therapy. Two to forty per cent of IFN-β-treated multiple sclerosis (MS) patients develop IFN-β-neutralizing antibodies (NAb) with subsequent attenuation of MxA protein induction. The aim of this study was to set up a simple MxA enzyme immunoassay (EIA) for the measurement of MxA protein and to evaluate the EIA test by comparing the results with flow cytometric analysis and the measurement of NAb.
Methods –  total of 51 IFN-β-treated relapsing–remitting MS (RRMS) patients were tested for MxA protein expression by using both MxA EIA assay and flow cytometric analysis. Thirteen patients were confirmed to be NAb-positive.
Results –  The correlation between EIA and flow cytometric analysis was significant with a wider range of measured levels in the EIA. Patients with NAb had low MxA levels, but in some patients, remaining MxA induction could be detected despite NAb.
Conclusions –  The MxA EIA assay seems to be a practical method for large-scale analysis of the bioactivity of IFN-β treatment.     

The immunomodulatory properties of in vitro immunoglobulins are dose-dependent

OBJECTIVES: The mechanism by which intravenous immunoglobulins (immunoglobulin G, IgG) exert their beneficial effect on multiple sclerosis (MS) is unknown. Furthermore, there is uncertainty about the optimal dosage of IgG. Therefore, we investigated the influence of different IgG dosages on cytokine production in MS. MATERIALS AND METHODS: Twenty-five MS patients and 15 healthy controls were enrolled. We measured the production of interferon gamma (IFN-gamma), tumour necrosis factor alpha (TNF) and interleukin 10 (IL-10) in peripheral blood lymphocytes by flowcytometry after stimulation without and with IgG in different doses (1, 5 and 10 mg/ml). RESULTS: IFN-gamma and TNF were decreased significantly (P = 0.001) in the untreated and interferon beta (IFN-beta) treated patients after stimulation with IgG. In contrast, IL-10 production was significantly enhanced (P = 0.001) at least in the untreated patient group. The reduction of the pro-inflammatory cytokines IFN-gamma and TNF after stimulation with different IgG doses was clearly dose-dependent in all groups. CONCLUSION: Besides a suppression of the pro-inflammatory cytokines IFN-gamma and TNF, IgG enhances the anti-inflammatory cytokine IL-10. This effect is dose-dependent, speaking in favour of higher IgG doses in the treatment of MS.     

Correlations between IL-4, IL-12 levels and CCL2, CCL5 levels in serum and cerebrospinal fluid of multiple sclerosis patients

Summary. Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS). Both cytokines and chemokines have been implicated in the pathogenesis of MS. The aim of the study was to assess whether cytokine levels are correlated with chemokine levels during a different stage of relapsing-remitting MS (RR-MS). The study included 53 patients with RR-MS (20 subjects in stable stage and 18 patients with relapse). By ELISA method, the levels of the interleukin-4 (IL-4), interleukin-12 (IL-12), CCL2 and CCL-5 chemokines were measured both in serum and cerebrospinal fluid (CSF) of all patients. The serum IL-4 and IL-12 levels and CSF CCL5 level of patients with stable RR-MS were significantly different from the control level and the IL-12 levels were correlated with CCL5 levels in serum. During the relapse, a significant change in chemokine levels both in serum and CSF and IL-12 in CSF were noted, however no correlations were found between cytokines and chemokines.     

Interferon effects on interleukin-10 secretion Mononuclear cell response to interleukin-10 is normal in multiple sclerosis patients

The mechanism of action of recombinant Interferon β_1b (rIFNβ_1b/IFN β-1b), the approved therapy for multiple sclerosis (MS), is still unclear. Here we present evidence that part of the therapeutic effects of rIFNβ_1b in MS might result from the induction of the secretion of interleukin (IL)-10, a cytokine previously designated cytokine synthesis inhibitory factor (CSIF). We observed that rIFNβ_1b stimulated significant IL-10 secretion by monocytes from MS patients after brief incubation (18 h), whereas rIFNγ, an inducer of MS exacerbations, was unable to stimulate IL-10 production in similar conditions. To determine the role of IL-10 as CSIF in the disease, we have also investigated its effects on TNFα and IL-6 secretion by peripheral blood mononuclear cells from MS patients. Recombinant human IL-10 significantly inhibited tumor necrosis factor α and IL-6 secretion induced by rIFNγ, lipopolysaccharide (LPS), and rIFNγ + LPS in MS patients and in control subjects. The induction of IL-10 secretion by rIFNβ_1b and the IL-10 inhibitory activity o pro-inflammatory cytokine secretion induced by rIFNγ in MS make this cytokine a potential candidate to treat the disease.     

Induction and regulation of interleukin-6 gene expression in rat astrocytes

Cells that produce interleukin-6 (IL-6) require the presence of signaling molecules since this cytokine is not normally constitutively expressed. It is now established that astrocytes produce IL-6; however, the precise inducing molecules and the kinetics of their action have not yet been clearly identified. In the current study, we show that either interleukin-1 beta (IL-1 beta) or tumor necrosis factor-alpha (TNF-alpha) exert a strong inducing signal for IL-6 in primary rat astrocytes. When the two cytokines are added together the response is synergistic, suggesting that each cytokine may induce IL-6 gene expression by different pathways. Interferon-gamma (IFN-gamma) does not affect IL-6 expression although if it is added in conjunction with IL-1 beta, an augmented induction of IL-6 occurs. In addition to the cytokines, bacterial lipopolysaccharide (LPS) and the calcium ionophore, A23187, induce IL-6 expression. IL-6 expression can be blocked by the glucocorticoid analogue, dexamethasone. IL-6 induction by LPS/Ca2+ ionophore is more sensitive to the suppressive effects of dexamethasone than is IL-6 induction by TNF-alpha/IL-1 beta. Cycloheximide (CHX), an inhibitor of protein synthesis, markedly increased levels of IL-6 mRNA in both unstimulated and stimulated astrocytes, indicating that ongoing protein synthesis is not required for astrocyte IL-6 gene expression. We propose that astrocyte-produced IL-6 may have a role in augmenting intracerebral immune responses in neurological diseases such as multiple sclerosis (MS), AIDS dementia complex (ADC), and viral infections. These diseases are characterized by infiltration of lymphoid and mononuclear cells into the central nervous system (CNS), and intrathecal production of immunoglobulins. IL-6 may act to promote terminal differentiation of B cells in the CNS, leading to immunoglobulin synthesis.