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. 2026 Feb 18;63(1):451. doi: 10.1007/s12035-025-05566-1

Mapping the Evolution of Experimental Autoimmune Encephalomyelitis Research (2000–2024): A Global Bibliometric and Knowledge Domain Analysis

Zhihua Dong 1,#, Yu He 1,#, Taisong Yin 1, Kun Xu 3, Xueli Liu 2, Hongxia Han 5, Lijuan Song 3,4, Zhibin Ding 1,3,4,✉, Xinyi Li 1,✉, Yanbing Su 6,✉
PMCID: PMC12913296  PMID: 41703101

Abstract

Experimental autoimmune encephalomyelitis (EAE) is a pivotal animal model for multiple sclerosis (MS) research. This study provides a comprehensive bibliometric analysis of 9,435 EAE-related publications from the Web of Science Core Collection (2000–2024) to map the research landscape, identify trends, and highlight emerging frontiers. The analysis reveals a shift from initial rapid growth to a stabilized output, with the USA, Germany, and China as the leading contributors. Immunology and Neurosciences form the core disciplines, with increasing integration of cell biology, microbiology, and pharmacology. Co-citation and keyword analyses demonstrate a clear evolution in research focus: while early studies centered on T-cell biology and classic neuroinflammation, recent investigations emphasize the gut-brain-immune axis, microglial/astrocyte reactivity, immunometabolism, and novel therapeutic strategies like microbiota-targeted interventions and nanomedicine. The Th17/Treg axis remains a central immunoregulatory hub. This analysis delineates the intellectual structure of the field, underscoring its progression from foundational immune mechanisms to complex, system-level understandings of neuroimmune crosstalk, and identifies promising directions for future MS therapeutic development.Experimental autoimmune encephalomyelitis (EAE) is a pivotal animal model for multiple sclerosis (MS) research. This study provides a comprehensive bibliometric analysis of 9,435 EAE-related publications from the Web of Science Core Collection (2000–2024) to map the research landscape, identify trends, and highlight emerging frontiers. The analysis reveals a shift from initial rapid growth to a stabilized output, with the USA, Germany, and China as the leading contributors. Immunology and Neurosciences form the core disciplines, with increasing integration of cell biology, microbiology, and pharmacology. Co-citation and keyword analyses demonstrate a clear evolution in research focus: while early studies centered on T-cell biology and classic neuroinflammation, recent investigations emphasize the gut-brain-immune axis, microglial/astrocyte reactivity, immunometabolism, and novel therapeutic strategies like microbiota-targeted interventions and nanomedicine. The Th17/Treg axis remains a central immunoregulatory hub. This analysis delineates the intellectual structure of the field, underscoring its progression from foundational immune mechanisms to complex, system-level understandings of neuroimmune crosstalk, and identifies promising directions for future MS therapeutic development.

Supplementary Information

The online version contains supplementary material available at 10.1007/s12035-025-05566-1.

Keywords: Experimental Autoimmune Encephalomyelitis, Bibliometrics, Knowledge mapping, Neuroimmunology

Introduction

Experimental autoimmune encephalomyelitis (EAE) has been established as the predominant animal model for studying multiple sclerosis (MS) [1], a chronic inflammatory demyelinating disorder affecting over 2.8 million patients worldwide. Through immunization with central nervous system (CNS) antigens such as myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG), and proteolipid protein (PLP), the EAE model faithfully recapitulates the hallmark pathological features of MS, including T cell-mediated neuroinflammation, blood–brain barrier (BBB) disruption, demyelination, and axonal injury [2, 3]. Given its remarkable reproducibility and pathological resemblance to human MS, the EAE model has become an indispensable platform for investigating neuroimmune interactions and validating therapeutic strategies.

The origins of the EAE model can be traced back to pioneering experiments in primates by Rivers and colleagues in 1933 [4]. During the 1970s-1980s, the establishment of MBP pathogenicity and subsequent standardization of antigenic peptides/animal strains marked the beginning of systematic model development. In recent decades, transgenic technologies have enabled the elucidation of Th1/Th17/Treg paradigms, while the development of spontaneous EAE and relapsing–remitting models has significantly enhanced its capacity to mimic MS clinical heterogeneity. Currently, EAE research has evolved beyond pure autoimmune mechanism exploration into a multidisciplinary frontier encompassing the gut-brain axis, immunometabolism, and epigenetic regulation [5].

