The role of infections in autoimmune encephalitides

revue neurologique 175 (2019) 420–426

Available online at

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International meeting of the French society of neurology & SPILF 2019

The role of infections in autoimmune encephalitides B. Joubert a, J. Dalmau a,b,c,* a

Institut d’Investigacions Biome`diques August Pi i Sunyer (IDIBAPS), Hospital Clı´nic, Universitat de Barcelona, 143, Casanova, 08036 Barcelona, Spain b Department of Neurology, University of Pennsylvania, PA 19104 Philadelphia, United States c Institucio´ Catalana de Recerca i Estudis Avanc¸ats (ICREA), Barcelona, Spain

info article

abstract

Article history:

Autoimmune encephalitides are autoimmune neurological disorders characterized by

Received 4 June 2019

rapidly progressive central nervous system symptoms associated with specific auto-anti-

Received in revised form

bodies targeting neuronal cell-surface proteins. The clinical features of encephalitis are

6 June 2019

frequently preceded by symptoms suggesting an infectious process, and specific pathogens

Accepted 11 July 2019

have been detected at the early phase of the disease in some patients, suggesting that it can

Available online 29 July 2019

be triggered by infections. Moreover, recent data have shown an association with specific HLA haplotypes, suggesting a genetic susceptibility to develop at least some subtypes of

Keywords:

autoimmune encephalitis. Nonetheless, the immunological mechanisms leading from an

Autoimmune encephalitis

adequate response to infection to autoimmunity against neuronal self-antigens remain

Post-infectious neurological

highly hypothetical. Molecular mimicry, inborn errors of the host immune system, as well as

disorders

epitope spreading and chronic activation of innate immunity actors, may be involved.

Herpes virus encephalitis

Importantly, the frequency of prodromal infectious symptoms and association with HLA

Autoimmunity

haplotypes differ among autoimmune encephalitides, suggesting that depending on the subtype distinct immunopathogenic mechanisms are involved. A direct link between infection and autoimmune encephalitis was recently provided by the demonstration that most of the so-called relapsing neurological symptoms post-herpes simplex virus encephalitis corresponded to viral-induced autoimmune encephalitis with antibodies against NMDA receptors or other, yet unknown, neuronal surface antigens. Although this association has also been demonstrated experimentally in mice, the underlying immunological mechanisms remain unknown. Overall, a body of clinical, epidemiological and experimental data suggests infections are involved in the pathogenesis of autoimmune encephalitides. Further studies, focusing on the interplays between pathogens, genetic determinants of the host immune response, and brain inflammation, are needed to clarify the immunological mechanisms that lead to autoimmune encephalitis after infection. # 2019 Elsevier Masson SAS. All rights reserved.

* Corresponding author at: Institut d’Investigacions Biome`diques August Pi i Sunyer (IDIBAPS), Hospital Clı´nic, Universitat de Barcelona, 143, Casanova, 08036 Barcelona, Spain. E-mail address: [email protected] (J. Dalmau). https://doi.org/10.1016/j.neurol.2019.07.004 0035-3787/# 2019 Elsevier Masson SAS. All rights reserved.

revue neurologique 175 (2019) 420–426

1.

Introduction

Autoimmune encephalitides (AE) are immune-mediated neurological disorders characterized by central nervous system (CNS) symptoms associated with auto-antibodies targeting cell-surface neuronal antigens. The clinical features of encephalitis are frequently preceded by flu-like or gastrointestinal symptoms [1]. The neuronal antigens targeted by the auto-antibodies found in the serum and/or cerebrospinal fluid (CSF) of the patients define different subtypes of AE, each with distinct clinical features and outcomes [1]. The importance of specific antigenic targets in AE is supported by multiple functional studies that consistently show that patients’ auto-antibodies are able to alter the function and/ or surface expression of the protein they bind to, thereby inducing neurological symptoms [2–5]. Therefore, autoimmunity against specific neuronal self-antigens, resulting in autoantibody production, appears to play a critical role in the pathophysiology of AE. Considering the relatively immune-privileged nature of the brain, these autoimmune diseases represent a break of immune tolerance. In patients whose AE is associated with a tumor, autoimmunity probably derives from the ectopic tumor expression of neuronal autoantigens, as for instance, NMDA receptors (NMDAR) in teratomas [6]. By contrast, in non-paraneoplastic AE causal factors are difficult to identify, and may be multifaceted. Association of certain AE subtypes with specific Human Leukocyte Antigen (HLA) haplotypes have highlighted the role of genetic susceptibility in some cases [7,8]. Importantly, infectious agents have long been suspected to be involved as triggers of autoimmunity since a substantial proportion of patients present with prodromal gastrointestinal or flu-like symptoms, and because in some patients pathogens can be detected at early stages of AE [9–14]. The role of infections in triggering autoimmunity against nervous system components has been shown for other inflammatory neurological disorders, such as Guillain-Barre´ syndrome or acute disseminated encephalomyelitis (ADEM) [15,16]. In addition, a direct link between AE and infection has been provided recently with the demonstration that herpes simplex virus encephalitis (HSE) can trigger a specific subtype of AE [17]. In this article, we review the existing evidence of a link between infections and the development of neuronal autoimmunity in patients with AE and propose directions for future research.

