J Neuroinflammation︱An Jing/Luan Guoming team work together to reveal a new pathogenesis of Rasmussen encephalitis

Written by ︱ Wang Yisong, Wang Peigang, Jing Jing editor ︱ Wang Sizhen Rasmussen encephalitis (Rasmussen's encephalitis, RE) is a chronic neurological disease of unknown etiology seen in children [1].
The average age of patients is 6 years old
.

The disease is extremely rare
.

In Europe, the incidence rate of people under the age of 18 is 2.
4 per 10 million [2]
.

Histopathological features of the disease include progressive neuronal loss in unilateral cerebral hemisphere, microglial nodules, and angiolymphatic cuffs
.

Typical clinical manifestations are frequent partial seizures or partial status seizures, accompanied by progressive hemiplegia of one limb and cognitive impairment
.

There is currently no effective treatment, and hemispheric transection is the only way to relieve seizures and improve cognition
.

However, the resulting contralateral motor dysfunction and severe decline in fine motor ability will have a serious impact on patients and their families [2-4]
.

 The disease was first discovered and reported by Canadian neurosurgeon Rasmussen in 1958.
Dr.
Rasmussen believed that the pathological characteristics of the cerebral cortex of patients with the disease were similar to those of viral encephalitis, so he proposed the virus infection theory on the etiology of RE [1]
.

However, follow-up studies have shown that there is a large number of infiltration and activation of CD8+ T cells in RE brain tissue, so some scholars have proposed an autoimmune theory of the disease
.

To date, the etiology and pathogenesis of the disease have not been fully elucidated
.

 On March 26, 2022, Professor Jing Jing's team from the School of Basic Medicine of Capital Medical University and Professor Luan Guoming's team from Sanbo Brain Hospital published a paper entitled "Rasmussen's encephalitis is characterized by relatively lower production of IFN- The research paper, β and activated cytotoxic T cell upon herpes viruses infection”, proposed that the insufficient local antiviral innate immune response in the brain after herpes virus infection may be an important cause of the development of RE: when a herpes virus infection occurs, RE.
The level of innate immunity in the patient's brain is relatively low, while the cytotoxic T cells are over-activated, and the resulting immune damage may be an important reason for the occurrence of RE
.

Herpes virus (human herpes virus, HHVs) is a class of enveloped double-stranded DNA viruses, HHVs pathogenic to humans include herpes simplex virus type 1 (HSV1), herpes simplex virus type 2 (HSV2), varicella zoster Virus (VZV), human cytomegalovirus (HCMV), Epstein-Barr virus (EBV), human herpesvirus 6 (HHV-6), human herpesvirus 7 (HHV7) and Kaposi's sarcoma-associated herpesvirus (KSHV)
.

The population is generally susceptible to herpes virus.
People with healthy immunity have no obvious clinical symptoms after infection, while patients with low immunity can cause serious diseases after infection
.

HHVs infection has the characteristics of latent and reactivation, that is, after acute infection, the virus can form latent infection in the host, and under appropriate conditions, the infection will relapse and symptoms will appear
.

Of particular note is that most viruses in this family are neurotropic and can cause central nervous system infections
.

 In the present study, the authors compared RE with another disorder with clinical manifestations of epilepsy, but without brain tissue atrophy, temporal lobe epilepsy (TLE), and also using patients with traumatic brain injury (TBI) as epilepsy-free controls
.

The study collected brain tissue samples from 30 patients with RE, and detected the expression levels of HHVs antigens by immunohistochemistry
.

Compared with TLE and traumatic brain injury patient groups, the positive rate of HSV-1, HCMV, EBV and HHV6 antigen expression in RE group was 50%-88.
5%, which was significantly higher than that in TLE group.
It was positively correlated with the degree of brain atrophy in RE patients, suggesting that HHVs infection may be involved in the disease progression of RE (Figure 1)
.

Figure 1 Distribution of herpesvirus in brain tissue of RE patients (Source: Wang et al.
, J Neuroinflammation, 2022) In order to explore the molecular mechanism of HHV infection-induced RE encephalitis, the authors analyzed the infiltration of CD8+ T cells in brain tissue samples and the Expression of relevant effector molecules
.

CD8+ T cell infiltration was found in 96.
7% of RE brain tissue and 90% of TLE brain tissue
.

Although CD8+ T cells were not significantly different between RE and temporal lobe epilepsy (TLE) brains, brain tissue atrophy was only seen in RE patients, and the degree of brain tissue atrophy in RE patients was not related to CD8a expression
.