The EAE research field has undergone significant transformation through cross-disciplinary integration, accompanied by exponential growth in scientific publications. This remarkable expansion, while demonstrating the field's vitality, has created substantial challenges in synthesizing knowledge across diverse domains. Traditional review methods are increasingly inadequate for tracking the complex dynamics of key mechanisms such as Th17/Treg immunoregulation and microbiota mediated neural modulation. This challenge is further compounded by the accelerating convergence between neuroimmunology, metabolism, and systems biology [6]. Moreover, the widespread adoption of advanced technologies including single cell omics and spatial transcriptomics has introduced new dimensions of complexity to research methodologies.

Bibliometric analysis is an essential methodology for comprehensively mapping complex knowledge structures and objectively identifying emerging research frontiers with therapeutic potential. Widely applied in neuroscience and immunology, it enables rigorous assessment of research trends, identification of key contributors, and forecasting of future directions[7]. Based on data retrieved from the Web of Science Core Collection, this study analyzes 9,435 EAE-related publications from 2000 to 2024. Using CiteSpace and VOSviewer, we visualize collaborative networks, co-citation clusters, and keyword dynamics, thereby constructing a comprehensive overview of global research productivity, interdisciplinary integration, and shifting research priorities within the field. This bibliometric investigation aims to delineate the global landscape of EAE research, identify leading contributors, and highlight emerging topics such as neuro–immune interactions and microbiome-targeted therapies [8, 9]. By identifying knowledge gaps and forecasting future trends, we hope to enhance the translational potential of the EAE model and contribute theoretical insights and strategic directions for the development of effective treatments for MS and other neuroimmunological disorders.

Materials and Methods

Data Source and Search Strategy

The data for this study were retrieved from the Web of Science (WoS) Core Collection, which includes the Science Citation Index Expanded (SCI-E) and Social Sciences Citation Index (SSCI), widely recognized as the most popular database for bibliometric analysis. The literature search was conducted using the following query: (TI = ("Experimental Autoimmune Encephalomyelitis" OR "Experimental Allergic Encephalomyelitis") OR AB = ("Experimental Autoimmune Encephalomyelitis" OR "Experimental Allergic Encephalomyelitis") OR AK = ("Experimental Autoimmune Encephalomyelitis" OR "Experimental Allergic Encephalomyelitis")). The inclusion criteria were: (i) publications between 2000 and 2024, (ii) original research articles and review articles only, and (iii) English language publications. A total of 9,435 published papers were retrieved and exported in the form of all records and references.

Data Standardization

In this study, keywords were standardized. The principles for processing keywords were as follows: (i) synonym terms were manually merged, e.g., “experimental autoimmune encephalomyelitis” and “experimental allergic encephalomyelitis” were merged into “experimental autoimmune encephalomyelitis”, similarly, “T cell” and “t lymphocytes” were merged into “T cell”; (ii) full names were replaced by recognized abbreviations, e.g., “myelin basic protein” was shortened for “MBP”, “oligodendrocyte progenitor cell” was shortened for “OPC”; (iii) plural forms were unified into a singular form, e.g., “neural stem cells” was united in “neural stem cell”.

Data Analysis

All bibliographic records were exported and analyzed with CiteSpace 6.4.R1 and VOSviewer 1.6.19. Co-citation network analysis and citation burst detection were conducted on journal dual-map overlays, reference citations, and author keywords utilizing CiteSpace. The time span was sliced into one-year intervals (January 2000–December 2024). Parameters were configured as follows: g-index (k = 5), link retaining factor (LRF) = 2.5, maximum links per node (L/N) = 10, look-back years (LBY) = 5, and e = 1.0; all remaining parameters were kept at default values. Clustering was carried out with the log-likelihood ratio (LLR) algorithm based on title, abstract, and keyword terms, generating conceptually homogeneous clusters that were labelled with noun phrases and colour-coded according to the average year of cluster citations. We performed a co-occurrence network analysis of countries, authors, and keywords using VOSviewer. Each node represents a country, author, or keyword, with connecting lines indicating co-occurrence relationships. Node size reflects relative importance, while clusters group thematically related nodes, visually distinguished by color and shape.