2. Autoimmune encephalitides: overview and relation with infections Most encephalitides with auto-antibodies against neuronal surface antigens have been identified during the last 12 years [1,9]. They usually manifest with acute or subacute CNS symptoms and frequently respond to immunotherapy [1]. In most patients the antibodies target proteins or receptors involved in synaptic transmission, such as glutamatergic receptors (NMDAR, AMPAR, and mGluR5), GABAergic receptors (GABAAR and GABABR), or the secreted, trans-synaptic protein LGI1 [9,12,18–21]. Multiple lines of evidence suggest that patients’ symptoms probably result from a direct

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pathogenic effect of the auto-antibodies [2,3,5]. Demographics, clinical features, and outcomes vary depending on the neuronal antigen targeted by the antibody [1]. Although most cases develop rapidly over weeks, relapses may occur, at times several years after the initial event [9,11]. The two most frequent AE subtypes, anti-NMDAR and anti-LGI1 encephalitis, illustrate the variety of clinical presentations, pathophysiology, and outcomes [9,22]. For instance, anti-NMDAR encephalitis affects mostly young women and children, and manifests with a highly predictable repertoire of CNS symptoms with prominent psychiatric and behavioral features along with memory impairment, seizures, and dysautonomia [9,11]. By contrast, LGI1 encephalitis affects more often elderly patients, and is characterized by severe predominantly anterograde memory impairment, seizures and cognitive deficit, which can be preceded by facio-brachial dystonic seizures [22–24]. Long-term outcomes are better in anti-NMDAR encephalitis patients, who often are able to return to their previous activities, whereas those with antiLGI1 encephalitis are more frequently left with cognitive disability that complicates their return to previous jobs or intellectual activities [11,25] [22,24,25]. At the molecular level, in vitro and in vivo models have shown that NMDAR antibodies cause internalization of the receptors and disruption of the crosstalk between NMDAR and other synaptic proteins [2,3,26,27]. Instead, LGI1 antibodies alter the normal interaction between LGI1 and pre and post-synaptic metalloproteases overall leading to hyperexcitability due to dysfunction of pre-synaptic voltage-gated potassium channels and post-synaptic AMPAR [5]. Systemic infections are frequently considered a potential trigger of neurological inflammatory diseases, particularly AE [28]. This is based on the elevated frequency of prodromal infection-like symptoms in patients with AE [1]. Prodromal features may include fever, headache, upper respiratory tract symptoms, or diarrhea, suggesting infections by common pathogens, and preceding neurological symptoms from days to weeks [9]. These prodromal symptoms have been reported in several types of AE including among other those associated with antibodies against NMDAR, GABAAR, mGLuR5, Neurexin3a, and dopamine-receptor-2 antibodies [9,10,12–14,29,30]. Less frequently, infections by specific pathogens, such as HIV, Toxoplasma gondii, or Plasmodium falciparum, or in rare instances vaccinations, have been reported as potential associations or triggers in a few patients with the indicated AE. [13,31–33]. By contrast, prodromal infection-like symptoms were not reported in patients with anti-LGI1, -CASPR2, -DPPX, -GABABR, or AMPAR antibodies [21,22,34–39], suggesting that systemic infections may contribute to triggering some types of AE more frequently than others. Consequently, these studies suggest that the immune activations pathways that disrupt tolerance for neuronal self-antigens can be diverse and different depending on the AE subtype.

3. From infection to encephalitis: clues for immunopathogenesis Infections by viral and bacterial pathogens are suspected to trigger a broad range of neurological inflammatory disorders.

