Herpes simplex virus encephalitis is a trigger of brain autoimmunity

Armangué, Thaís; Leypoldt, Frank; Málaga, Ignacio; Raspall-Chaure, Miquel; Martí, Itxaso; Nichter, Charles; Pugh, John; Vicente-Rasoamalala, Mònica; Lafuente-Hidalgo, Miguel; Macaya, Alfons; Ke, Michael C.; Titulaer, Maarten J.; Höftberger, Romana; Sheriff, Heather; Glaser, Carol; Dalmau, Josep

doi:10.1002/ana.24083

Cited by 400 publications

(351 citation statements)

References 20 publications

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“…Second, it is of potential etiological interest that NR1‐specific B cells were efficiently expanded in vitro by toll‐like receptor agonism because this is an established property of herpes simplex virus (HSV),26 and HSV is both a known trigger of classical NMDAR‐antibody encephalitis,27, 28 and of NR1‐IgG and NR1‐IgM generation in patients without typical clinical features of NMDAR‐antibody encephalitis 21, 29. However, this hypothesis would necessitate preformed NR1‐reactive cells.…”

Section: Discussionmentioning

confidence: 99%

N‐methyl‐D‐aspartate receptor antibody production from germinal center reactions: Therapeutic implications

Makuch

Wilson

Al-Diwani

et al. 2018

Annals of Neurology

107

102

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IntroductionN‐methyl‐D‐aspartate receptor (NMDAR) antibody encephalitis is mediated by immunoglobulin G (IgG) autoantibodies directed against the NR1 subunit of the NMDAR. Around 20% of patients have an underlying ovarian teratoma, and the condition responds to early immunotherapies and ovarian teratoma removal. However, despite clear therapeutic relevance, mechanisms of NR1‐IgG production and the contribution of germinal center B cells to NR1‐IgG levels are unknown.MethodsClinical data and longitudinal paired serum NR1‐reactive IgM and IgG levels from 10 patients with NMDAR‐antibody encephalitis were determined. Peripheral blood mononuclear cells from these 10 patients, and two available ovarian teratomas, were stimulated with combinations of immune factors and tested for secretion of total IgG and NR1‐specific antibodies.ResultsIn addition to disease‐defining NR1‐IgG, serum NR1‐IgM was found in 6 of 10 patients. NR1‐IgM levels were typically highest around disease onset and detected for several months into the disease course. Moreover, circulating patient B cells were differentiated into CD19+CD27++CD38++ antibody‐secreting cells in vitro and, from 90% of patients, secreted NR1‐IgM and NR1‐IgG. Secreted levels of NR1‐IgG correlated with serum NR1‐IgG (p < 0.0001), and this was observed across the varying disease durations, suggestive of an ongoing process. Furthermore, ovarian teratoma tissue contained infiltrating lymphocytes which produced NR1‐IgG in culture.InterpretationSerum NR1‐IgM and NR1‐IgG, alongside the consistent production of NR1‐IgG from circulating B cells and from ovarian teratomas suggest that ongoing germinal center reactions may account for the peripheral cell populations which secrete NR1‐IgG. Cells participating in germinal center reactions might be a therapeutic target for the treatment of NMDAR‐antibody encephalitis. Ann Neurol 2018;83:553–561

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Section: Discussionmentioning

confidence: 99%

N‐methyl‐D‐aspartate receptor antibody production from germinal center reactions: Therapeutic implications

Makuch

Wilson

Al-Diwani

et al. 2018

Annals of Neurology

107

102

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“…The trigger of the disease in the rest of female patients as well as in young children and male patients is largely unknown, although in some cases other tumors (such as small‐cell lung cancer2) have been identified. In a small subset of patients the anti‐NMDAR immune response is triggered by herpes simplex encephalitis 4. Irrespective of the trigger of anti‐NMDAR encephalitis, data from previous studies suggested an enhancement of the immune response within the CNS, with potential antigen‐driven affinity maturation and clonal expansion of plasma cells 16.…”

Section: Discussionmentioning

confidence: 99%

“…Encephalitis associated with anti‐ N ‐methyl‐ d ‐asparate receptor (anti‐NMDAR) antibodies (“antibodies”) can be triggered by the presence of peripheral tumors1, 2 or preceding viral CNS infection or occur in the absence of such obvious events 3, 4. It typically presents with neurocognitive deficits variably accompanied by psychiatric symptoms, epileptic seizures, and disorders of movement and consciousness.…”