Results

Current Status and Research Trends

Figure 1 illustrates the annual trends in publication output, average citations per paper, and total annual citations in the field of EAE from 2000 to 2024. The number of publications steadily increased from 261 in 2000 to a peak of 516 in 2013. Following an initial decline after 2013, the annual output recovered to 499 by 2021 before dropping to 352 in 2024. Although a downward trend was observed from 2022 to 2024, annual output remained above 350, indicating that EAE continues to attract substantial research interest. Total citations rose sharply between 2000 and 2011, reaching a peak of 34,501 in 2011, and subsequently declined. The average number of citations per paper showed an initial increase from 80.36 in 2000 to 108.38 in 2002, followed by a sustained decline to 2.23 in 2024.

Fig. 1.

Fig. 1

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Annual publication trend in the field of EAE from 2000 to 2024

Geographical Distribution and International Collaboration

A total of 83 countries contributed to EAE research from 2000 to 2024. The top five most productive countries were the USA, Germany, China, the UK and Japan (Fig. 2A). The USA consistently led in publication output. Notably, China entered the field later than other major contributors but demonstrated rapid growth, increasing from only 3 annual publications in 2005 to surpassing Germany's output in 2016, and further rising to 90 publications in 2024. Germany's output peaked in 2015 before gradually declining, while Japan and the UK maintained relatively stable but modest publication levels.

Fig. 2.

Fig. 2

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A Annual publication output of the top 5 most productive countries in the field of EAE from 2000 to 2024. B Collaboration networks of the countries with at least 10 publications. C Global collaboration map of countries in the field of EAE from 2000 to 2024

The collaboration network (Fig. 2B) included 43 countries with at least 10 publications. The USA served as the central hub with strong collaborations with Germany, the UK and China, and maintained the highest number of partners (n = 42), followed closely by Germany (n = 41) and the UK (n = 36). However, most countries lacked stable and extensive collaborative ties. A geographical mapping of collaborating countries (Fig. 2C) showed broad global participation, including 23 countries from Europe, 11 from Asia, 3 each from North and South America, 2 from Oceania, and 1 from Africa.

Authors’ Collaboration Networks

Authors’ collaboration patterns were visualized using VOSviewer (Fig. 3A). A total of 130 authors with at least 20 publications each were included. The author collaboration network revealed distinct research clusters with varying connection strengths. Cluster analysis identified a tightly interconnected group comprising Rostami A, Zhang GX, Xiao BG, and Ma CG, suggesting sustained collaborative relationships. Notably, the strongest dyadic collaboration was observed between Offner H and Vandenbark AA (76 co-authored publications), followed closely by Rostami A and Zhang GX (68 joint publications). These quantitative findings demonstrate both the formation of research teams and particularly intensive bilateral partnerships within the EAE research community. Among the most prolific authors, Zhang GX and Rostami A each published 95 articles, followed by Offner H (92) and Gold R (91) (Fig. 3B). In terms of citation impact, Kuchroo VK ranked highest with 12,992 citations, followed by Sobel RA (12,925) and Weiner HL (9,740) (Fig. 3C).

Fig. 3.

Fig. 3

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A Authors’collaborative networks. B The top 10 most prolific authors and their publication counts. C The top 10 most cited authors and their total citations

Institutional Contributions

Globally, 2,511 institutions were involved in EAE research. Table 1 lists the top 20 most influential institutions. Of these, 13 were based in the USA, with others from Germany (3), France (1), the UK (1), Sweden (1), and China (1). The University of California system was the most productive (429 publications), while Harvard University and its affiliates dominated in total citations and H-index scores. Notably, Harvard Medical School, Harvard University, and its affiliated medical centers occupied the top fiver positions in both average citations per paper and H-index, underscoring their leading role in driving high-impact research in the field.

Table 1.

