Intrathecal EBV antibodies are part of the polyspecific immune response in multiple sclerosis

Otto, Carolin; Oltmann, Anke; Stein, Angela; Frenzel, Katrin; Schroeter, Jan; Habbel, Piet; Gärtner, B; Hofmann, Jörg; Ruprecht, Klemens

doi:10.1212/wnl.0b013e318215286d

Cited by 45 publications

(49 citation statements)

References 25 publications

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“…There has been some epidemiologic evidence linking MS to other viral infections, especially to Epstein-Barr virus (EBV), however the underling mechanism is elusive (Otto et al 2011). About 90% of patients with MS show an elevated antibody index against one or more neurotropic viruses (Otto et al 2011), although this is possibly due as part of a polyspecific intrathecal humoral immune response (Otto et al 2011). Patients with HIV also show high intrathecal immunoactivation, up to the point that intrathecal immunoglobulin production can be measured even after years of effective HAART treatment and undetectable viral load (Eden et al 2007).…”

Section: Discussionmentioning

confidence: 99%

Multiple sclerosis typical clinical and MRI findings in a patient with HIV infection

et al. 2011

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MS is usually considered late in patients with HIV. A typical MS course with suggestive MRI lesions and absence of severe immune suppression should suggest the diagnosis. It is possible that as with other MS patients, earlier initiation of specific treatments for MS will prevent the high burden of the disease and disability in these patients, but stronger evidence for specific recommendations remains to be obtained.

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Section: Discussionmentioning

confidence: 99%

Multiple sclerosis typical clinical and MRI findings in a patient with HIV infection

et al. 2011

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“…This suggests virus-specific responses within the CNS and thus indirectly suggests the presence of virus in this compartment [32]. This intrathecal response, however, has also been suggested to be part of the polyspecific response in MS [33]. Whether EBV is present in MS brains and particularly in the MS plaques is an important issue with conflicting reports in the literature.…”

Section: Is Ebv Present In Ms Brains?mentioning

confidence: 99%

Viruses and Multiple Sclerosis

Virtanen¹,

Jacobson²

2012

CNSNDDT

139

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Multiple sclerosis (MS) is a heterogeneous disease that develops as an interplay between the immune system and environmental stimuli in genetically susceptible individuals. There is increasing evidence that viruses may play a role in MS pathogenesis acting as these environmental triggers. However, it is not known if any single virus is causal, or rather several viruses can act as triggers in disease development. Here, we review the association of different viruses to MS with an emphasis on two herpesviruses, Epstein-Barr virus (EBV) and human herpesvirus 6 (HHV-6). These two agents have generated the most impact during recent years as possible co-factors in MS disease development. The strongest argument for association of EBV with MS comes from the link between symptomatic infectious mononucleosis and MS and from seroepidemiological studies. In contrast to EBV, HHV-6 has been found significantly more often in MS plaques than in MS normal appearing white matter or non-MS brains and HHV-6 re-activation has been reported during MS clinical relapses. In this review we also suggest new strategies, including the development of new infectious animal models of MS and antiviral MS clinical trials, to elucidate roles of different viruses in the pathogenesis of this disease. Furthermore, we introduce the idea of using unbiased sequence-independent pathogen discovery methodologies, such as next generation sequencing, to study MS brain tissue or body fluids for detection of known viral sequences or potential novel viral agents.

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“…AIs for antibodies against VZV were determined exactly as previously described by enzyme-linked immunosorbent assays (Enzygnost, Siemens Healthcare Diagnostics) [7]. A standard curve consisting of serial dilutions of standard human plasma (SHP, Siemens Healthcare Diagnostics) was included on each ELISA plate.…”

Section: Methodsmentioning

confidence: 99%

“…To characterize intrathecal antiviral immune responses in detail, but also for clinical differential diagnostic purposes, it appears desirable to clarify whether elevated antiviral AIs reflect virus-driven or polyspecific intrathecal immune responses. Others and we have previously shown that this can be achieved by calculating the fraction ( F S ) of the intrathecally-synthesized virus-specific immunoglobulin (Ig)G of the total intrathecally-synthesized IgG [5-7]. Nevertheless, the fraction of intrathecally-produced VZV-specific IgG of the total intrathecally-produced IgG ( F S anti-VZV) in patients with VZV reactivation and MS has hitherto not been compared.…”

Section: Introductionmentioning

confidence: 99%

The fraction of varicella zoster virus-specific antibodies among all intrathecally-produced antibodies discriminates between patients with varicella zoster virus reactivation and multiple sclerosis

Otto

Hofmann

Finke

et al. 2014

Fluids Barriers CNS

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BackgroundPrimary infection with or reactivation of varicella zoster virus (VZV) can cause neurologic complications, which typically result in an intrathecal production of VZV-specific antibodies. Intrathecal antibodies to VZV are detectable by an elevated antibody index (AI). However, elevated VZV AIs are also found in more than half of patients with multiple sclerosis (MS), where they are thought to be part of a polyspecific intrathecal immune response. Determination of the fraction of intrathecally-produced virus-specific antibodies among all intrathecally produced antibodies may discriminate between virus-specific and polyspecific intrathecal immune responses, but the fraction of intrathecally-produced VZV-specific immunoglobulin (Ig)G of the total intrathecally produced IgG (FS anti-VZV) in patients with MS and VZV reactivation has hitherto not been compared.FindingsFS anti-VZV was calculated in patients with a clinically isolated syndrome suggestive of multiple sclerosis (MS) or MS (n = 20) and in patients with VZV reactivation (7 samples from 5 patients), which all had elevated VZV AIs. The median FS anti-VZV was 35-fold higher in patients with VZV reactivation (45.1%, range 13.5-73%) than in patients with CIS/MS (1.3%, range 0.3-5.3%; p = 0.0001). While there was thus no overlap of FS anti-VZV values between groups, VZV AIs completely overlapped in patients with CIS/MS (1.6-14.8) and VZV reactivation (2.1-8.1).ConclusionsThe fraction of intrathecally-produced VZV-specific IgG of the total intrathecally produced IgG discriminates between patients with VZV reactivation and MS. Our results provide further evidence that intrathecally-produced VZV antibodies are part of the polyspecific immune response in patients with MS.

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Intrathecal EBV antibodies are part of the polyspecific immune response in multiple sclerosis

Abstract: Intrathecally produced anti-EBV antibodies are part of the polyspecific intrathecal immune response in CIS/MS and only rarely detectable in patients with CIS, both arguing against a direct CNS infection with EBV in patients with CIS/MS.

Cited by 45 publications

References 25 publications

Multiple sclerosis typical clinical and MRI findings in a patient with HIV infection

Multiple sclerosis typical clinical and MRI findings in a patient with HIV infection

Viruses and Multiple Sclerosis

The fraction of varicella zoster virus-specific antibodies among all intrathecally-produced antibodies discriminates between patients with varicella zoster virus reactivation and multiple sclerosis

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