Intravenous Immunoglobulins Are a Therapeutic Option in the Treatment of Multiple Sclerosis Relapse

Elovaara, Irina; Kuusisto, Hanna; Wu, Xingchen; Rinta, S.; Dastidar, Prasun; Reipert, Birgit M.

doi:10.1097/wnf.0b013e31820a17f3

Cited by 29 publications

(24 citation statements)

References 38 publications

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“…In the context of MOG 35-55 -induced EAE pathogenesis, this finding might be relevant, as recent evidence suggest that autoimmune-prone FcγRIIb-deficient mice exhibit more pronounced MOG 35-55 -induced EAE disease [60]. Importantly, intravenous Ig (IVIG) injection, which is reportedly therapeutic in MOG 35-55 -induced EAE [69] and has exhibited some evidence of efficacy in MS [70], may act by targeting the low-affinity IgG inhibitory receptor FcγRIIb [71]. Therefore, one could speculate that EndoS treatment in MOG 35-55 -EAE may have a dual anti-inflammatory activity, both inhibiting the activation of the complement and shifting the binding of pathogenic IgG toward the inhibitory action mediated through FcγRIIb.…”

Section: Discussionmentioning

confidence: 99%

IgG glycan hydrolysis by EndoS inhibits experimental autoimmune encephalomyelitis

Benkhoucha

Molnarfi

Santiago-Raber

et al. 2012

J Neuroinflammation

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Studies in experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis, have shown that B cells markedly influence the course of the disease, although whether their effects are protective or pathological is a matter of debate. EndoS hydrolysis of the IgG glycan has profound effects on IgG effector functions, such as complement activation and Fc receptor binding, suggesting that the enzyme could be used as an immunomodulatory therapeutic agent against IgG-mediated diseases. We demonstrate here that EndoS has a protective effect in myelin oligodendrocyte glycoprotein peptide amino acid 35–55 (MOG35-55)-induced EAE, a chronic neuroinflammatory demyelinating disorder of the central nervous system (CNS) in which humoral immune responses are thought to play only a minor role. EndoS treatment in chronic MOG35-55-EAE did not impair encephalitogenic T cell priming and recruitment into the CNS of mice, consistent with a primary role of EndoS in controlling IgG effector functions. In contrast, reduced EAE severity coincided with poor serum complement activation and deposition within the spinal cord, suggesting that EndoS treatment impairs B cell effector function. These results identify EndoS as a potential therapeutic agent against antibody-mediated CNS autoimmune disorders.

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Section: Discussionmentioning

confidence: 99%

IgG glycan hydrolysis by EndoS inhibits experimental autoimmune encephalomyelitis

Benkhoucha

Molnarfi

Santiago-Raber

et al. 2012

J Neuroinflammation

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“…[111][112][113][114][115][116][117] The humoral immune response may be particularly important when studying neurodegeneration. 1,4,[37][38][39][40][41]118 For example, patients with progressive disease are more likely to have B-cell follicle-like structures in the cerebral meninges.…”

Section: Antibodies As Contributors To Neurodegeneration and The Pathmentioning

confidence: 99%

Pathogenic mechanisms of neurodegeneration based on the phenotypic expression of progressive forms of immune-mediated neurologic disease

