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# Editorial: Knocking on neuroimmunology's doors: an entrechat concerning the immune system balance and its cell metabolism orchestration

Manolo Sambucci, Valérie Dardalhon, Daniela Latorre

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Manolo Sambucci, Valérie Dardalhon, Daniela Latorre. Editorial: Knocking on neuroimmunology's doors: an entrechat concerning the immune system balance and its cell metabolism orchestration. 2023, 10.3389/fimmu.2023.1236217. hal-04272280

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OPEN ACCESS

EDITED AND REVIEWED BY
Hans-Peter Hartung,
Heinrich Heine University of Düsseldorf,
Germany

*CORRESPONDENCE
Manolo Sambucci

<figure><img src="image_2.png" /></figure>

m.sambucci@hsantalucia.it

RECEIVED 07 June 2023

ACCEPTED 19 June 2023

PUBLISHED 26 June 2023

CITATION

Sambucci M, Dardalhon V and Latorre D (2023) Editorial: Knocking on neuroimmunology's doors: an entrechat concerning the immune system balance and its cell metabolism orchestration. *Front. Immunol.* 14:1236217.
doi: 10.3389/fimmu.2023.1236217

COPYRIGHT

© 2023 Sambucci, Dardalhon and Latorre.
This is an open-access article distributed
under the terms of the *Creative Commons*
*Attribution License (CC BY)*. The use,
distribution or reproduction in other
forums is permitted, provided the original
author(s) and the copyright owner(s) are
credited and that the original publication in
this journal is cited, in accordance with
accepted academic practice. No use,
distribution or reproduction is permitted
which does not comply with these terms.

Editorial: Knocking on
neuroimmunology's doors: an
entrechat concerning the
immune system balance and its
cell metabolism orchestration

Manolo Sambucci¹*, Valérie Dardalhon² and Daniela Latorre³

¹Neuroimmunology Unit, Santa Lucia Foundation IRCCS, Rome, Italy, ²Institut de Génétique Moléculaire de Montpellier, Université de Montpellier, Centre National de la Recherche Scientifique (CNRS), Montpellier, France, ³Institute of Microbiology, ETH Zurich, Zurich, Switzerland

KEYWORDS

neuroimmunology, multiple sclerosis, immune system balance, myasthenia (myasthenia gravis - MG), narcolepsy type I

Editorial on the Research Topic

Knocking on neuroimmunology's doors: an entrechat concerning the immune system balance and its cell metabolism orchestration

The physiological state of health of organisms depends on a fine tuning of immune activation and immune regulation pathways. Immune cells interact millions time a day with external environmental factors but also with symbiotic microorganism. It is a highly complex task for the immune system to address specific responses limiting host damage. The balance is dynamic but the mechanisms relevant for the immune-based disorders are not well understood. An example of such dynamic, combination of factors and events involved in the development of immune-based disease is provided by central nervous system (CNS) autoimmune disorders, arising neuroimmunology as field of study.

This Research Topic collects contributions addressing new evidence on the fundamental role of the immune system's balance as key element in the crosstalk with the nervous system, with a particular focus on demyelinating disorder such as multiple sclerosis (MS) as well as on other brain-related autoimmune disorders such as narcolepsy type I (NT1) or disorders of the neuromuscular junction such as myasthenia gravis (MG).

MS is a chronic, inflammatory, demyelinating and neurodegenerative disease of the CNS. Although the causes of MS are still unknown, the involvement of an abnormal immune response, including the existence of autoreactive T cells and defects in T regulatory functions, is key in the pathophysiological mechanism of disease (1, 2). Here, Kunkl et al. reviewed the topic from a different perspective, summarizing current knowledge of the contribution of pathogenic T helper cells (Th) subsets on the astrocytic changes and altered behaviour observed in MS.
<figure><img src="image_3.png" /></figure>

Check for updates

OPEN ACCESS

EDITED AND REVIEWED BY
Hans-Peter Hartung,
Heinrich Heine University of Düsseldorf,
Germany

*CORRESPONDENCE
Manolo Sambucci

<figure><img src="image_4.png" /></figure>

m.sambucci@hsantalucia.it

RECEIVED 07 June 2023

ACCEPTED 19 June 2023

PUBLISHED 26 June 2023

CITATION

Sambucci M, Dardalhon V and Latorre D (2023) Editorial: Knocking on neuroimmunology's doors: an entrechat concerning the immune system balance and its cell metabolism orchestration. *Front. Immunol.* 14:1236217.
doi: 10.3389/fimmu.2023.1236217

