Is the modulatory effect of pregnancy in multiple sclerosis associated with changes in blood apoptotic molecules?

Rinta S, Airas L, Elovaara I. Is the modulatory effect of pregnancy in multiple sclerosis associated with changes in blood apoptotic molecules? Acta Neurol Scand: 2010: 122: 168–174. © 2010 John Wiley & Sons A/S. Objective – We examined whether the modulatory effect of pregnancy on multiple sclerosis (MS) is associated with changes in the apoptotic molecules in sera. Subjects and methods – The serum levels of tumor necrosis factor‐related apoptosis‐inducing ligand (sTRAIL), sFas, Fas ligand (sFasL) and macrophage migration inhibitory factor were analyzed from 19 MS patients and 14 controls during late pregnancy and post‐partum. The obtained results were related to disease activity and the progression of MS. Results – Disease activity decreased during pregnancy. The levels of sTRAIL and sFasL increased from late pregnancy to post‐partum situation in both MS patients and controls, but in MS patients the changes in the levels of sTRAIL from late pregnancy to post‐partum were smaller than in controls. Conclusions – Post‐partum upregulation of TRAIL and FasL seems to be caused by physiologic reactivation of the mother’s immune system after pregnancy. An increased risk of relapses in MS post‐partum may be associated with changes in the immunomodulatory potential of these apoptotic molecules.     

BAFF is up-regulated in central nervous system of neuro-Behçet's disease

We report that B cell-activating factor of the tumor necrosis factor family (BAFF) is expressed in central nervous system (CNS) of neuro-Beh?et's disease (NBD). This study investigated BAFF and BAFF-R (BAFF receptor) in NBD, compared to multiple sclerosis (MS) and to non inflammatory neurological diseases (NIND). Cerebrospinal fluid (CSF) was used to determine the level of BAFF messenger RNA (mRNA) and the level of BAFF-R mRNA in unfractionated cells. A sandwich ELISA was used to quantify soluble BAFF protein levels in serum and in CSF. BAFF and BAFF-R expression in CSF were increased in NBD and MS patients compared to NIND patients. RNA levels of BAFF and BAFF-R were significantly correlated in NBD and MS patients. Serum sBAFF levels were increased in NBD and MS patients, but did not correlate with BAFF expression in CSF. CNS-produced BAFF may support inflammatory cell survival in NBD.     

Frequency and severity of headache is worsened by Interferon-β therapy in patients with multiple sclerosis

Patti F, Nicoletti A, Pappalardo A, Castiglione A, Lo Fermo S, Messina S, D’Amico E, Cimino V, Zappia M. Frequency and severity of headache is worsened by Interferon‐β therapy in patients with multiple sclerosis.
Acta Neurol Scand: 2012: 125: 91–95.
© 2011 John Wiley & Sons A/S. Background – The relationship between multiple sclerosis (MS) and headache (HA) is not well known. It was reported that interferon‐beta (IFNβ) could induce or worsen HA. Objective – To evaluate the impact of IFNβ treatment on HA and the relationship between HA and the various commercial preparations of IFNβ in mildly disabled patients with MS. Methods – A specific questionnaire was administered to 357 relapsing‐remitting MS patients. Characteristics of HAs were considered, including the temporal relationships with IFNβ administration. Results – One hundred and seventeen patients were treated with weekly intramuscular injections of interferon IFNβ‐1a (Avonex^®), 84 with subcutaneous injections of IFNβ‐1b (Betaferon^®) every other day, 48 and 108 with three times weekly subcutaneous injections of IFNβ‐1a (Rebif^®) 22 mcg or IFNβ‐1a (Rebif^®) 44 mcg, respectively. Three hundred and fourteen patients were affected by HA, and among them, 219 patients suffered of pre‐existing HA. In this latter group, 121 subjects (55%) noted a worsening of their HA after starting IFNβ therapy; this was more frequently reported by patients treated with Avonex^® and Rebif^® 44. Ninety‐five patients experienced new HA. Conclusion – IFNβ treatment could worsen HA in patients with pre‐existing HA or cause the appearance of new HA. Among different IFNβ preparations, Rebif^® 44 and Avonex^® seemed to be more cephalalgic than the other drugs.     

