Oligoclonal immunoglobulins in cerebrospinal fluid during varicella zoster virus (VZV) vasculopathy are directed against VZV

Burgoon, Mark P.; Hammack, Barbara N.; Owens, Gregory P.; Maybach, Amy L.; Eikelenboom, Merijn; Gilden, Donald H.

doi:10.1002/ana.10685

Cited by 45 publications

(26 citation statements)

References 15 publications

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“…32 Although occasional plasma cells producing anti-EBV antibodies could be present in MS CSF, the absence of anti-EBV reactivity by MS rAbs examined here, which collectively represent the majority of MS patients' clonally expanded plasma cell populations, argues against the role of EBV in MS brain pathogenesis.…”

Section: Ebv-positive Lymphomasmentioning

confidence: 60%

Absence of Epstein-Barr virus in the brain and CSF of patients with multiple sclerosis

Sargsyan¹,

Shearer²,

Ritchie³

et al. 2010

Neurology

180

127

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Objective: Epstein-Barr virus (EBV) is a ubiquitous human herpesvirus that becomes latent in B-lymphocytes and has been implicated in the pathogenesis of multiple sclerosis (MS). We searched for latent and active EBV infection in MS brain and CSF.Methods: Nested and non-nested real-time PCR were used to detect cell-specific and EBVspecific transcripts in 15 fresh-frozen and 5 formalin-fixed paraffin-embedded MS plaques and in single MS CSF B-lymphocytes and plasma cells. Intrathecal anti-EBV antibody synthesis was measured by ELISA. Immunocytochemistry was used to detect binding of MS CSF and recombinant antibodies (rAbs) generated from clonally expanded plasma cells in MS CSF to EBV-infected cells. Results:No EBV RNA was found in MS CSF B-lymphocytes or plasma cells. In active MS plaques, EBV-encoded RNA (EBER)-1 was the only and rarely detected transcript. The frequency of detected intrathecal anti-EBV antibody synthesis in patients with MS did not differ from that in non-MS inflammatory CNS disease control patients. Anti-EBV antibodies were detected in the CSF of patients with MS, but MS rAbs did not react with EBV. Epstein-Barr virus (EBV) is a common herpesvirus that is widespread in all human populations. EBV is spread orally and is the etiologic agent of infectious mononucleosis. Conclusions:1 Most primary infections are asymptomatic. More than 90% of adults are positive for serum immunoglobulin G (IgG) antibodies to the EBV capsid antigen.2 EBV becomes latent in peripheral blood B cells. EBV infection has been associated with multiple sclerosis (MS). 3In a large meta-analysis, EBV-seropositive individuals were found to have an increased risk for MS (odds ratio [OR] ϭ 13.5). 4 In a subsequent prospective study, a fourfold elevation in serum anti-EBV nuclear antigen (EBNA)-2 antibody titer was associated with a fourfold increased risk of developing MS.5 Further evidence of a link between EBV and MS came from reported enhanced immunoreactivity to EBV-specific proteins BRRF2 and EBNA-1 in serum and CSF of patients with MS, and the demonstration that a small fraction of CSF oligoclonal IgG of 13% of patients with MS was removed by incubation with purified BRRF2 and EBNA-1 proteins.6 Recently, about 90% of B-lymphocytes in active and chronic-active MS perivascular white matter lesions and about 80% of brain-infiltrating plasma cells were reported to be infected with EBV. 7 Immunohistologic detection of latent e-Pub ahead of print on March 10, 2010, at www.neurology.org.

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Section: Ebv-positive Lymphomasmentioning

confidence: 60%

Absence of Epstein-Barr virus in the brain and CSF of patients with multiple sclerosis

Sargsyan¹,

Shearer²,

Ritchie³

et al. 2010

Neurology

180

127

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“…In cryptococcal meningitis, the OGBs are adsorbed specifically with cryptococcal antigen, but not with candida antigen (6), and the OGBs in the CSF of patients with HTLV-1 myelopathy contain anti-HTLV-1 p24 antibody (7). Most recently, the oligoclonal IgG in CSF during varicella zoster virus (VZV) vasculopathy was shown to be antibody directed against VZV (8). An overview of the specificity of OGBs in CNS infectious disorders is provided in Gilden et al (9).…”

Section: Introductionmentioning

confidence: 99%

B cells in multiple sclerosis

Mark¹

2004

Front Biosci

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The most common laboratory abnormality in multiple sclerosis (MS) is an increased amount of cerebrospinal fluid IgG and the presence of oligoclonal bands. Despite studies of the humoral response that suggest the involvement of an infectious agent or autoantigen in disease, the major targets of the oligoclonal response are still unknown. Identification of these targets will reveal valuable insights into the cause and pathogenesis of MS and is likely to lead to effective treatment.