Top 20 most productive institutes in the field of EAE from 2000 to 2024

Rank Institution TP TC ACPP H
1 University of California system 429 36866 85.93 100
2 Harvard University 354 44012 124.33 110
3 Harvard University Medical Affiliates 316 40707 128.82 106
4 US Department of Veterans Affairs 316 16108 50.97 66
5 Veterans Health Administration 314 15885 50.59 65
6 Harvard Medical School 298 38986 130.83 106
7 Institut national de la sante et de la recherche medicale 222 10429 46.98 53
8 Brigham & women's hospital 222 33071 148.97 94
9 University system of ohio 221 11788 53.34 59
10 National institutes of health 196 19899 101.53 65
11 Stanford University 189 23661 125.19 72
12 University of Texas System 182 17597 96.69 60
13 University of London 180 14940 83 61
14 University of Gottingen 179 13679 76.42 59
15 Karolinska institutet 172 7464 43.4 45
16 Thomas Jefferson University 163 7883 48.36 51
17 University of California San Francisco 158 17162 108.62 66
18 Chinese academy of sciences 156 6717 43.06 44
19 Helmholtz Association 154 13481 87.54 53
20 Max Planck Society 146 15681 107.4 63
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TP total publications, TC total citations, ACPP average citation per publication

Journal Distribution and Impact

Over the past 25 years, 1,002 journals have published EAE-related articles. Figure 4A shows cumulative publication trends in the top 10 journals. The Journal of Immunology and Journal of Neuroimmunology demonstrated steady growth from 2000 to 2015. In contrast, Frontiers in Immunology exhibited a sharp increase in output from 2015 to 2022.

Fig. 4.

Fig. 4

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A Temporal trends in cumulative publication volume of the top 10 journals (2000–2024). B The 10 most prolific journals in terms of publication output. C The 10 most highly cited journals. D The dual-map overlay of journals

According to Fig. 4B, the Journal of Immunology was the most prolific journal (782 publications), followed by the Journal of Neuroimmunology (647) and Frontiers in Immunology (270). In terms of total citations (Fig. 4C), Journal of Immunology again ranked first (55,876 citations), followed by Proceedings of the National Academy of Sciences of the United States of America (PNAS; 27,218) and Journal of Experimental Medicine (22,980). When considering average citations per paper, Journal of Experimental Medicine topped the list (180.94), followed by PNAS and Journal of Immunology (Table 2). A dual-map overlay (Fig. 4D) visualized disciplinary citation flows, revealing that journals in molecular biology and genetics were frequently cited by research in health, medicine, and immunology, indicating strong interdisciplinary exchange. Moreover, articles from the disciplines of Health, Nursing, and Medicine are often cited by studies in Molecular Biology and Immunology.

Table 2.

Top 10 prolific journals in the field of EAE

Rank Journal TP TC ACPP H
1 Journal of Immunology 782 55876 71.45 119
2 Journal of Neuroimmunology 647 21063 32.55 71
3 Frontiers in Immunology 270 6595 24.43 42
4 Journal of Neuroinflammation 267 8376 31.37 49
5 Proceedings of the National Academy of Sciences of the United States of America 258 27218 105.5 90
6 PLOS ONE 228 9271 40.66 51
7 European Journal of Immunology 141 7642 54.2 49
8 Scientific Reports 129 2972 23.04 33
9 Journal of Experimental Medicine 127 22980 180.94 81
10 International Journal of Molecular Sciences 123 1874 15.24 24
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TP total publications, TC total citations, ACPP average citation per publication

Interdisciplinary Integration

As illustrated in Fig. 5A, Immunology is positioned as the pivotal node within the interdisciplinary network, followed closely by Neurosciences as the secondary hub, both demonstrating a high degree of interdisciplinary integration. These two domains exhibit dense interconnections with Cell Biology, Biochemistry & Molecular Biology, Pharmacology & Pharmacy, and Clinical Neurology. Figure 5B presents a temporal heatmap delineating annual disciplinary outputs. Immunology (3,737 publications) and Neurosciences (3,166 publications) emerge as the most prolific disciplines. Biochemistry & Molecular Biology demonstrated a monotonic increase, reaching 59 articles in 2024. During 2010 to 2024, Multidisciplinary Sciences came into the spotlight, consistently surpassing 30 publications annually. Since 2013, Cell Biology and Pharmacology & Pharmacy have sustained annual contributions exceeding 30 articles.

