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Integration of Th17- and lymphotoxin-derived signals initiates meningeal-resident stromal cell remodeling to propagate neuroinflammation.
Open accessAbstract
Tertiary lymphoid tissues (TLTs) have been observed in the meninges of multiple sclerosis (MS) patients, but the stromal cells and molecular signals that support TLTs remain unclear. Here, we show that T helper 17 (Th17) cells induced robust TLTs within the brain meninges that were associated with local demyelination during experimental autoimmune encephalitis (EAE). Th17-cell-induced TLTs were underpinned by a network of stromal cells producing extracellular matrix proteins and chemokines, enabling leukocytes to reside within, rather than simply transit through, the meninges. Within the CNS, interactions between lymphotoxin αβ (LTαβ) on Th17 cells and LTβR on meningeal radio-resistant cells were necessary for the propagation of de novo interleukin-17 responses, and activated T cells from MS patients expressed elevated levels of LTβR ligands. Therefore, input from both Th17 cells and the lymphotoxin pathway induce the formation of an immune-competent stromal cell niche in the meninges.
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“The presentation of MS induced leptomeningeal inflammation can be variable, ranging from disorganized collections of immune cells to organized ectopic lymphoid follicle-like structures”
From Living on the Edge of the CNS: Meninges Cell Diversity in Health and Disease (2021) · cites this paper as Pikor et al., 2015
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Advances in Meningeal Immunity
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InfluentialT cell responses in the central nervous system
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Dorrier, C., Jones, H. E., Pintarić, L., Siegenthaler, J. A., & Daneman, R. (2021) · Nature reviews. Neuroscience · doi:10.1038/s41583-021-00525-w · Cited by 204
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“Crosstalk between Th17 cells and stromal cells was also recently shown to be important in an experimental model of multiple sclerosis, where stromal LTβR signaling promoted extracellular matrix deposition, T cell effector cytokine responses, and chemokine production that supported leukocyte retention in the meninges (…”
BackgroundMolecular anatomy of adult mouse leptomeninges
Pietilä, R., Del Gaudio, F., He, L., Vázquez-Liébanas, E., Vanlandewijck, M., Muhl, L., Mocci, G., Bjørnholm, K. D., Lindblad, C., Fletcher-Sandersjöö, A., et al. (2023) · Neuron · doi:10.1016/j.neuron.2023.09.002 · Cited by 145
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“…in MS are potentiated by leptomeningeal fibroblasts which form a reticular cell network consisting of activated fibroblasts in a scaffold-like structure, and that these fibroblasts “scaffolds” might be driven by a subset of meningeal fibroblast that express podoplanin (Pikor et al., 2015, 2017).”
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“This hypothesis was investigated in detail in the SJL Th17 adoptive transfer model (76): Pikor and colleagues could show that IL-17 and IL-22 together act on meningeal FRCs to induce remodeling of actin and collagen and production of ECM components, which ultimately leads to formation of fibrous networks providing pro…”
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“It has been recently shown that Th17-derived IL-17 and IL-22 activate meningeal stromal cells, which support the de novo IL-17 responses in the meninges (94).”
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“TLOs develop as ectopic lymphocyte clusters in connective tissues or parenchyma of diseased organs in various nonresolving chronic inflammatory diseases, including autoimmune diseases (7, 8), cancers (9), chronic infectious diseases (10), transplant rejections (11), and chronic inflammatory diseases like atheroscleros…”
BackgroundLymphoid Aggregates in the CNS of Progressive Multiple Sclerosis Patients Lack Regulatory T Cells
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“Experimental autoimmune encephalomyelitis (EAE), a rodent model sharing features with MS, revealed not only that the pro-inflammatory CCR6-directed Th17 cells enter the CNS via the choroid plexus, a distinct meningeal structure (48), but also are involved in eLF induction (49, 50).”