COPYRIGHT

© 2023 Sambucci, Dardalhon and Latorre. This is an open-access article distributed under the terms of the *Creative Commons Attribution License (CC BY)*. The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

# Editorial: Knocking on neuroimmunology's doors: an entrechat concerning the immune system balance and its cell metabolism orchestration

Manolo Sambucci¹*, Valérie Dardalhon² and Daniela Latorre³

¹Neuroimmunology Unit, Santa Lucia Foundation IRCCS, Rome, Italy, ²Institut de Génétique Moléculaire de Montpellier, Université de Montpellier, Centre National de la Recherche Scientifique (CNRS), Montpellier, France, ³Institute of Microbiology, ETH Zurich, Zurich, Switzerland

KEYWORDS

neuroimmunology, multiple sclerosis, immune system balance, myasthenia (myasthenia gravis - MG), narcolepsy type I

## Editorial on the Research Topic

### Knocking on neuroimmunology's doors: an entrechat concerning the immune system balance and its cell metabolism orchestration

The physiological state of health of organisms depends on a fine tuning of immune activation and immune regulation pathways. Immune cells interact millions time a day with external environmental factors but also with symbiotic microorganism. It is a highly complex task for the immune system to address specific responses limiting host damage. The balance is dynamic but the mechanisms relevant for the immune-based disorders are not well understood. An example of such dynamic, combination of factors and events involved in the development of immune-based disease is provided by central nervous system (CNS) autoimmune disorders, arising neuroimmunology as field of study.

This Research Topic collects contributions addressing new evidence on the fundamental role of the immune system's balance as key element in the crosstalk with the nervous system, with a particular focus on demyelinating disorder such as multiple sclerosis (MS) as well as on other brain-related autoimmune disorders such as narcolepsy type I (NT1) or disorders of the neuromuscular junction such as myasthenia gravis (MG).

MS is a chronic, inflammatory, demyelinating and neurodegenerative disease of the CNS. Although the causes of MS are still unknown, the involvement of an abnormal immune response, including the existence of autoreactive T cells and defects in T regulatory functions, is key in the pathophysiological mechanism of disease (1, 2). Here, *Kunkl et al.* reviewed the topic from a different perspective, summarizing current knowledge of the contribution of pathogenic T helper cells (Th) subsets on the astrocytic changes and altered behaviour observed in MS.
T cell polarization to either proinflammatory or regulatory cells is also influenced by metabolism. Several bodies of evidences in fact are showing that changes in nutrient availability can alter T cells function, giving particular attention to cellular metabolic remodelling in neurological disease (3–5). *Pompura et al.* reviewed current evidence on metabolic requirements of CD4⁺ T cell subsets as well as the role of lipids in T cell function, focusing on how the changes in lipid profile observed in patients with MS may influence the inflammatory functional phenotypes of T cells in the disease. Regarding the CNS and immune regulation, accumulating evidence suggests that circular RNA (circRNAs) could have an active role (6). *Mycko et al.* provided new insights into the role of circRNAs in the pathomechanism of MS, identifying two circRNAs and a group of miRNAs that are differentially expressed in MS patients and correlated with the disease state and severity, thus opening new venues for novel potential biomarkers and treatments of the disease. Remaining in the context of intrinsic factors underlying MS pathophysiological mechanisms, *Derakhshani et al.* found an increase of Hemoglobin Subunit Delta (HBD) in MS patients, suggesting the involvement of oxidative stress in MS development. To conclude, several microbial infections have been implicated in the aetiology of MS (7, 8) and increasing evidence points to an association of COVID-19 with a broad range of neurological disorders (9). In this Research Topic, *MacDougall et al.* reviewed the state of art regarding SARS-CoV-2 infection and MS, focusing on disease exacerbation and proposing an interesting model for how SARS-CoV2 can potentially shape CNS autoimmunity.

In this Research Topic, *Meng et al.* provide new insights on the immunomodulatory role of type 1 regulatory T cells (Tr1) in generalized myasthenia gravis. Moreover, *Moschetti et al.* analyzed T cell infiltrates in intracranial aneurysm (IA), describing the existence of T cells endowed with pro-inflammatory features as well as of Eomes⁺ Tr-1-like T cells that failed to display an immunomodulatory phenotype.