视神经脊髓炎患者血清及脑脊液中B淋巴细胞活化因子的表达水平与临床意义

目的 探讨视神经脊髓炎患者血清及脑脊液中B淋巴细胞活化因子的表达水平及其临床意义。方法 选取2011年1月-2015年1月本院收治的视神经脊髓炎(NMO)患者50例及多发性硬化(MS)患者50例,将其分别作为NMO组与MS组,另选取同期于本院进行体检的非炎性神经系统疾病患者50例作为对照组,对3组血清及脑脊液中的B淋巴细胞活化因子(BAFF)水平进行检测。结果 与对照组比较,NMO组与MS组血清中BAFF水平均无明显变化(P>0.05),而NMO组与MS组脑脊液中BAFF水平均明显升高(P<0.05); 与MS组比较,NMO组脑脊液中BAFF水平明显升高(P<0.05)。NMO组与MS组脑脊液中BAFF水平与EDSS评分呈正相关,即脑脊液中BAFF水平随EDSS评分升高而升高(r=0.887,0.885,P<0.01)。结论 视神经脊髓炎患者脑脊液中的B淋巴细胞活化因子水平较高,可能是诊断视神经脊髓炎的重要标志物,对疾病严重程度的判定具有重要的临床意义。     

Identification of new sensitive biomarkers for the in vivo response to interferon‐β treatment in multiple sclerosis using DNA‐array evaluation

Objective: Neutralizing antibodies (NAbs) occur in a proportion of multiple sclerosis (MS) patients treated with interferon (IFN)‐β. NAbs impair the effect of treatment. The biological effect of IFN‐β can be measured as the induction of the myxovirus resistance protein A (MxA) molecule. However, other markers could be more sensitive for evaluating the response to IFN‐β. We used DNA array analysis to identify genes that are strongly induced in blood cells by IFN‐β, and measured their expression in MS patients with different NAb levels. Methods: Gene expression was studied on DNA arrays in untreated patients, in NAb negative patients, and in MS patients with varying NAb levels 9–12 h and 36–48 h after IFN‐β administration. The expression of selected genes was measured by real‐time PCR. NAb levels were assessed by a cytopathic effect assay. Results: Several hundred genes were induced 9–12 h after an injection of IFN‐β. The molecules CXCL10, CCL2 and IFI27 were among the most strongly induced. Gene induction was generally much less pronounced after 36–48 h, but IFI27 remained strongly induced. The strong induction of these molecules and MxA was confirmed by real‐time PCR. Induction of MxA, CCL2, CXCL10 and IFI27 was reduced in patients with low NAb levels and lost in patients with intermediate/high NAb levels. Conclusion: We identify IFI27, CCL2 and CXCL10 as sensitive biomarkers for the response to IFN‐β. The expression of these markers adequately reflects bioactivity of IFN‐ß as documented by the decreased induction in low NAb‐positive patients and the lost induction in patients with moderate/high NAb levels.     

Upregulation of TRAIL expression on human T lymphocytes by interferon beta and glatiramer acetate

We measured the in vivo and in vitro effects of interferon (IFN)beta and glatiramer acetate (GA) on the expression of the regulatory molecule, tumor necrosis factor related apoptosis inducing ligand (TRAIL), in patients with multiple sclerosis (MS). We confirmed the prior observation that TRAIL is enhanced on anti-CD3 activated T cells by the in vitro addition of IFNbeta. T cells from IFNbeta-treated patients stimulated with anti-CD3 only, had higher levels of TRAIL than untreated patients, suggesting that in vivo IFNbeta exposure has an effect on TRAIL expression in association with T cell activation. In vitro IFNbeta-induced TRAIL upregulation on anti-CD3 or phytohemagglutinin-activated T cells was comparable for IFNbeta-treated and non-treated MS patients and controls, indicating that IFN receptors were neither saturated nor down-regulated by current IFNbeta therapy. Although GA in vivo or in vitro did not induce TRAIL, the IFNbeta +GA combination in vitro enhanced TRAIL expression to higher levels than IFNbeta alone on CD4+ T cells obtained from MS patients, regardless of GA treatment status, and healthy donors, and on GA reactive T cell lines derived from GA-treated patients or controls. Whether any observed therapeutic effects of GA/IFNbeta combination therapy will correlate with TRAIL expression and function remains to be determined.     

Multiple sclerosis and cognitive decline: is ApoE‐4 a surrogate marker?