This result prompted the authors to analyze the expression of the major effector molecule granzyme B (GZMB) in CD8+ T cells
.

CD8+ T cells were positive for GZMB antibody staining in 90% of RE and 80% of TLE cases
.

However, analysis using AimPlex® multiplex immunization found that the concentrations of GZMB and soluble FasL (sFasL) in RE brain tissue were significantly higher than those in TLE tissue, suggesting that although both CD8+ T cells in RE and TLE brains expressed GZMB, only In RE brain, GZMB was released extracellularly, causing apoptosis of neurons infected with HHVs
.

In summary, the results of RE and TLE were compared and analyzed (Fig.
2), and the preliminary conclusions were drawn: Although both TLE and RE cases were infected with HHVs, CD8+ T cells in TLE cases were in a quiescent state, while CD8+ T cells in RE cases were in a quiescent state.
Activated and released GZMB into HHVs-infected cells, resulting in neuronal damage
.

Figure 2 Expression of CD+8 T cells in the brain tissue of RE patients (Source: Wang et al.
, J Neuroinflammation, 2022) In order to further explore the mechanism of CD8+ T cell activation when the brain tissue of RE patients is infected with HHV, the authors first detected The expression of inflammatory factors in brain tissue and cerebrospinal fluid (CSF) of RE and TLE patients
.

Unexpectedly, most pro- and anti-inflammatory factors, such as interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL- 6.
IL-4 and IL-10 did not show significant differences in RE and TLE brain tissues, but the expression level of IFN-β, a key factor in antiviral innate immunity, was significantly lower in RE cases than in TLE groups (Figure 3).

.

Further analysis also found that the expression levels of DNA-recognizing immune molecules STING and IFI16 in the upstream signaling pathway of IFN-β were also significantly lower in RE than in TLE group
.

These results suggest that when RE cases face HHVs infection, the innate immune signaling pathway is difficult to be fully activated, so sufficient IFN-β cannot be produced to control viral infection
.

Figure 3 Expression of IFN-β in brain tissue of RE patients (Source: Wang et al.
, J Neuroinflammation, 2022) Conclusion and discussion, inspiration and prospect Based on the above results, the author proposes to explain the pathogenesis of Rasmussen encephalitis (RE) A new model of the mechanism
.

In the central nervous system, in the face of HHVs infection, innate immunity (IFN-β) and adaptive immunity (CD8+ T cells) usually act synergistically to limit viral infection and latent virus reactivation
.

However, in RE patient brain tissue, due to insufficient innate immune response and insufficient IFN-β synthesis, relatively low levels of IFN-β impair the defense against HHVs, making them susceptible to infection-reactivation
.

Long-term chronic viral infection activates HHVs-specific CD8+ T cells
.

Activation of CD8+ T cells compensates for IFN-β deficiency and controls the spread of HHVs by inducing apoptosis in infected cells
.

However, this compensation will inevitably lead to the loss of a large number of neurons, eventually causing chronic unilateral progressive atrophy of the cerebral hemisphere
.

Although the model proposed in this study explains many of the pathological features of RE, it still needs to be further validated by in vitro studies and animal experiments
.

In future work, the establishment of RE animal models may provide an important platform for understanding the pathogenesis of RE
.

Link to the original text: https://doi.
org/10.
1186/s12974-022-02379-0 Wang Yisong, School of Basic Medicine, Capital Medical University, Liu Dong, Sanbo Brain Hospital, Capital Medical University, and Wang Xin, Peking University International Hospital are the joint first for the paper The authors are Associate Professor Wang Peigang, School of Basic Medicine, Capital Medical University, Professor Luan Guoming, Sanbo Brain Hospital, Capital Medical University, and Professor Jing Jing, School of Basic Medicine, Capital Medical University are the co-corresponding authors of the paper
.

Corresponding authors Professor Jing Jing (left), Professor Luan Guoming (middle), and Associate Professor Wang Peigang (right)
.

(Photo provided from: Professor Jing’s laboratory) About the author (swipe up and down to read) Jing Jing, professor, doctoral supervisor, is currently the deputy director of the Department of Pathogen Biology and the director of the Microbiology Teaching and Research Section of the School of Basic Medicine, Capital Medical University
.

The main research directions are the pathogenic mechanism and preventive measures of arboviruses, and the relationship between herpes virus infection and major brain diseases
.

In recent years, as the corresponding author, he has published more than 40 high-level papers in such journals as "Cell Reports", "PLoS Pathogens", "Journal of Virology", "Antiviral Research", "PloS NTD" and "Vaccine"
.