Finally, in their original article, *Ayoub et al.* reveal an altered composition of the proteome in the cerebrospinal fluid of NT1 patients, showing a dysregulation in the complement system, thus further supporting converging evidence of an immune-mediated mechanism underlying the disease pathophysiology (10).

Altogether, these works provide an update on the state of art on the immune-mediated mechanisms in neurological diseases highlighting the interpretation of nervous system as “special immune-controlled site”. This novel information could help the development of more targeted therapies.

## Author contributions

MS conceptualized and write the original draft of editorial, review and editing. VD and DL review and editing. All authors contributed to the article and approved the submitted version.

## Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

## Publisher's note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

## References

1. Sambucci M, Gargano F, Guerrera G, Battistini L, Borsellino G. One, no one, and one hundred thousand: T regulatory cells' multiple identities in neuroimmunity. *Front Immunol* (2019) 10:2947. doi: 10.3389/fimmu.2019.02947

2. van Langelaar J, Rijvers L, Smolders J, van Luijn MM. B and T cells driving multiple sclerosis: identity, mechanisms and potential triggers. *Front Immunol* (2020) 11:760. doi: 10.3389/fimmu.2020.00760

3. Pompura SL, Wagner A, Kitz A, LaPerche J, Yosef N, Dominguez-Villar M, et al. Oleic acid restores suppressive defects in tissue-resident FOXP3 tregs from patients with multiple sclerosis. *J Clin Invest* (2021) 131(2):e138519. doi: 10.1172/JCI138519

4. Endo Y, Asou HK, Matsugae N, Hirahara K, Shinoda K, Tumes DJ, et al. Obesity drives Th17 cell differentiation by inducing the lipid metabolic kinase, Acc1. *Cell Rep* (2015) 12:1042–55. doi: 10.1016/j.celrep.2015.07.014

5. Haghikia A, Jörg S, Duscha A, Berg J, Manzel A, Waschbisch A, et al. Dietary fatty acids directly impact central nervous system autoimmunity via the small intestine. *Immunity* (2015) 43:817–29. doi: 10.1016/j.immuni.2015.09.007

6. Zurawska AE, Mycko MP, Selmaj I, Raine CS, Selmaj KW. Multiple sclerosis: circRNA profile defined reveals links to b-cell function. *Neurol Neuroimmunol Neuroinflamm* (2021) 8(5). doi: 10.1212/NXI.0000000000001041

7. Guan Y, Jakimovski D, Ramanathan M, Weinstock-Guttman B, Zivadinov R. The role of Epstein-Barr virus in multiple sclerosis: from molecular pathophysiology to *In vivo* imaging. *Neural Regener Res* (2019) 14(3):373–86. doi: 10.4103/1673-5374.245462

8. Jacobs BM, Giovannoni G, Cuzick J, Dobson R. Systematic review and meta-analysis of the association between Epstein-Barr virus, multiple sclerosis and other risk factors. *Mult Scler* (2020) 26(11):1281–97. doi: 10.1177/1352458520907901

9. Latorre D. Autoimmunity and SARS-CoV-2 infection: unraveling the link in neurological disorders. *Eur J Immunol* (2022) 52(10):1561–71. doi: 10.1002/eji.202149475

10. Latorre D, Sallusto F, Bassetti CLA, Kallweit U. Narcolepsy: a model interaction between immune system, nervous system, and sleep-wake regulation. *Semin Immunopathol* (2022) 44(5):611–23. doi: 10.1007/s00281-022-00933-9
T cell polarization to either proinflammatory or regulatory cells is also influenced by metabolism. Several bodies of evidences in fact are showing that changes in nutrient availability can alter T cells function, giving particular attention to cellular metabolic remodelling in neurological disease (3–5). *Pompura et al.* reviewed current evidence on metabolic requirements of CD4⁺ T cell subsets as well as the role of lipids in T cell function, focusing on how the changes in lipid profile observed in patients with MS may influence the inflammatory functional phenotypes of T cells in the disease. Regarding the CNS and immune regulation, accumulating evidence suggests that circular RNA (circRNAs) could have an active role (6). *Mycko et al.* provided new insights into the role of circRNAs in the pathomechanism of MS, identifying two circRNAs and a group of miRNAs that are differentially expressed in MS patients and correlated with the disease state and severity, thus opening new venues for novel potential biomarkers and treatments of the disease. Remaining in the context of intrinsic factors underlying MS pathophysiological mechanisms, *Derakhshani et al.* found an increase of Hemoglobin Subunit Delta (HBD) in MS patients, suggesting the involvement of oxidative stress in MS development. To conclude, several microbial infections have been implicated in the aetiology of MS (7, 8) and increasing evidence points to an association of COVID-19 with a broad range of neurological disorders (9). In this Research Topic, *MacDougall et al.* reviewed the state of art regarding SARS-CoV-2 infection and MS, focusing on disease exacerbation and proposing an interesting model for how SARS-CoV2 can potentially shape CNS autoimmunity.