Carmona O, Masuet C, Santiago O, Alía P, Moral E, Alonso‐Magdalena L, Casado V, Arbizu T. Multiple sclerosis and cognitive decline: is ApoE‐4 a surrogate marker?
Acta Neurol Scand: 2011: 124: 258–263.
© 2011 John Wiley & Sons A/S. Background – The role of the apolipoprotein E (ApoE) polymorphism has been well demonstrated in neurodegenerative disorders such as Alzheimer. However, its role in multiple sclerosis (MS) remains unclear. Aims – The aims of our study were as follows: (i) to assess whether ApoE‐4 might be a surrogate marker of cognitive decline in MS; (ii) to confirm the presence of cognitive impairment in mildly disabled patients treated with interferon‐beta; and (iii) to analyse the correlation between cognitive disturbances and clinical variables. Material and methods – Fifty relapsing‐remitting MS patients underwent a battery of neuropsychological tests and were genotyped for ApoE. Their scores were compared with those of 35 controls. Results – No association was found between ApoE‐4 and cognitive impairment. Significant differences in most domains were observed between MS and the control group. Cognitive decline was not related to disability progression. Conclusion – No association between cognitive impairment and ApoE‐4 or clinical markers was detected in our MS patients.     

Impact of cladribine on soluble adhesion molecules in multiple sclerosis

Mitosek‐Szewczyk K, Stelmasiak Z, Bartosik‐Psujek H, Belniak E. Impact of cladribine on soluble adhesion molecules in multiple sclerosis.
Acta Neurol Scand: 2010: 122: 409–413.
© 2010 The Authors Journal compilation © 2010 Blackwell Munksgaard. Background – Soluble forms of vascular cell adhesion molecule‐1 (VCAM‐1), intracellular adhesion molecule‐1 (ICAM‐1) and E‐Selectin play a role in the regulation of blood–brain barrier damage and represent markers of the clinical course of multiple sclerosis (MS) and magnetic resonance imaging activity. We determined sICAM, sVCAM and sE‐Selectin concentrations in the cerebrospinal fluid (CSF) and serum of patients with remitting–relapsing multiple sclerosis before and after cladribine treatment as well as in a control group. Methods – We examined 17 patients diagnosed according to McDonald’s criteria. Thirteen healthy age‐matched subjects served as controls. The ELISA method was used to measure sICAM‐1, sVCAM‐1 and sE‐Selectin. Results – The concentration of sICAM and sE‐Selectin decreased in sera (difference between patients and controls was statistically significant, in the former P < 0.04, in the latter P < 0.0003) but not in the CSF of MS patients after cladribine treatment. Conclusions – The reduction in sICAM and sE‐Selectin concentrations after cladribine treatment indicates an immuno‐suppressive effect of the drug. The changes in levels of sICAM and sE‐Selectin after cladribine treatment reflect disease activity and indicate a reduction in the inflammatory reaction.     

Intrathecal levels of vitamin D and IgG in multiple sclerosis

Holmøy T, Lossius A, Gundersen TE, Moen SM, Castellazzi M, Fainardi E, Casetta I. Intrathecal levels of vitamin D and IgG in multiple sclerosis.
Acta Neurol Scand: 2012: 125: e28–e31.
© 2011 John Wiley & Sons A/S. Background – Intrathecal synthesis of IgG is a hallmark of multiple sclerosis (MS). Vitamin D may modulate B‐cell function and dampen the synthesis of IgG. Objective – To investigate the relation between vitamin D levels in cerebrospinal fluid and serum and intrathecal synthesis of IgG. Methods – 25‐hydroxyvitamin D (25(OH)D) and IgG were assessed in cerebrospinal fluid and serum in 40 patients with MS. Results – There was no significant correlation between the IgG index and 25(OH)D levels in cerebrospinal fluid or serum. The levels of 25(OH)D in cerebrospinal fluid and serum did not differ between patients with and without intrathecal synthesis of IgG. There was a non‐significant trend towards a positive correlation between the concentrations of 25(OH)D and IgG in the cerebrospinal fluid, but not in serum. Conclusion – Physiological variation in vitamin D does not exert a major impact on intrathecal synthesis of IgG in MS.     

Expression of B-cell-activating factor of the TNF family (BAFF) and its receptors in multiple sclerosis

The role of B cells and antibodies in the pathogenesis of multiple sclerosis (MS) is controversial. We investigated the expression of B-cell-activating factor of the tumor necrosis factor family (BAFF), a protein indispensable for B-cell survival, and of its three receptors in MS patients and controls. BAFF mRNA levels in monocytes, and BAFF-receptor mRNA in B and T cells, were higher in patients than in healthy controls; yet, BAFF protein levels in cerebrospinal fluid and plasma were similar in patients and headache controls. In addition, each MS disease course was associated with a unique expression pattern for all four molecules.     