Fig. 5.

Fig. 5

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A The interdisciplinary network map. B The heatmap of the academic field trends

Analysis of Highly Cited Articles

Table 3 shows the top 10 most cited articles on EAE. These ten highly influential publications, each with over 1,000 citations, appeared in journals including Nature Immunology, Nature Medicine, Nature, Immunity, and The Journal of Immunology. The most cited article (3,407 citations) was "A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17" by Park, H. (2005). The most recent highly cited paper (2,009 citations) was "A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases" (Nature Medicine, 2015).

Table 3.

Top 10 articles with the highest citations in the field of EAE

Rank Year First Author Title Journal Citations
1 2005 Park, H A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17 Nature Immunology 3407
2 2015 Coll, RC A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases Nature Medicine 2009
3 2008 Quintana, FJ Control of T(reg) and T(H)17 cell differentiation by the aryl hydrocarbon receptor Nature 1434
4 2002 Lock, C Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis Nature Medicine 1368
5 2002 Monney, L Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease Nature 1325
6 2008 Veldhoen, M The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins Nature 1309
7 2002 Fillatreau, S B cells regulate autoimmunity by provision of IL-10 Nature Immunology 1296
8 2009 Sutton, CE Interleukin-1 and IL-23 induce innate IL-17 production from gammadelta T cells, amplifying Th17 responses and autoimmunity Immunity 1289
9 2008 Yang, XXO T helper 17 lineage differentiation is programmed by orphan nuclear receptors ROR alpha and ROR gamma Immunity 1285
10 2006 Komiyama, Y IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis Journal of Immunology 1252
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Co-Citation Clustering Analysis of References

To systematically explore the intellectual structure and emerging research hotspots in the field of EAE, we conducted co-citation clustering analysis of references using CiteSpace. The visualized network (Fig. 6) identified 21 major clusters, each labeled with a unique ID, reflecting distinct thematic areas that together compose the knowledge landscape of EAE research from 2000 to 2024.

Fig. 6.

Fig. 6

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A Keyword co-occurrence network. Node size indicates keyword frequency, and node color denotes the year of first appearance, transitioning from blue (2000) to red (2024). B Keyword clustering map. Cluster labels (e.g., #0 “t helper”, #1 “reactive astrocyte”, #3 “gut microbiome”, etc.) were automatically generated by the LLR algorithm, with each cluster representing a distinct research theme. Edges denote co-occurrence relationships; denser clusters signify stronger semantic associations

The most prominent cluster #0 “t helper” primarily focuses on the immunopathogenic role of Th17 cells especially those activated by IL-23 as demonstrated by Langrish et al. (2005). This cluster forms the theoretical backbone of immune-related research in EAE. Cluster #1 “reactive astrocyte” focuses on astrocytic reactivity, especially the neurotoxic A1 subtype, and their roles in mediating neuroinflammation. This area has gained increasing attention in recent years, as exemplified by Baecher-Allan et al. (2018), highlighting the significance of glial regulation in CNS pathology. Cluster #3 “gut microbiome” represents a rapidly emerging theme exploring the gut-brain axis. Research such as Jangi et al. (2016) emphasizes how gut microbiota influence immune homeostasis and EAE susceptibility, suggesting novel directions for disease modulation via microbial pathways. Other notable clusters include: #2 “myelin oligodendrocyte glycoprotein (MOG)” – focused on MOG as a key autoantigen in immune tolerance and demyelination modeling. Cluster #4 “optic neuritis” is associated with early-stage visual dysfunction and serves as a clinical and experimental indicator of CNS inflammation.

From a temporal perspective, clusters located on the left side of the map, such as #2, #5, and #17, are shaded in cooler tones, indicating foundational research published before 2010. In contrast, clusters on the right, such as #1, #3, and #4, are marked in warmer colors and represent emerging topics since 2018. Additionally, clusters like #6 “microglial activity”, #10 “central nervous system barrier”, and #11 “relapsing–remitting multiple sclerosis” underscore the deepening focus on the interplay between immune and neurodegenerative mechanisms. In summary, the co-citation clustering analysis reveals a clear evolution from classical immune-centric studies toward an integrated neuroimmune and microbiome-oriented paradigm, suggesting that future research will increasingly emphasize T cell regulation, glial cell functions, gut-brain interactions, and CNS barrier dynamics. Supplementary Table S1 introduces the main content of each cluster and its representative references.