Section: Introductionmentioning

confidence: 99%

NMDAR encephalitis: passive transfer from man to mouse by a recombinant antibody

Malviya

Barman

Golombeck

et al. 2017

Ann Clin Transl Neurol

Self Cite

112

106

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ObjectiveAutoimmune encephalitis is most frequently associated with anti‐NMDAR autoantibodies. Their pathogenic relevance has been suggested by passive transfer of patients' cerebrospinal fluid (CSF) in mice in vivo. We aimed to analyze the intrathecal plasma cell repertoire, identify autoantibody‐producing clones, and characterize their antibody signatures in recombinant form.MethodsPatients with recent onset typical anti‐NMDAR encephalitis were subjected to flow cytometry analysis of the peripheral and intrathecal immune response before, during, and after immunotherapy. Recombinant human monoclonal antibodies (rhuMab) were cloned and expressed from matching immunoglobulin heavy‐ (IgH) and light‐chain (IgL) amplicons of clonally expanded intrathecal plasma cells (cePc) and tested for their pathogenic relevance.ResultsIntrathecal accumulation of B and plasma cells corresponded to the clinical course. The presence of cePc with hypermutated antigen receptors indicated an antigen‐driven intrathecal immune response. Consistently, a single recombinant human GluN1‐specific monoclonal antibody, rebuilt from intrathecal cePc, was sufficient to reproduce NMDAR epitope specificity in vitro. After intraventricular infusion in mice, it accumulated in the hippocampus, decreased synaptic NMDAR density, and caused severe reversible memory impairment, a key pathogenic feature of the human disease, in vivo.InterpretationA CNS‐specific humoral immune response is present in anti‐NMDAR encephalitis specifically targeting the GluN1 subunit of the NMDAR. Using reverse genetics, we recovered the typical intrathecal antibody signature in recombinant form, and proved its pathogenic relevance by passive transfer of disease symptoms from man to mouse, providing the critical link between intrathecal immune response and the pathogenesis of anti‐NMDAR encephalitis as a humorally mediated autoimmune disease.

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“…With antiepileptic medications, steroids, plasma exchange, and intravenous immunoglobulin (IVIg), the patient improved and was discharged to skilled nursing care. Anti-NMDAR encephalitis and other immune-mediated encephalitides can be triggered by HSV [152]. In contradistinction to the initial HSVE, significant contrast enhancement on brain MRI has been observed [153], and may be a biomarker of autoimmune relapse, though future studies with greater patient numbers are needed.…”

Section: Case 2: A-79-year-old Woman In Sementioning

confidence: 99%

“…Multiple case reports and, more recently, case series have demonstrated that many patients with HSVE relapse develop anti-NMDAR immunoglobulins [152,[169][170][171][172][173][174]. Antibodies targeting other known neuronal antigens and unidentified neuronal antigens have also been reported in this setting [152,153,174,175]. The precise pathogenic mechanisms remain to be elucidated, but may involve mechanisms of molecular mimicry or an autoimmune response to the release of neuronal antigens associated with host cell lysis.…”

Section: Immune-mediated Encephalitis and Apparent Hsve Relapsementioning

confidence: 99%

Herpes Simplex Virus-1 Encephalitis in Adults: Pathophysiology, Diagnosis, and Management

2016

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Herpetic infections have plagued humanity for thousands of years, but only recently have advances in antiviral medications and supportive treatments equipped physicians to combat the most severe manifestations of disease. Prompt recognition and treatment can be lifesaving in the care of patients with herpes simplex-1 virus encephalitis, the most commonly identified cause of sporadic encephalitis worldwide. Clinicians should be able to recognize the clinical signs and symptoms of the infection and familiarize themselves with a rational diagnostic approach and therapeutic modalities, as early recognition and treatment are key to improving outcomes. Clinicians should also be vigilant for the development of acute complications, including cerebral edema and status epilepticus, as well as chronic complications, including the development of autoimmune encephalitis associated with antibodies to the N-methyl-D-aspartate receptor and other neuronal cell surface and synaptic epitopes. Herein, we review the pathophysiology, differential diagnosis, and clinical and radiological features of herpes simplex virus-1 encephalitis in adults, including a discussion of the most common complications and their treatment. While great progress has been made in the treatment of this life-threatening infection, a majority of patients will not return to their previous neurologic baseline, indicating the need for further research efforts aimed at improving the long-term sequelae.

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Herpes simplex virus encephalitis is a trigger of brain autoimmunity

Cited by 400 publications

References 20 publications

N‐methyl‐D‐aspartate receptor antibody production from germinal center reactions: Therapeutic implications

N‐methyl‐D‐aspartate receptor antibody production from germinal center reactions: Therapeutic implications

NMDAR encephalitis: passive transfer from man to mouse by a recombinant antibody

Herpes Simplex Virus-1 Encephalitis in Adults: Pathophysiology, Diagnosis, and Management

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