In this Research Topic, *Meng et al.* provide new insights on the immunomodulatory role of type 1 regulatory T cells (Tr1) in generalized myasthenia gravis. Moreover, *Moschetti et al.* analyzed T cell infiltrates in intracranial aneurysm (IA), describing the existence of T cells endowed with pro-inflammatory features as well as of Eomes⁺ Tr-1-like T cells that failed to display an immunomodulatory phenotype.

Finally, in their original article, *Ayoub et al.* reveal an altered composition of the proteome in the cerebrospinal fluid of NT1 patients, showing a dysregulation in the complement system, thus further supporting converging evidence of an immune-mediated mechanism underlying the disease pathophysiology (10).

Altogether, these works provide an update on the state of art on the immune-mediated mechanisms in neurological diseases highlighting the interpretation of nervous system as “special immune-controlled site”. This novel information could help the development of more targeted therapies.

## Author contributions

MS conceptualized and write the original draft of editorial, review and editing. VD and DL review and editing. All authors contributed to the article and approved the submitted version.

## Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

## Publisher's note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

## References

1. Sambucci M, Gargano F, Guerrera G, Battistini L, Borsellino G. One, no one, and one hundred thousand: T regulatory cells' multiple identities in neuroimmunity. *Front Immunol* (2019) 10:2947. doi: 10.3389/fimmu.2019.02947

2. van Langelaar J, Rijvers L, Smolders J, van Luijn MM. B and T cells driving multiple sclerosis: identity, mechanisms and potential triggers. *Front Immunol* (2020) 11:760. doi: 10.3389/fimmu.2020.00760

3. Pompura SL, Wagner A, Kitz A, LaPerche J, Yosef N, Dominguez-Villar M, et al. Oleic acid restores suppressive defects in tissue-resident FOXP3 tregs from patients with multiple sclerosis. *J Clin Invest* (2021) 131(2):e138519. doi: 10.1172/JCI138519

4. Endo Y, Asou HK, Matsugae N, Hirahara K, Shinoda K, Tumes DJ, et al. Obesity drives Th17 cell differentiation by inducing the lipid metabolic kinase, Acc1. *Cell Rep* (2015) 12:1042–55. doi: 10.1016/j.celrep.2015.07.014

5. Haghikia A, Jörg S, Duscha A, Berg J, Manzel A, Waschbisch A, et al. Dietary fatty acids directly impact central nervous system autoimmunity via the small intestine. *Immunity* (2015) 43:817–29. doi: 10.1016/j.immuni.2015.09.007

6. Zurawska AE, Mycko MP, Selmaj I, Raine CS, Selmaj KW. Multiple sclerosis: circRNA profile defined reveals links to b-cell function. *Neurol Neuroimmunol Neuroinflamm* (2021) 8(5). doi: 10.1212/NXI.0000000000001041

7. Guan Y, Jakimovski D, Ramanathan M, Weinstock-Guttman B, Zivadinov R. The role of Epstein-Barr virus in multiple sclerosis: from molecular pathophysiology to *In vivo* imaging. *Neural Regener Res* (2019) 14(3):373–86. doi: 10.4103/1673-5374.245462

8. Jacobs BM, Giovannoni G, Cuzick J, Dobson R. Systematic review and meta-analysis of the association between Epstein-Barr virus, multiple sclerosis and other risk factors. *Mult Scler* (2020) 26(11):1281–97. doi: 10.1177/1352458520907901

9. Latorre D. Autoimmunity and SARS-CoV-2 infection: unraveling the link in neurological disorders. *Eur J Immunol* (2022) 52(10):1561–71. doi: 10.1002/eji.202149475

10. Latorre D, Sallusto F, Bassetti CLA, Kallweit U. Narcolepsy: a model interaction between immune system, nervous system, and sleep-wake regulation. *Semin Immunopathol* (2022) 44(5):611–23. doi: 10.1007/s00281-022-00933-9