Keyword Co-Occurrence and Burst Analysis

The keyword co-occurrence analysis revealed strong thematic associations, with distinct clusters emerging to delineate major research priorities in the field. Our temporal analysis divided the 25-year research period (2000–2024) into four phases, with corresponding network visualizations presented in Fig. 7. The initial phase (2000–2006) identified 5 key clusters: #1 Neuroinflammation Mechanisms (IFN-γ, TNF-α and microglia activation), #2 Autoimmune Regulation (T cell tolerance and MHC restriction), #3 Immunotherapeutic Targets (glatiramer acetate and cytokine modulation), #4 Oxidative Stress Damage (ROS and BBB disruption), and #5 Neural Repair and Protection (remyelination and stem cell therapy). Subsequent analysis of 2007–2012 demonstrated evolving priorities with clusters including #1 Neural Repair and Regeneration (axon regeneration and OPC differentiation), #2 Immunomodulatory Therapy (fingolimod and Treg induction), #3 Neuroinflammatory Microenvironment (chemokine networks and glial crosstalk), and #4 Cellular Immune Regulation (Th17/Th1 balance and IL-17 signaling).

Fig. 7.

Fig. 7

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The co-occurrence network of keywords in four periods. 2000–2006, 2007–2012, 2013–2018, 2019–2024

The 2013–2018 period showed continued progression with #1 Neuroprotection and Regeneration (BDNF and neurotrophic factors), #2 Immunomodulatory Mechanisms (JAK-STAT pathways and immune checkpoint regulation), #3 Autoimmune Regulation (antigen presentation and molecular mimicry), and #4 Neuroinflammatory Microenvironment (microglial polarization and inflammasome activation). Most recently (2019–2024), the field has expanded into 6 clusters: #1 Neuroinflammation and Neurodegeneration (protein aggregates and synaptic loss), #2 Immunomodulation and Cell Therapy (CAR-T and nanomedicine), #3 Myelin Repair and Neuroprotection (Nogo-A inhibition and oligodendrogenesis), #4 Immunometabolism and Neuroimmunology (kynurenine pathway and bioenergetics), #5 Oxidative Stress and Inflammasome (NLRP3 and mitochondrial dysfunction), and #6 Gut-Brain Axis and Microbiome (SCFAs and microbial metabolites). Throughout this quarter-century span, consistent research themes have included neuroimmune interactions (#2 in all periods) and neural repair mechanisms (#1 or #3 in all periods), while emerging domains such as gut-brain axis research (#6) and immunometabolism (#4) have gained prominence since 2019. Notably, Cluster 5 (oxidative stress pathways) and Cluster 6 (microbiome interactions) represent novel research frontiers that have emerged in the most recent period. The most frequently used keywords for the four evaluated periods are shown in Table S2.

Figure 8 presents the top 25 keywords with the strongest citation bursts, which further illuminate shifting thematic emphases over time. During 2000–2009, high-burst terms included “nitric oxide” (strength = 17.21), “myelin basic protein” (16.08), and “oligodendrocyte glycoprotein” (11.15), underscoring early mechanistic studies on inflammation and demyelination. More recent bursts, such as “gut microbiota” (11.92), reflect the rise of microbiome research in EAE pathogenesis and interventions such as fecal microbiota transplantation. Emerging terms from 2021–2024, including “NLRP3 inflammasome” (6.17) and “catalytic antibody” (3.91), point to a growing interest in innate immunity, novel inflammatory pathways, and targeted therapeutic mechanisms. Collectively, the keyword analysis delineates the shifting intellectual priorities in EAE research, mapping a trajectory from immunological foundations to complex systemic interactions and intervention-oriented studies.

Fig. 8.

