Herpes simplex virus encephalitis: intrathecal synthesis of oligoclonal virus-specific IgG, IgA and IgM antibodies.
ABSTRACT Paired specimens of serum and CSF from seven patients with acute herpes simplex virus encephalitis were examined during the acute illness or the convalescent stage or during both stages. Imprint immunofixation analyses of viral antibodies separated by agarose electrophoresis and by electrofocusing disclosed intrathecal production of herpes simplex virus IgG antibodies in all seven patients, and of IgA and IgM antibodies in six and three of six patients, respectively. Intrathecal production of herpes simplex virus-specific IgG and IgA was observed in two patients from whom samples were collected after 1 year, while intrathecal production of virus-specific IgM was not demonstrated later than 5 weeks after onset. The intrathecally synthesized IgG and IgM, and to a lesser extent IgA antibodies displayed oligoclonal characteristics. Oligoclonal bands of IgG were observed in the CSF of all patients. Evidence is presented to show that the bulk of the oligoclonal CSF IgG represents herpes simplex virus-specific antibodies. Intrathecally synthesized populations of herpes simplex virus antibodies cross-reacting with varicella-zoster virus were identified in three of the patients.
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ABSTRACT: Although partly disease-irrelevant, intrathecal immunoglobulins (Ig) synthesis is a typical feature of multiple sclerosis (MS) and is driven by the tertiary lymphoid organs (TLO). A long-known hallmark of this non-specific intrathecal synthesis is the MRZ pattern, an intrathecal synthesis of Ig against measles, rubella, and zoster viruses. This non-specific intrathecal synthesis could also be directed against a wide range of pathogens. However, it is highly problematic since brain TLO should not be able to drive the clonal expansion of lymphocytes against alien antigens that are thought to be absent in MS brain. We propose to explain the paradox of non-specific intrathecal synthesis by discussing the natural properties of TLO. In fact, besides local antigen-driven clonal expansion, circulating plasmablasts and plasma cells (PC) are non-specifically recruited from blood and gain access to survival niches in the inflammatory CNS. This mechanism, which has been described in other inflammatory disorders, takes place in the TLO. As a consequence, PCs recruited in brain mirror the individual's history of immunization and intrathecal synthesis of IgG in MS may target a broad range of common infectious agents, a hypothesis in line with epidemiological data. Moreover, the immunization schedule and its timing may interfere with PC recruitment. If this hypothesis is correct, the reaction against EBV appears paradoxical: although early infection of MS patients is systematic, intrathecal synthesis is far lower than expected, suggesting a crucial interaction between MS onset and timing of EBV infection. A growing body of evidence suggests that the non-specific intrathecal synthesis observed in MS is also common in many chronic CNS inflammatory disorders. Assuming that cortical TLO in MS are associated with typical sub-pial lesions, we have coined the concept of "TLO-pathy" to describe these lesions and take examples of them from non-MS disorders. Lastly, we propose that intrathecal synthesis could be considered a strong hallmark of CNS TLO and might be used to monitor future TLO-targeted therapies.Frontiers in Neurology 03/2014; 5:27. DOI:10.3389/fneur.2014.00027
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ABSTRACT: Before PCR testing of cerebrospinal fluid (CSF), laboratory diagnosis of herpes encephalitis (HSE) was based on virus isolation from brain biopsy. Viral isolation from CSF has limited clinical value due to low virus recovery; the cause for which has not been demonstrated. To investigate the role of anti-HSV antibodies on recovery of HSV from CSF via cell culture. HSV-positive CSF samples were evaluated for their ability to neutralize HSV in cell culture. The presence of HSV-specific IgG and IgM antibodies were analyzed using HSV-infected cells. To identify whether HSV-specific IgG is the cause of viral inhibition, IgG was removed using anti-human IgG magnetic beads. Viral inhibition from CSF originating from asymptomatic patients was examined as a comparison. CSF from 13 patients with acute HSV CNS disease was analyzed. All displayed high levels of viral neutralization to both HSV-1 and HSV-2 regardless of the infecting subtype. Interestingly, all the CSF samples stained strongly for anti-IgG antibody but none for anti-IgM antibody. Removal of IgG from CSF eliminated the viral inhibitory activity. Neutralizing IgG antibody was also found to be common in CSF of most patients, even in the absence of HSV disease. Viral specific IgG is the major determinant of viral inhibition in CSF and prevents virus recovery in cell culture. In CSF from HSE un-infected patients, viral inhibitory IgG originates from circulating serum antibody and is commonly present in CSF. However, this inhibitory IgG is not protective for the development of HSV disease.Journal of clinical virology: the official publication of the Pan American Society for Clinical Virology 07/2012; 55(2):164-7. DOI:10.1016/j.jcv.2012.07.002 · 3.47 Impact Factor
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ABSTRACT: The presence of HuD-specific oligoclonal IgG bands in the CSF was investigated in five patients with paraneoplastic neurological syndromes. All patients revealed intrathecal synthesis of HuD specific antibodies in the CSF, as estimated from elevated antibody indices (>1.5) in an IgG-ELISA using recombinant HuD-protein as antigen. Isoelectrofocussing combined with affinity blotting showed reactivity of IgG bands with recombinant HuD antigen in all CSF samples. These data support the idea that HuD specific antibodies in the CSF are produced mainly by B-cell clones in the central nervous system. These findings support the hypothesis of autoimmunity in the pathogenesis of anti-Hu associated paraneoplastic neurological syndromes.Journal of Neuroimmunology 11/2000; 111(1):241-244. DOI:10.1016/S0165-5728(00)00391-X · 2.79 Impact Factor