TRAIL, CXCL10 and CCL2 plasma levels during long-term Interferon-beta treatment of patients with multiple sclerosis correlate with flu-like adverse effects but do not predict therapeutic response

High serum levels of soluble TRAIL (sTRAIL) before or during the first year of Interferon-beta (IFN-beta) therapy were shown to predict an individual therapeutic response of patients with relapsing-remitting multiple sclerosis (RRMS). Here, we investigated whether sTRAIL plasma levels during long-term IFN-beta treatment correlate with future therapeutic response or adverse effects of treatment. Postinjection short-time bursts of sTRAIL were associated with flu-like symptoms and IP-10/CXCL10 as well as MCP-1/CCL2 induction, and were detected after up to 6 years of continuous IFN-beta therapy. However, neither sTRAIL nor chemokine levels allowed prediction of one- and two-year clinical treatment response in 30 RRMS patients, prospectively followed by blinded investigators.     

Review: On TRAIL for malignant glioma therapy?

J. M. A. Kuijlen, E. Bremer, J. J. A. Mooij, W. F. A. den Dunnen and W. Helfrich (2010) Neuropathology and Applied Neurobiology 36, 168–182
On TRAIL for malignant glioma therapy? Glioblastoma (GBM) is a devastating cancer with a median survival of around 15 months. Significant advances in treatment have not been achieved yet, even with a host of new therapeutics under investigation. Therefore, the quest for a cure for GBM remains as intense as ever. Of particular interest for GBM therapy is the selective induction of apoptosis using the pro‐apoptotic tumour necrosis factor‐related apoptosis‐inducing ligand (TRAIL). TRAIL signals apoptosis via its two agonistic receptors TRAIL‐R1 and TRAIL‐R2. TRAIL is normally present as homotrimeric transmembrane protein, but can also be processed into a soluble trimeric form (sTRAIL). Recombinant sTRAIL has strong tumouricidal activity towards GBM cells, with no or minimal toxicity towards normal human cells. Unfortunately, GBM is a very heterogeneous tumour, with multiple genetically aberrant clones within one tumour. Consequently, any single agent therapy is likely to be not effective enough. However, the anti‐GBM activity of TRAIL can be synergistically enhanced by a variety of conventional and novel targeted therapies, making TRAIL an ideal candidate for combinatorial strategies. Here we will, after briefly detailing the biology of TRAIL/TRAIL receptor signalling, focus on the promises and pitfalls of recombinant TRAIL as a therapeutic agent alone and in combinatorial therapeutic approaches for GBM.     

脑脊液BAFF、VEGF水平在视神经 脊髓炎患者中的变化及其意义

目的 探讨脑脊液B淋巴细胞活化因子(BAFF)、血管内皮生长因子(VEGF)水平在视神经脊髓炎(NMO)患者中的变化及其意义。方法 选取2015年1月-2018年1月本院收治的NMO患者50例作为NMO组,选取同期多发性硬化症(MS)患者50例作为MS组及非炎性神经系统疾病患者50例作为对照组,所有患者均检测脑脊液BAFF、VEGF水平、急性期扩展残疾状态量表(EDSS)评分、水通道蛋白4抗体(AQP4-Ab)滴度,分析BAFF、VEGF与EDSS评分、AQP4-Ab滴度的关系。结果 NMO组和MS组脑脊液BAFF、VEGF水平明显高于对照组,NMO组脑脊液BAFF、VEGF水平和EDSS评分、AQP4-Ab滴度阳性率明显高于对照组(P<0.05); Pearson相关性分析显示,脑脊液BAFF、VEGF水平均与EDSS评分呈正相关(r=0.695,0.668,P<0.05),但均与AQP4-Ab滴度无关(r=0.121,0.116,P>0.05)。结论 脑脊液BAFF、VEGF水平与NMO的发生发展有关,检测二者水平可作为鉴别NMO、MS及评估NMO病情的重要参考指标。     