Undertook 1 key project supported by the National Natural Science Foundation of China-Yunnan Joint Fund, 3 general projects, 1 key project and 1 general project of the Beijing Natural Science Foundation, and 2 invention patents were approved
.

 Luan Guoming, Neurosurgery Expert, Professor, Chief Physician, Doctoral Supervisor, Sanbo Brain Hospital, Capital Medical University; Head of the Third Department, Department of Neurosurgery, Capital Medical University; Vice President and Executive Director of China Anti-epilepsy Association; Neurosurgery of Chinese Medical Doctor Association Chairman of the Regulation Professional Committee; Chairman of the China Branch of the World Neuromodulation Society; Director of the Epilepsy Research Institute of the Beijing Institute of Major Brain Diseases
.

"Chinese Journal of Neurosurgery", "Chinese Journal of Minimally Invasive Neurosurgery", "Chinese Journal of Clinical Neurosurgery", "International Journal of Neurology and Neurosurgery", "Journal of Stereotactic and Functional Neurosurgery", "Clinical and Research of Epilepsy" ", "Chinese Journal of Neuromedicine", "Journal of Epilepsy" and "World Neuromodulation Society Journal" and other journal editorial board, reviewer
.

 Wang Peigang, associate professor and master tutor of the Department of Pathogen Biology, School of Basic Medicine, Capital Medical University
.

The main research direction is the molecular mechanism of mosquito-borne virus-host interaction, and the relationship between herpes virus infection and major brain diseases
.

Published more than ten papers as the corresponding author
.

Currently undertaking 2 general projects of the National Natural Science Foundation of China
.

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4.
18~4.
30) [2] Scientific research skills︱Introduction to magnetic resonance brain network analysis (online : 2022.
4.
6~4.
16) [3] Training course︱References for scientific research drawing and academic image training (swipe up and down to read) [1] Rasmussen T, Olszewski J, Lloydsmith D.
Focal seizures due to chronic localized encephalitis [J].
Neurology, 1958, 8(6): 435-445.
[2]Varadkar S, Bien CG, Kruse CA, Jensen FE, Bauer J, Pardo CA, Vincent A, Mathern GW, Cross J H.
Rasmussen's encephalitis:clinical features, pathobiology, and treatment advances [J].
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[3]Guan Y, Chen S, Liu C, Du X, Zhang Y, Chen S, Wang J, Li T, Luan G.
Timing and type of hemispherectomy for Rasmussen's encephalitis: Analysis of 45 patients [J].
Epilepsy Res, 2017, 132(109-115.
[4]Wang DD, Benkli B, Auguste KI, Garcia PA, Sullivan J, Barkovich AJ, Chang EF, Tihan T.
Unilateral holohemispheric central nervous system lesions associated with medically refractory epilepsy in the pediatric population: a retrospective series of hemimegalencephaly and Rasmussen's encephalitis [J].
J Neurosurg Pediatr, 2014, 14(6): 573-584.
Plate making︱Wang Sizhen End of this articleTiming and type of hemispherectomy for Rasmussen's encephalitis: Analysis of 45 patients [J].
Epilepsy Res, 2017, 132(109-115.
[4]Wang DD, Benkli B, Auguste KI, Garcia PA, Sullivan J, Barkovich AJ, Chang EF, Tihan T.
Unilateral holohemispheric central nervous system lesions associated with medically refractory epilepsy in the pediatric population: a retrospective series of hemimegalencephaly and Rasmussen's encephalitis [J].
J Neurosurg Pediatr, 2014, 14(6): 573-584.
Edition ︱ Wang Sizhen finished this articleTiming and type of hemispherectomy for Rasmussen's encephalitis: Analysis of 45 patients [J].
Epilepsy Res, 2017, 132(109-115.
[4]Wang DD, Benkli B, Auguste KI, Garcia PA, Sullivan J, Barkovich AJ, Chang EF, Tihan T.
Unilateral holohemispheric central nervous system lesions associated with medically refractory epilepsy in the pediatric population: a retrospective series of hemimegalencephaly and Rasmussen's encephalitis [J].
J Neurosurg Pediatr, 2014, 14(6): 573-584.
Edition ︱ Wang Sizhen finished this articlea retrospective series of hemimegalencephaly and Rasmussen's encephalitis [J].
J Neurosurg Pediatr, 2014, 14(6): 573-584.
Plate making︱Wang Sizhen End of this papera retrospective series of hemimegalencephaly and Rasmussen's encephalitis [J].
J Neurosurg Pediatr, 2014, 14(6): 573-584.
Plate making︱Wang Sizhen End of this paper