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“…Studies in which the specificity of CSF OGBs was analyzed showed that the antibodies were directed against the agent that causes disease (1)(2)(3)(4)(5)(6)(7)(8). For example, the OGBs in SSPE CSF and brain are antibodies directed against MV (1).…”

mentioning

confidence: 99%

Laser-capture microdissection of plasma cells from subacute sclerosing panencephalitis brain reveals intrathecal disease-relevant antibodies

Burgoon

Keays

Owens

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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Increased IgG and oligoclonal bands (OGBs) are found in the cerebrospinal fluid (CSF) of humans with chronic infectious CNS diseases such as neurosyphilis, cryptococcal and tuberculous meningitis, Lyme disease, some viral meningitides, varicella zoster virus vasculopathy, and subacute sclerosing panencephalitis (SSPE), a chronic encephalitis caused by measles virus (MV). Studies in which the specificity of CSF OGBs was analyzed showed that the antibodies were directed against the agent that causes disease (1-8). For example, the OGBs in SSPE CSF and brain are antibodies directed against MV (1). These studies have led to the hypothesis that the oligoclonal IgG in the brain and CSF of patients with a chronic inflammatory CNS disease of unknown etiology, such as multiple sclerosis (MS), sarcoidosis, and Behcet's disease, is antibody directed against the agent that causes disease. Although OGBs are found in 88-100% of CSF from MS patients (9), the corresponding antigens remain unknown (10, 11). Such unanswered questions point to the need for improved techniques to identify disease-relevant antibodies and their cognate antigens and suggest the promise of such techniques in revealing the causes of inflammatory diseases with unknown etiologies.Here, we used laser-capture microdissection (LCM) to isolate individual CD38ϩ plasma cells from the brain of a patient with SSPE. Single-cell RT-PCR was used to amplify individual IgG heavy (H) and light (L) chain sequences expressed by each cell. Based on overrepresented Ig sequences, we constructed functional recombinant antibodies and identified their target antigens.Materials and Methods SSPE Brain. Brain removed from a 14-year-old male SSPE patient 5 h after death was flash-frozen and stored at Ϫ70°C. Sections (7 m) of frozen SSPE brain were prepared on nonplus glass slides (Fisher Scientific) at Ϫ30°C, fixed in acetone for 5 min at Ϫ20°C, and immunostained at 0°C for CD38ϩ cells. Briefly, sections were treated with 0.1% H 2 O 2 for 30 sec, incubated for 2 min with PBS containing 10% goat serum and then with a 1:50 dilution of mouse anti-human CD38 antibody (DakoCytomation, DAKO) for 10 min, rinsed in PBS, and incubated for 5 min with a 1:100 dilution of horseradish peroxidase-conjugated horse anti-mouse antibody (Vector Laboratories) and 5% goat serum in PBS. After rinsing in PBS, sections were incubated for 5 min with DAB substrate (Vector Laboratories), counterstained with hematoxylin, dehydrated in nuclease-free graded alcohols to 100% ethanol, and cleared with two rinses of H 2 0-free xylene. To preserve RNA, all aqueous solutions contained 200 units͞ml RNase inhibitor (Fisher Scientific), and the total time of tissue exposure to aqueous solutions was Ͻ25 min at 0°C. Staining was visualized by light microscopy.LCM and RT-PCR. LCM was performed on a PixCell IIe microscope (Arcturus Engineering, Mountain View, CA) with CapSure HS caps by using a pulse power of 70 mW, a 7.5-m laser spot diameter, pulse duration of 5 ms, and target voltage of 170 mV. Individual CD38ϩ cells ...

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Oligoclonal immunoglobulins in cerebrospinal fluid during varicella zoster virus (VZV) vasculopathy are directed against VZV

Cited by 45 publications

References 15 publications

Absence of Epstein-Barr virus in the brain and CSF of patients with multiple sclerosis

Absence of Epstein-Barr virus in the brain and CSF of patients with multiple sclerosis

B cells in multiple sclerosis

Laser-capture microdissection of plasma cells from subacute sclerosing panencephalitis brain reveals intrathecal disease-relevant antibodies

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