BackgroundThe Ins and Outs of Central Nervous System Inflammation—Lessons Learned from Multiple Sclerosis
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“In particular, Il-17 producing CD4+ Th17 cells have been shown to be essential for the formation of TLOs in the central nervous system of mice during chronic experimental autoimmune encephalomyelitis (EAE), where stromal LTβR signaling promoted extracellular matrix deposition, T cell effector cytokine responses, and c…”
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“Moreover, we found that renal TLOs induced in aged Il17a-/- mice were smaller compared with wild-type aged mice, this finding was consistent with other disease models focused on TLOs regulated by IL-17A, such as experimental autoimmune encephalitis [25] and lipopolysaccharide-induced pulmonary inflammation [26].”
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“Longitudinal assessment of the presence of different types of meningeal immune cells at different stages of the disease would require advanced PET imaging and MRI techniques (33) and/or the application of a relevant animal model that captures meningeal inflammation and other aspects of MS pathology, as we have describ…”
Dynamic fibroblast–immune interactions shape recovery after brain injury
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Asam, S., Nayar, S., Gardner, D. H., & Barone, F. (2021) · Immunological Reviews · doi:10.1111/imr.12987 · Cited by 52
The role of the complement system in Multiple Sclerosis: A review
Saez-Calveras, N., & Stüve, O. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.970486 · Cited by 51
“In EAE models, this tissue harbors C3+ cells (74).”
BackgroundMorgan, B. P., Gommerman, J. L., & Ramaglia, V. (2021) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.600656 · Cited by 51
“…leptomeninges within brains that have a relatively intact BBB (Serafini et al., 2004; Lassmann et al., 2007; Magliozzi et al., 2007, 2010; Howell O. W. et al., 2011; Lucchinetti et al., 2011; Popescu et al., 2011; Choi et al., 2012; Absinta et al., 2015; Howell et al., 2015; Haider et al., 2016).”
BackgroundDendritic cells in central nervous system autoimmunity
Sie, C., & Korn, T. (2016) · Seminars in Immunopathology · doi:10.1007/s00281-016-0608-7 · Cited by 47
“Follicular DCs were identified within tertiary lymphoid structures of the meninges in chronic autoimmune inflammation [139, 140].”
BackgroundEctopic Lymphoid Follicles in Multiple Sclerosis: Centers for Disease Control?
Negron, A., Stüve, O., & Forsthuber, T. G. (2020) · Frontiers in Neurology · doi:10.3389/fneur.2020.607766 · Cited by 47
“Meningeal stromal cells also secrete IL-23, required for TH17 maintenance, in inflammatory conditions (113, 114, 121, 188).”
BackgroundMitsdoerffer, M., Liberto, G. D., Dötsch, S., Sie, C., Wagner, I., Pfaller, M., Kreutzfeldt, M., Fräßle, S. P., Aly, L., Knier, B., et al. (2021) · Brain · doi:10.1093/brain/awab093 · Cited by 49
“9 Also, IL-17 and podoplanin produced by Th17 cells were suggested to induce MEBAGs during EAE.”
Serafini, B., Rosicarelli, B., Veroni, C., Zhou, L., Reali, C., & Aloisi, F. (2016) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/nlw063 · Cited by 46
“In experimental autoimmune encephalomyelitis (EAE), ELS formation in the CNS has been associated with Th17 cells that produce the lymphoid tissue-associated glycoprotein podoplanin (19).”
BackgroundInfluentialNew advances in CNS immunity against viral infection
Manglani, M., & McGavern, D. B. (2017) · Current Opinion in Virology · doi:10.1016/j.coviro.2017.12.003 · Cited by 43
“Current Opinion in Virology 2018, 28:116–126 immune cells can enter the CNS through the blood meningeal barrier [12 ,32], as depicted in Figure 3.”