Fig. 8

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The 25 most prominent keywords by citation-burst strength, highlighting the hotspots in specific research domains; red lines, duration of bursts

Discussion

General Trends and Global Research Landscape

The temporal analysis of EAE-related publications (2000–2024) delineates three distinct evolutionary phases. The first phase (2000–2013) exhibited exponential growth, with annual publications surging from 260 to 520, marking the consolidation of EAE as the preeminent preclinical model for multiple sclerosis research. The subsequent phase (2013–present) demonstrated stabilization, maintaining an annual output exceeding 350 publications, indicative of a transition from rapid expansion to methodological refinement. Concurrently, the mean citation rate per article experienced a significant decline from 80.36 to 2.23, a phenomenon attributable to both the expansion-induced dilution effect within the literature and the paradigmatic shift from foundational, high-impact discoveries to specialized technical investigations. This pattern reflects the maturation of EAE research into an established scientific domain characterized by incremental advancements.

Geospatial analysis reveals a pronounced concentration of EAE research productivity within five core nations: the USA, Germany, China, the United Kingdom, and Japan. The USA maintains research hegemony, demonstrating both quantitative dominance and centrality in global collaborative networks. China's delayed but accelerated post-2010 engagement has established a strategic triad of research cooperation with the USA and Germany. European nations, particularly Germany, the UK, France, and Sweden, display intensive intracontinental collaboration patterns, while research engagement across Africa, non-Chinese Asia, and Latin America remains fragmented, characterized by sparse bilateral partnerships. This asymmetric global distribution highlights persistent disparities in research capacity and underscores the imperative for systemic initiatives to promote transnational knowledge exchange and infrastructure development.

Institutional productivity analysis reveals a predominance of USA research entities, comprising 13 of the top 20 institutions by publication output. Harvard-affiliated institutions maintain preeminence, evidenced by superior cumulative citation counts and H-index metrics, underscoring their sustained contributions to EAE model innovation. The Chinese Academy of Sciences emerges as China's sole representative among leading institutions, demonstrating significant impact in model standardization, mechanistic investigations, and global scientific collaboration. Journal influence metrics identify the Journal of Immunology and Journal of Neuroimmunology as primary knowledge dissemination platforms, effectively bridging immunological and neurological research domains. The collaboration network reveals established research teams and productive partnerships, with key investigators like Offner/Vandenbark and Rostami/Zhang demonstrating particularly strong bilateral collaborations. The interdisciplinary analysis confirms immunology and neuroscience as core domains, while growing integration with cell biology and pharmacotherapy reflects the field's increasing complexity. These analyses collectively demonstrate the maturation of EAE research into an established scientific discipline, characterized by stabilized productivity, increasing methodological specialization, and growing international collaboration. While Western nations continue to dominate research output, emerging contributions from China and evolving interdisciplinary integration point to new directions for advancing neuroimmunological research.

EAE Modeling Evolution and Advances in Immunopathological Mechanisms

Antigen Specificity and Pathological Subtype Characteristics of Classical Induced EAE Models

Temporal keyword-burst analysis (Fig. 8) corroborates the foundational role of these antigens. During 2000–2009, "myelin basic protein" (burst strength = 16.08) and "oligodendrocyte glycoprotein" (11.15) emerged as the dominant high-burst terms, reflecting the field's early focus on dissecting the mechanisms of inflammation- and demyelination-driven pathology. MBP, MOG, and PLP serve as fundamental antigens that constitute a characteristic "antigen-model cluster" in EAE research, with each demonstrating distinct capacities for modeling MS pathological subtypes. MBP, comprising 30%−40% of CNS myelin proteins [10], represents the prototypical EAE-inducing antigen, producing acute monophasic disease that effectively models MS acute inflammation [11]. PLP, a major CNS transmembrane protein [12], uniquely induces relapsing–remitting EAE in SJL mice, faithfully recapitulating the hallmark recurrent demyelination of RRMS [13]. Despite its minimal abundance (0.01%−0.05% of myelin proteins) [14], MOG's surface localization enables robust chronic EAE induction across multiple strains via epitopes like MOG35-55, establishing its utility for studying progressive MS mechanisms. This antigen-specific modeling paradigm provides a systematic framework for investigating MS heterogeneity [15].

