The immunobiology of herpes simplex virus encephalitis and post-viral autoimmunity

Abstract

Herpes simplex virus encephalitis (HSE) is the leading cause of non-epidemic encephalitis in the developed world and, despite antiviral therapy, mortality and morbidity is high. The emergence of post-HSE autoimmune encephalitis reveals a new immunological paradigm in autoantibody-mediated disease. A reductionist evaluation of the immunobiological mechanisms in HSE is crucial to dissect the origins of post-viral autoimmunity and supply rational approaches to the selection of immunotherapeutics. Herein, we review the latest evidence behind the phenotypic progression and underlying immunobiology of HSE including the cytokine/chemokine environment, the role of pathogen-recognition receptors, T- and B-cell immunity and relevant inborn errors of immunity. Second, we provide a contemporary review of published patients with post-HSE autoimmune encephalitis from a combined cohort of 110 patients. Third, we integrate novel mechanisms of autoimmunization in deep cervical lymph nodes to explore hypotheses around post-HSE autoimmune encephalitis and challenge these against mechanisms of molecular mimicry and others. Finally, we explore translational concepts where neuroglial surface autoantibodies have been observed with other neuroinfectious diseases and those that generate brain damage including traumatic brain injury, ischaemic stroke and neurodegenerative disease. Overall, the clinical and immunological landscape of HSE is an important and evolving field, from which precision immunotherapeutics could soon emerge.

Keywords: autoimmune encephalitis; herpes simplex virus encephalitis; immunology; immunotherapeutics; viral encephalitis.

Figure 1

Host immune response to HSV. An early innate immune response, triggered by viral pathogen-associated molecular patterns (PAMPs), occurs through dimerization of the PRRs generating transcription of IFNs and other cytokines; predominantly through TLR3 and its downstream molecules. This stimulates the release of pro-inflammatory cytokines, which facilitate blood–brain barrier breakdown and recruitment of, predominantly, CD8⁺ T cells but also other arms of the adaptive immune system. To counter adaptive cell-mediated immune elaboration, HSV-1 attempts to evade host MHC expression through a variety of different mechanisms. These processes ultimately contribute to the antiviral response and local neuroinflammation. 2′,5′OAS = 2′-5′-oligoadenylate synthetase; APC = antigen-presenting cell; CCL-5 = chemokine CC motif ligand 5; cGAS = cyclic GMP-AMP synthase; CXCL10 = chemokine CXC motif ligand 10; HSV-1 = herpes simplex virus; IFNs = interferons; IL = interleukin; IRF-3 = interferon regulatory factor 3; MAG = myelin associated glycoprotein; MDA5 = melanoma differentiation-associated protein 5; MHC = major histocompatibility complex; NMHC-IIA = non-muscle myosin heavy chain-IIA; PRRs = pattern recognition receptors; RLRs = retinoic acid inducible gene-I (RIG-I)-like receptors; STING = stimulator of interferon genes; TLRs = toll-like receptors; TNF-α = tumour necrosis factor alpha.

Figure 2

Proposed mechanism of secondary autoimmunization post-HSE. The deep cervical lymph nodes are implicated here as the primary peripheral lymphatic drainage site from the meningeal lymphatics of the CNS with a schematic overview of germinal cell (GC) reactions and subsequent inflammatory milieu leading to CNS antibody-mediated neuronal dysfunction (modified from Sun et al.). Ab = antibody; ASC = antibody secreting cell; BBB = blood­–brain barrier, HSE = herpes simplex virus encephalitis; NMDAR = N-methyl D-aspartate receptor.

Figure 3

Future perspectives in HSE research and possible immunotherapeutic options. (A) Sampling from different compartments in the body from patients with herpes simplex virus encephalitis (HSE), including peripheral blood, CSF and deep cervical lymph nodes (dCLNs) is illustrated. Immune cells can be separated using fluorescence-activated cell sorting (FACS) and individual populations can be analysed using high-throughput single cell RNA-sequencing through a 10× genomics chromium plate—for example—and analysed using an RNA sequencer to generate intercompartmental genomic expression data. (B) Phage-immunoprecipitation and sequencing (PhIP-Seq) process begins with a T7-peptide library generated from DNA sequences encoding 36-amino acid peptides from 24 329 open reading frames. DNA sequences are amplified and cloned into a T7 phage, which is then mixed with patient samples containing autoantibodies for immunoprecipitation by capture via magnetic beads. Immunoprecipitated DNA from respective phages are recovered and PCR amplified to be stored and analysed within a sequencing library. (C) Illustrates potential immunotherapeutic options in patients with HSE or post-HSE autoimmune encephalitis that require further research to support their clinical utility. ⊕ = stimulation; ⊖ = inhibition; FcγR = the receptors for the Fc region of IgG; ICAM-1 = intercellular cell adhesion molecule 1; IVIg = intravenous immunoglobulin; PLEX = plasma exchange; Th = T helper cells; Treg = regulatory T cell; VCAM-1 = vascular cell adhesion molecule 1.