Levin¹,

Lee²,

Gardner³

et al. 2012

DNND

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Considering there are no treatments for progressive forms of multiple sclerosis (MS), a comprehensive understanding of the role of neurodegeneration in the pathogenesis of MS should lead to novel therapeutic strategies to treat it. Many studies have implicated viral triggers as a cause of MS, yet no single virus has been exclusively shown to cause MS. Given this, human and animal viral models of MS are used to study its pathogenesis. One example is human T-lymphotropic virus type 1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Importantly, HAM/TSP is similar clinically, pathologically, and immunologically to progressive MS. Interestingly, both MS and HAM/TSP patients were found to make antibodies to heterogeneous nuclear ribonucleoprotein (hnRNP) A1, an RNA-binding protein overexpressed in neurons. Anti-hnRNP A1 antibodies reduced neuronal firing and caused neurodegeneration in neuronal cell lines, suggesting the autoantibodies are pathogenic. Further, microarray analyses of neurons exposed to anti-hnRNP A1 antibodies revealed novel pathways of neurodegeneration related to alterations of RNA levels of the spinal paraplegia genes (SPGs). Mutations in SPGs cause hereditary spastic paraparesis, genetic disorders clinically indistinguishable from progressive MS and HAM/TSP. Thus, there is a strong association between involvement of SPGs in neurodegeneration and the clinical phenotype of progressive MS and HAM/TSP patients, who commonly develop spastic paraparesis. Taken together, these data begin to clarify mechanisms of neurodegeneration related to the clinical presentation of patients with chronic immune-mediated neurological disease of the central nervous system, which will give insights into the design of novel therapies to treat these neurological diseases.

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“…However, the PRIVIG study also reported that the number of newly active lesions was lower and that the reduction of brain parenchymal volume was significantly smaller in an RRMS group with a high dose of hIgG (0.4 g/kg of bodyweight) than in a placebo group . There have also been reports showing the efficacy of hIgG for relapse prevention and the attenuation of acute exacerbation . Finally, it is important to note that the safety of disease‐modifying therapies, such as IFN‐β, glatiramer acetate and fingolimod, has not been fully confirmed in pregnant or breastfeeding patients with RRMS .…”

Section: Discussionmentioning

confidence: 99%

Human immunoglobulin G suppresses the production of matrix metalloproteinase‐9 in peripheral blood mononuclear cells of patients with multiple sclerosis

Okada

2015

Clinical & Exp Neuroim

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Objective Matrix metalloproteinase (MMP)-9 is a key molecule that indicates disruption of the blood-brain barrier (BBB), and is recognized as a candidate biomarker of disease activity in multiple sclerosis (MS). The aim of the present study was to determine whether human immunoglobulin G (hIgG) could reduce the production of MMP-9 in peripheral blood mononuclear cells (PBMC) from patients with MS. Methods We investigated the effect of hIgG on the expression of MMP-9 and tissue inhibitor of metalloproteinase (TIMP)-1 in PBMC of patients with relapsing-remitting MS (RRMS) compared with healthy controls (HC) in vitro. Results Patients with RRMS were not receiving any disease-modifying therapies when blood was sampled in this study. Although levels of MMP-9 and TIMP-1 in PBMC were not different between RRMS and HC groups, the MMP-9/TIMP-1 ratio was significantly increased in patients with RRMS when compared with HC. PBMC that were stimulated with lipopolysaccharide (LPS, 1 lg/mL) expressed a higher level of MMP-9 in RRMS than the HC groups, although the level of TIMP-1 was equal between groups. hIgG reduced the level of MMP-9 in PBMC from both patients with RRMS and HC with LPS stimulation in a dose-dependent manner, but had no effect on the expression of TIMP-1. The MMP-9/TIMP-1 ratio in both patients with RRMS and HC was also decreased by hIgG. The effect of hIgG was not through neutralization of MMP-9. hIgG alone did not induce MMP-9 mRNA, and suppressed the upregulation of mRNA in PBMC stimulated with LPS. Conclusions These results suggest that hIgG could be effective in treating patients with RRMS though the inhibition of the transmigration of immune cells into the brain parenchyma.

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Intravenous Immunoglobulins Are a Therapeutic Option in the Treatment of Multiple Sclerosis Relapse

Cited by 29 publications

References 38 publications

IgG glycan hydrolysis by EndoS inhibits experimental autoimmune encephalomyelitis

IgG glycan hydrolysis by EndoS inhibits experimental autoimmune encephalomyelitis

Pathogenic mechanisms of neurodegeneration based on the phenotypic expression of progressive forms of immune-mediated neurologic disease

Human immunoglobulin G suppresses the production of matrix metalloproteinase‐9 in peripheral blood mononuclear cells of patients with multiple sclerosis

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