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For instance, epidemiological studies have suggested an association between flu outbreaks and the seasonal occurrence of type-1 narcolepsy (discussed later), and between increased positivity of antibodies against Epstein-Barr virus (EBV) proteins and multiple sclerosis (MS) [40,41]. Similarly, cases of ADEM have been reported following various viral infections [42–45]. For entities such as Sydenham chorea or some forms of acute cerebellitis, an infectious syndrome predating the neurological symptoms forms part of the disease [46,47]. However, the immunopathological mechanisms leading from infection to neurological autoimmunity are poorly understood. In MS, the relationship with EBV infection was confirmed by epidemiological association with infectious mononucleosis, increased anti-EBV seropositivity, and EBV-specific oligoclonal bands in some patients [48–50]. Moreover, some EBV antigens are structurally related to the myelin basic protein, and EBV-specific T-cells react against this protein, suggesting a mechanism of molecular mimicry [51,52]. Chronic pathogen-induced deregulation of components of innate immunity is another mechanism considered involved in disrupting immune tolerance in MS and other inflammatory neurological disorders. For instance, dysfunction of toll-like receptors (TLR) that act as sensors of DNA, RNA, or peptides from pathogens, has been considered involved in MS, while overexpression of TLR-7 and -9 has been implicated in myasthenia gravis patients with latent EBV infection of thymus cells [53–55]. Alternative mechanisms such as epitope spreading and cryptic antigens exposure have also been proposed, but with little experimental support to date [28]. All these mechanisms can potentially be amplified by other factors such as co-capture of cognate self-antigens with viral antigens, or the involvement of endogenous retroviruses acting as ‘‘superantigens’’ boosting the immune response [56–58]. Future studies should investigate whether similar mechanisms are also involved in AE. Several genetic factors can favor autoimmune responses. For instance, type-1 narcolepsy is associated with specific HLA class II variants, and has a temporal relationship with influenza outbreaks and vaccination campaigns [59,60]. Interestingly, these HLA-II variants code for MHC class II molecules expressed by autoreactive T-cells which recognize hypocretin and influenza virus peptides, suggesting a mechanism of molecular mimicry that is dependent on HLAII genes variations [61]. Associations with HLA-II gene variants also exist in some subtypes of AE. For instance, a strong association with HLA-II haplotypes DRB1*11:01 and DRB1*07:01 has been shown in patients with CASPR2 and LGI1 encephalitis, respectively [7,62–64]. In contrast, the potential association of anti-NMDAR encephalitis with specific HLA haplotypes is weak and so far not highly supported [63–65]. It is still unclear if a particular alloantigen, combined with such HLA haplotypes, is needed to trigger the autoimmune response against LGI1 or CASPR2. Overall, clinical and genetic data suggest a link between systemic infections and AE. It is likely that pathogens, under some circumstances, can induce autoimmunity against CNS selfantigens leading to AE. The precise immunological mechanisms are still unknown, and the association between specific pathogens and subtypes of AE should be a task for future studies.

4. Herpes encephalitis is a trigger for autoimmune encephalitis HSE is a severe CNS infection that results in 5–15% mortality and 40–50% neurological sequelae [66–68]. In addition, 10–25% of patients experience relapsing neurological symptoms despite appropriate treatment and virus clearance [69,70]. These relapsing symptoms have been reported mostly in children who a few weeks or months after the viral infection develop new clinical features such as choreoathetosis, decreased level of consciousness, and seizures [69,71]. In some instances the neurological relapse is caused by reactivation of the virus but in most cases HSV-1 is no longer detectable in the CSF by the moment of the relapse [69,72]. In these patients, antiviral treatment is not effective; instead, clinical improvement has been shown with treatment with steroids, suggesting an inflammatory, likely immune-mediated disorder [71]. Moreover, most patients with neurological relapsed not caused by viral reactivation, develop antibodies targeting surface neuronal antigens similar to the antibodies found in AE patients [73]. These antibodies target NMDAR in most of the cases, but anti-GABABR, -Dopamine-2R, and AMPAR antibodies, or antibodies against unknown neuronal antigens have also been found [73–78]. Recently, a prospective observational study including 51 patients with new-onset HSE showed that 27% developed autoimmune encephalitis postHSE [17]. More than 100 of such patients have been reported, providing a distinctive clinical syndrome. AE post-HSE affects patients of all ages, with a slight female predominance [73,74]. AE usually develops after a median of 30 days from onset of HSE; in most cases it presents as a second component of a biphasic process (the initial component being the viral infection). However, in some patients the autoimmune process can develop in contiguity with the symptoms related to the viral infection, without a clear biphasic process [17]. Up to 64% patients with AE post-HSE develop serum or CSF NMDAR antibodies while the remaining 36% develop antibodies targeting unknown surface neuronal antigens; other antibodies such as anti-GABABR, -Dopamine-2R, and -AMPAR antibodies are infrequent [17,77]. Notably, the clinical presentation differs in young children compared with teenagers or adults. Most children under 4 years of age present with choreoathetosis, along with decreased level of consciousness, seizures, and behavioral changes. By contrast, adults and children age > 4 years of age rarely develop choreoathetosis and predominantly show behavioral abnormalities and psychiatric symptom, while having less frequent seizures and impairment of consciousness [17]. Brain magnetic resonance imaging (MRI) and routine CSF analysis do not show specific findings, although frequent disruption of the blood-brainbarrier with prolonged gadolinium enhancement has been observed [17,73]. Treatment with steroids, intravenous immunoglobulins, cyclophosphamide, or rituximab is more effective in adults or teenagers than in young children. Moreover, the outcome of young children with AE post-HSE is substantially worse than that of patients with classical NMDAR encephalitis, although cases of dramatic improvement have been observed [17,76,79]. This poorer prognosis could be the result of preexistent parenchymal damage, persistent blood-brain barrier