BackgroundTargeting senescence to delay progression of multiple sclerosis
Oost, W., Talma, N., Meilof, J. F., & Laman, J. D. (2018) · Journal of Molecular Medicine · doi:10.1007/s00109-018-1686-x · Cited by 47
Lymphotoxin-alpha expression in the meninges causes lymphoid tissue formation and neurodegeneration
Bates, R. E. J., Browne, E., Schalks, R., Jacobs, H., Tan, L. Y., Parekh, P., Magliozzi, R., Calabrese, M., Mazarakis, N. D., & Reynolds, R. (2022) · Brain · doi:10.1093/brain/awac232 · Cited by 42
“…various stages of complexity in the meninges overlying the brainstem, cerebellum, spinal cord and in the ventricles (Kuerten et al., 2012; Magliozzi et al., 2004; Peters et al., 2011; Pikor et al., 2015), none of these models exhibited the cortical grey matter pathology that is commonly seen in MS.”
BackgroundInfluentialHarp, C. R. P., Archambault, A. S., Cheung, M. D., Williams, J. W., Czepielewski, R. S., Duncker, P. C., Kilgore, A. J., Miller, A. T., Segal, B. M., Kim, A. H. J., et al. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1909098116 · Cited by 43
“Also, it is important to note that the encephalitogenic donor CD4 T cell lines used to induce passive EAE in our model are very strongly Th1-skewed and thus distinct from models exhibiting ELT in B6 or SJL (Swiss Jim Lambert) mice involving IL-17– skewed CD4 T cells (12, 18).”
BackgroundResultLymphotoxin in physiology of lymphoid tissues - implication for antiviral defense
Koroleva, E., Fu, Y.-X., & Tumanov, A. (2016) · Cytokine · doi:10.1016/j.cyto.2016.08.018 · Cited by 34
Tertiary lymphoid organs in systemic autoimmune diseases: pathogenic or protective?
Shipman, W. D., Dasoveanu, D., & Lu, T. T. (2017) · F1000Research · doi:10.12688/f1000research.10595.1 · Cited by 42
Leptomeningeal inflammation in multiple sclerosis: Insights from animal and human studies
Wicken, C., Nguyen, J. V., Karna, R., & Bhargava, P. (2018) · Multiple Sclerosis and Related Disorders · doi:10.1016/j.msard.2018.09.025 · Cited by 40
Ma, T., Wang, F., Xu, S., & Huang, J. H. (2021) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2021.01.028 · Cited by 38
Wilharm, A., Brigas, H. C., Sandrock, I., Ribeiro, M. A., Amado, T., Reinhardt, A., Demera, A., Hoenicke, L., Strowig, T., Carvalho, T., et al. (2020) · Mucosal Immunology · doi:10.1038/s41385-020-0330-6 · Cited by 41
Tertiary Lymphoid Structures in the Central Nervous System: Implications for Glioblastoma
van de Walle, T., Vaccaro, A., Ramachandran, M., Pietilä, I., Essand, M., & Dimberg, A. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.724739 · Cited by 38
“The BBB consists of specialized brain microvascular endothelial cells and pericytes as well as the astrocyte endfeet and basal lamina, which comprise the glia limitans (15).”
