The importance of ruling out herpes simplex virus encephalitis in N-methyl-ᴅ-aspartate receptor encephalitis studies

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encephalitis. 2023;3(3):79-80
Publication date (electronic) : 2023 June 27
doi :
1Department of Medical Virology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
2Department of Neurology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
Correspondence: Esma’il Akade Department of Medical Virology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Golestan Blvd., Esfand St., Ahvaz 1579461357, Iran E-mail:,
Received 2023 May 8; Revised 2023 June 2; Accepted 2023 June 2.

Dear Editor,

We are writing to express our thoughts on the article entitled, “Regulatory T cell profiles in patients with N-methyl-ᴅ-aspartate receptor-antibody encephalitis,” published in encephalitis [1]. The study aimed to investigate the role of regulatory T cells (Treg cells) in N-methyl-ᴅ-aspartate receptor (NMDAR) encephalitis, which is caused by production of autoantibodies against NMDARs. While the findings of the study are significant, it is essential to consider the impact of previous herpes simplex virus (HSV) infection on the results.

HSV-1 is a double-stranded DNA virus with seropositivity rates reaching approximately 40% among adults in industrialized nations and as high as 80% to 90% in the developing world. This virus is the primary cause of sporadic infectious encephalitis worldwide across all age groups. Epidemiological change over the past two decades has involved the increase in cases of HSV-1 linked to genital infections. As a result of this shift, HSV-1 has surpassed HSV-2 as the most common cause of neonatal encephalitis. Awareness of the condition revealed that 18 to 30% of individuals with HSV encephalitis of either type develop anti-NMDAR antibodies either during or shortly after the infection [2].

Interestingly, HSVs take advantage of Treg cells in various ways. The HSV-1 ocular infection murine model demonstrates a positive correlation between the level of Treg cells and viral infectivity, along with a need for Treg cells in latency establishment. Additionally, host stress contributes to HSV-1 reactivation through elevated Treg cell control of CD8+ T cells, allowing viral replication with reduced immune surveillance. These findings suggest that Treg cell regulation could be a critical target for managing HSV infection [3].

In the context of HSV-2, mice deficient in Treg cells exhibit inadequate control of viral replication subsequent to infection, indicating a potential function for Tregs in effective immune responses. Through the implementation of an adoptive transfer approach involving T-cell receptor transgenic CD4 T cells, studies elucidate the necessity of Tregs in prompt accumulation of HSV-2–specific CD4 T cells within the affected tissues, as observed in both Treg-intact and Treg-deficient murine models prior to HSV-2 infection [4].

Despite the few studies on the role of Treg cells in HSV-induced cases of encephalitis, current findings highlight the importance of considering the potential impact of previous herpes virus infection on the results of studies investigating Treg cells in NMDAR encephalitis. To evaluate the change in regulatory T cells accurately in NMDAR encephalitis, it is crucial to rule out previous history of HSV encephalitis. This can be done through comprehensive medical history, including any past infections or immune-related conditions, and performing relevant diagnostic tests as needed.

An accurate diagnosis is critical for proper management of encephalitis and for preventing unnecessary interventions. We believe that the study by Iro et al. [1] can substantially improve the outcomes of patients with NMDAR encephalitis. However, the prevalence of herpes viruses in encephalitis and their impact on immune cells underscore the need for additional research in this area.


Conflicts of Interest

No potential conflict of interest relevant to this article was reported.

Author Contributions

Conceptualization: Akade E; Validation, Supervision: Jalilian S, Bahadoram M; Investigation: Akade E; Writing–original draft: Akade E; Writing–review & editing: Jalilian S


1. Iro MA, Rollier CS, Irani SR, et al. Regulatory T cell profiles in patients with N-methyl-D-aspartate receptor-antibody encephalitis. encephalitis 2023;3:15–23.
2. Matthews E, Beckham JD, Piquet AL, Tyler KL, Chauhan L, Pastula DM. Herpesvirus-associated encephalitis: an update. Curr Trop Med Rep 2022;9:92–100.
3. Yu W, Geng S, Suo Y, et al. Critical role of regulatory T cells in the latency and stress-induced reactivation of HSV-1. Cell Rep 2018;25:2379–2389.e3.
4. Soerens AG, Da Costa A, Lund JM. Regulatory T cells are essential to promote proper CD4 T-cell priming upon mucosal infection. Mucosal Immunol 2016;9:1395–1406.

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