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disruption or additional factors (young brain vulnerability) not yet characterized. Persistent neuronal antibody positivity after one year of follow-up is associated with poorer outcomes, regardless of the antigenic target [17]. The NMDAR antibodies from patients with AE post-HSE target the same GluN1 subunit as do the antibodies from patients with the classical form of anti-NMDAR encephalitis [73]. However, the pathogenic effects of the neuronal antibodies in AE post-HSE have not been assessed, and the potential role of cytotoxic T-cell mechanisms is also unknown. A similar syndrome of AE post-viral infection has been reported in a few patients with Japanese encephalitis, and isolated case reports related to other infections (e.g. varicella zoster virus) [80–82]. The association between HSE and development of AE was recently shown in an animal model. Intranasal inoculation of HSV-1 in mice led to the production of NMDAR antibodies in more than half of the animals, along with decreased levels of hippocampal NMDAR[83]. The role of molecular mimicry has been suggested, but no sequence similarity between HSV-1 and NMDAR has been identified [84]. Adaptive immune mechanisms are strongly stimulated in HSE including neutralizing antibodies and interferon-g producing T-cells [85,86]. Consequently, brain parenchyma inflammation can persist years after HSE [87] and, as indicated, a substantial number of patients develop neuronal surface antibodies [75,78,88,89]. Although new antibody synthesis within the first three weeks following HSE was significantly associated with the subsequent development of AE, not all patients with new neuronal antibody synthesis post-HSE developed AE [17]. Moreover, patients often develop antibodies against multiple neuronal surface targets. This has suggested a mechanism by which a massive release of neuronal auto-antigens in the context of important local inflammation, may contribute to the development of autoimmunity. TLRs, especially TLR3, are essential for detecting HSV-1 in the brain and limiting infection spreading by inducing production of type I interferons and recruitment of macrophages and T-cells [90,91]. Genetic defects of TLR3 and dysfunction of TLR3 pathway proteins, have been described in children and adults with HSE [92–96]. A recent study showed that a patient with alterations in the TLR3 pathway developed not only relapsing viral infections, but also eventually developed AE post-HSE [97]. However, it is currently unclear whether patients with AE post-HSE have a specific genetic predisposition to develop the autoimmune complication. Future studies should also clarify the repertoire of synaptic proteins involved in this autoimmune disorder.

5.

Conclusion

Clinical observations indicate that some subtypes of AE can be triggered by infections. This concept has been strengthened by the demonstration that most relapsing symptoms post-HSE are in fact AE. However, many intriguing questions remain unanswered for this and other disorders. For example, it is unknown why some infectious pathogens seem to be more involved than others, or why some subtypes of AE seem to be associated more frequently with prodromal viral-like

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symptoms than others. Future studies should focus in the identification of genetic factors (e.g. HLA susceptibility genes, TLR3 receptor pathway) in patients with AE. It will also be important to clarify whether single case reports of AE with viruses other than herpes simplex are truly pathogenically linked or are only temporally coincidental. Overall, understanding the mechanisms responsible for driving a normal immune response against an infection towards an immune attack against self-neuronal antigens, will help to diagnose and treat patients with AE and improve our knowledge on the immunology and neurobiology of these disorders.

Disclosure of interest The authors declare that they have no competing interest.

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