BackgroundInfluentialContribution of B cells to cortical damage in multiple sclerosis
Bhargava, P., Hartung, H.-P., & Calabresi, P. A. (2022) · Brain · doi:10.1093/brain/awac233 · Cited by 36
Nayar, S., Pontarini, E., Campos, J., Berardicurti, O., Smith, C. G., Asam, S., Gardner, D. H., Colafrancesco, S., Lucchesi, D., Coleby, R., et al. (2022) · Communications Biology · doi:10.1038/s42003-022-03344-6 · Cited by 35
Wang, A. A., Luessi, F., Neziraj, T., Pössnecker, E., Zuo, M., Engel, S., Hanuscheck, N., Florescu, A., Bugbee, E., Xianjie, I., et al. (2024) · Science Translational Medicine · doi:10.1126/scitranslmed.adi0295 · Cited by 37
Shen, S., Cui, Y., Li, M., Yu, K., Zhu, Q., Zhang, X., Shen, W., Li, H., Jiang, H., Li, M., et al. (2024) · Neuro-Oncology · doi:10.1093/neuonc/noae167 · Cited by 35
Perivascular stromal cells: Directors of tissue immune niches
Sbierski‐Kind, J., Mroz, N. M., & Molofsky, A. B. (2021) · Immunological Reviews · doi:10.1111/imr.12984 · Cited by 35
Regulation of Lymph Node Vascular–Stromal Compartment by Dendritic Cells
Dasoveanu, D., Shipman, W. D., Chia, D. J., Chyou, S., & Lu, T. T. (2016) · Trends in Immunology · doi:10.1016/j.it.2016.08.013 · Cited by 35
Central Nervous System Fibroblast-Like Cells in Stroke and Other Neurological Disorders
Xu, L., & Yao, Y. (2021) · Stroke · doi:10.1161/strokeaha.120.033431 · Cited by 34
Shou, Y., Koroleva, E. P., Spencer, C. M., Shein, S. A., Korchagina, A. A., Yusoof, K. A., Parthasarathy, R., Leadbetter, E. A., Akopian, A. N., Muñoz, A. R., et al. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.712632 · Cited by 34
Stromal cell niches in the inflamed central nervous system.
Pikor, N. B., Cupovic, J., Onder, L., Gommerman, J. L., & Ludewig, B. (2017) · The Journal of Immunology · doi:10.4049/jimmunol.1601566 · Cited by 33
“promoting TLT formation at various sites of chronic inflammation (87), including EAE (31, 78).”
BackgroundInfluentialSelf-citationSiponimod therapy implicates Th17 cells in a preclinical model of subpial cortical injury
Ward, L. A., Lee, D. S. W., Sharma, A. K., Wang, A. A., Naouar, I., Xianjie, I., Pikor, N. B., Nuesslein‐Hildesheim, B., Ramaglia, V., & Gommerman, J. L. (2019) · JCI Insight · doi:10.1172/jci.insight.132522 · Cited by 32
“Since transferred proinflammatory T 183 cells appear in the brain starting at day 5 post-transfer (22), we administered BAF312 to 184 recipient SJL/J mice at days 3, 5 or 8 post A/T and assessed EAE severity using a 16-point 185 composite clinical scoring index, comparing the three treatment groups to a group of vehic…”
BackgroundMethodInfluentialLi, C., Lam, E., Perez‐Shibayama, C., Ward, L. A., Zhang, J., Lee, D. S. W., Nguyen, A., Ahmed, M., Brownlie, E., Korneev, K. V., et al. (2019) · Science Immunology · doi:10.1126/sciimmunol.aax1027 · Cited by 33
Bcl6 controls meningeal Th17–B cell interaction in murine neuroinflammation
Hartlehnert, M., Börsch, A., Li, X., Burmeister, M., Gerwien, H., Schafflick, D., Heming, M., Lu, I., Narayanan, V., Strecker, J., et al. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2023174118 · Cited by 30
“Of note, FRCs or FDCs both constitute nonhematopoietic (i.e., CD45 neg ) stromal cell types (35) and were thus not included in our CD45 high -restricted scRNA-seq screen.”
InfluentialAge-dependent gray matter demyelination is associated with leptomeningeal neutrophil accumulation
Zuo, M., Fettig, N. M., Bernier, L., Pössnecker, E., Spring, S., Pu, A., Xianjie, I., Lee, D. S., Ward, L. A., Sharma, A. K., et al. (2022) · JCI Insight · doi:10.1172/jci.insight.158144 · Cited by 31
“This stromal cell remodeling creates an immunocompetent niche in the leptomeninges (23) that is spatially associated with subpial cortical gray matter demyelination, microglial/macrophage activation, disruption of the glial limitans, and evidence of an oxidative stress response (24).”