MRI and visual-evoked potentials in partners of multiple sclerosis patients

Hawkes CH, Chawda S, Derakshani S, Muhammed N, Visentin E, Boniface D. MRI and visual‐evoked potentials in partners of multiple sclerosis patients.
Acta Neurol Scand: 2012: 125: 424–430.
© 2011 John Wiley & Sons A/S. Objective – Some epidemiological evidence, particularly concerning the role of Epstein Barr Virus implies that multiple sclerosis (MS) may be transmissible and if correct, this might be revealed by increased prevalence of MS in cohabiting partners. Methods – We addressed this problem by neurological assessment, visual‐evoked potentials (VEP) and magnetic resonance imaging (MRI) in 112 partners of patients with MS in comparison to a control group of 93 individuals with clinically non‐significant head or neck pain and in comparison to UK prevalence. Results – We found one instance of conjugal definite MS. Including this case, VEP were abnormal in five instances with either significant delay (n = 3) or increased interocular latency difference (IOLD) (n = 2) in partners of MS patients thus raising the possibility of subclinical optic nerve demyelination. The mean absolute value of IOLD in partners was greater than the value in controls (P = 0.033). There were no significant differences in MRI findings between the two groups. Conclusion – The finding of one conjugal pair and abnormal VEP in a further four MS partners could have several explanations. It is compatible with the concept of a transmissible agent, although our observations could be due to several biases as well as the play of chance alone.     

The Combination of Interferon‐Beta and HMG‐CoA Reductase Inhibition in Multiple Sclerosis: Enthusiasm Lost too Soon?

Recent studies support the notion that statins, widely prescribed cholesterol‐lowering agents, may target key elements in the immunological cascade leading to inflammation and tissue damage in the pathogenesis of multiple sclerosis (MS). Compelling experimental and observational clinical studies highlighted the possibility that statins may also exert immunomodulatory synergy with approved MS drugs, resulting in several randomized clinical trials testing statins in combination with interferon‐beta (IFN‐β). Some data, however, suggest that this particular combination may not be clinically beneficial, and might actually have a negative effect on the disease course in some patients with MS. In this regard, a small North American trial indicated that atorvastatin administered in combination with IFN‐β may increase disease activity in relapsing‐remitting MS. Although other trials did not confirm this finding, the enthusiasm for studies with statins dwindled. This review aims to provide a comprehensive overview of the completed clinical trials and reports of the interim analyses evaluating the combination of IFN‐β and statins in MS. Moreover, we try to address the evident question whether usage of this combination routinely requires caution, since the number of IFN‐β‐treated MS patients receiving statins for lowering of cholesterol is expected to grow.     

B‐cell–activating factor is elevated in serum of patients with myasthenia gravis

Introduction: Myasthenia gravis (MG) is a B‐cell–mediated autoimmune disease. B‐cell–activating factor (BAFF) is a major factor in B‐cell development and activation. In this study we investigated serum BAFF levels in MG patients. Methods: We compared the serum BAFF levels of 20 MG patients with gender‐matched healthy controls. We assayed serum concentrations of BAFF and anti‐acetylcholine receptor antibody (AChR) titers. Results: Serum BAFF levels of MG patients with AChR antibodies were significantly higher than those of healthy controls. A significant positive correlation was observed between serum BAFF levels and anti‐AChR antibody titers. BAFF values did not correlate with disease severity. Conclusions: BAFF may play a major role in the pathogenesis of MG, and it may provide a potential target for therapy in patients with MG. Muscle Nerve 54 : 1030–1033, 2016     

Myelin glycosphingolipid immunoreactivity and CSF levels in multiple sclerosis

Haghighi S, Lekman A, Nilsson S, Blomqvist M, Andersen O. Myelin glycosphingolipid immunoreactivity and CSF levels in multiple sclerosis.
Acta Neurol Scand: 2012: 125: 64–70.
© 2011 John Wiley & Sons A/S. Objectives – Patients with multiple sclerosis were reported to harbour antibodies not only against proteins and glycoproteins but also against glycolipids, including sulfatide and galactosylceramide (GalCer), the two major glycosphingolipids of myelin. However, previous results were inconsistent concerning glycosphingolipid levels, antibody type, dominance of serum or Cerebrospinal fluid compartments and relationship to the multiple sclerosis (MS) course. Results – We hereby report that the cerebrospinal fluid levels of sulfatide were increased in patients with MS (n = 46) compared with controls (n = 50, P < 0.001). In addition, patients had higher serum IgM anti‐glycosphingolipid titres than controls (P = 0.03 for sulfatide, <0.001 for GalCer), while the anti‐glycosphingolipid IgM antibodies in the cerebrospinal fluid were essentially normal. However, in seven of 46 patients cerebrospinal fluid IgG antibodies against GalCer (P = 0.004) could be detected, which was not found in any of the control individuals, and this finding might mirror the occurrence of more specific B‐cell clones behind the blood–brain barrier. Conclusions – The IgM immunoreactivity in serum did not show any relationship to the type of course or severity of MS, arguing against a phenomenon secondary to myelin damage. Thus, the IgM antibody findings are compatible with an early antigen challenge or autoimmunity associated with natural antibodies.