BackgroundInfluentialMaheshwari, S., Dwyer, L., & Sîrbulescu, R. F. (2023) · Neurobiology of Disease · doi:10.1016/j.nbd.2023.106077 · Cited by 34
Jing, F., & Choi, E. Y. (2016) · Immune Network · doi:10.4110/in.2016.16.5.271 · Cited by 31
“5: 271-280, October, 2016 274 communication between them in mice with experimental autoimmune encephalomyelitis (EAE), and propagate neuroinflammation through LTab expression (43).”
BackgroundReste, M., Ajazi, K., Sayi‐Yazgan, A., Janković, R., Bufan, B., Brandau, S., Bækkevold, E. S., Petitprez, F., Lindstedt, M., Adema, G. J., et al. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1439413 · Cited by 32
Chamoun, M. N., Blumenthal, A., Sullivan, M. J., Schembri, M. A., & Ulett, G. C. (2018) · Critical Reviews in Microbiology · doi:10.1080/1040841x.2018.1426556 · Cited by 30
“Emerging evidence indicates that IL-17 plays a role in the central nervous system (CNS) to orchestrate tissue remodelling during conditions of neuropathy (Pikor et al. 2015).”
BackgroundKee, R., Naughton, M., McDonnell, G. V., Howell, O. W., & Fitzgerald, D. C. (2022) · Biomedicines · doi:10.3390/biomedicines10102604 · Cited by 34
“Further evidence that LTβR signalling supports the accumulation of B cells within TLS was demonstrated in another EAE study using SJL mice [31].”
Background
Metadata
- Authors
- Pikor, N. B., Astarita, J. L., Summers-Deluca, L., Galicia, G., Qu, J., Ward, L. A., Armstrong, S., Dominguez, C. X., Malhotra, D., Heiden, B., Kay, R., Castanov, V., Touil, H., Boon, L., O’Connor, P., Bar-Or, A., Prat, A., Ramaglia, V., Ludwin, S., Turley, S. J., & Gommerman, J. L.
- Affiliations
- University of Toronto (CA)
- Harvard University (US)
- Genentech (US)
- Montreal Neurological Institute and Hospital (CA)
- University Medical Center Utrecht (NL)
- Centre Hospitalier de l’Université de Montréal (CA)
- Amsterdam UMC Location University of Amsterdam (NL)
- Queen's University (CA)
- Corresponding author
- Gommerman, Jennifer L.
- ORCID
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2015-12
- Volume
- 43
- Issue
- 6
- Pages
- 1160-1173
- ISSN
- 1074-7613 (ISSN-L)
- OpenAlex
- W2212030004
- Cited by
- 229
- References
- 31
- Citations by year
- 2026: 21 · 2025: 22 · 2024: 27 · 2023: 16 · 2022: 23 · 2021: 34 · 2020: 17 · 2019: 22 · 2018: 18 · 2017: 14 · 2016: 14 · 2015: 1
- FWCI
- 12.44
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Multiple Sclerosis Society of Canada
- Multiple Sclerosis Society
- U.S. Public Health Service (P01 AIO45757)
- Canadian Institutes of Health Research (MOG 67157)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK074500)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Multiple Sclerosis Research Studies
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- tertiary lymphoid tissue, meninges, Th17 cells, lymphotoxin beta receptor, stromal cells, neuroinflammation, multiple sclerosis, experimental autoimmune encephalitis, demyelination, extracellular matrix, chemokines, leukocyte homing, IL-17
- MeSH terms
- Adult, Animals, Encephalomyelitis, Autoimmune, Experimental, Female, Flow Cytometry, Humans, Immunohistochemistry, Inflammation, Lymphotoxin-alpha, Male, Meninges, Signal Transduction, CD4-Positive T-Lymphocytes, Polymerase Chain Reaction, Stromal Cells, Mice, Knockout, Multiple Sclerosis, Relapsing-Remitting, Mice, Th17 Cells
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