Genetic and Environmental Interaction Mechanisms in Spontaneous EAE Models

Spontaneous EAE models represent a distinct experimental paradigm wherein animals develop neuroinflammatory and demyelinating pathology autonomously through genetic manipulation or immune dysregulation, independent of exogenous antigen administration. These models are broadly categorized into three mechanistic subtypes: (1) TCR transgenic models, where MBP-specific TCR mice (e.g., Ac1-11/Ac1-9) demonstrate 100% penetrance in RAG-deficient backgrounds, establishing Treg deficiency as a critical disease determinant[16]; (2) B-T cell collaborative models, exemplified by 2D2 × Th transgenic mice showing 60% incidence with CNS tertiary lymphoid formation [17]; and (3) environmentally-triggered models, where microbial antigens (TLR4/9 ligands) overcome genetic resistance in PLP139-151 TCR mice [18]. Notably, disease phenotypes exhibit striking context-dependence, as evidenced by 2D2 mice's 4% spontaneous EAE incidence versus 30% optic neuritis prevalence [19], highlighting the influence of local antigen availability. While these models address key limitations of traditional immunization approaches by better recapitulating MS immunopathogenesis, their translational utility requires careful consideration of genetic background and microbiome interactions that substantially modulate disease penetrance.

Core Cellular Subpopulations and Molecular Pathways in EAE Immunopathological Mechanisms

As the quintessential animal model of MS, EAE has been dissected by a canon of highly cited studies (Table 3: Top 10 articles with the highest citations in EAE research), each explicitly delineating the indispensable roles of T and B cells in driving and restraining neuroinflammation. These landmark investigations converge on a unifying principle: EAE pathogenesis is orchestrated by a dynamic immune network in which T and B lymphocytes serve as both dominant effectors and critical regulators.

Pathogenicity and Regulatory Balance of T Cell Subpopulations

CD4 + T cells constitute the principal pathogenic mediators in EAE, with their differentiated effector subsets (Th1, Th17, and GM-CSF-producing T cells) orchestrating neuroinflammation through signature cytokine secretion (IFN-γ, IL-17, and GM-CSF) that activates myeloid cells and compromises vascular integrity [20, 21]. CD8 + T cells demonstrate functional pleiotropy, exhibiting both cytotoxic oligodendrocyte damage (as evidenced by their autonomous pathogenicity in adoptive transfer studies) [22, 23] and immunoregulatory capacity via CD8 + Treg-mediated suppression of inflammatory cascades [24]. This dual functionality appears contingent upon CD4 + T cell-derived co-stimulation and local microenvironmental cues, with the EAE-resistant phenotype observed in CD8 + T cell-deficient models further substantiating their immunomodulatory potential.

Bidirectional Immunoregulatory Functions of B Cells

B cells demonstrate striking functional plasticity in EAE pathogenesis, exhibiting dichotomous roles contingent upon antigenic context. As pathogenic effectors, MOG-specific B cells enhance T cell activation through antigen presentation, elevating spontaneous EAE incidence to 60% in 2D2 × Th double transgenic models [17, 25]. Conversely, regulatory B cell (Breg) subsets mediate immunosuppression via IL-10/IL-35 secretion and PD-L1/GITRL surface expression [26]. This functional dichotomy exhibits marked antigen-dependence: B cell depletion abolishes MOG protein-induced EAE yet remains ineffective in MOG35-55 peptide models, underscoring the critical role of antigen integrity in B cell functionality. Mechanistically, B cell-derived IL-6 exacerbates disease progression, while Itga4 expression is indispensable for Breg-mediated immunoregulation [27]. These findings collectively position B cells as pivotal immunomodulatory switches in EAE, offering a molecular framework for targeted B cell therapies in neuroinflammatory disorders.

Comprehensive Therapeutic Approaches for EAE

Treg/Th17 Imbalance: A Therapeutic Target for Immune Homeostasis

Consistent with its designation as a seminal immunological insight, the article by Quintana et al. ranked among the ten most-cited EAE studies (Table 3) demonstrates that the aryl hydrocarbon receptor (AHR) orchestrates the reciprocal differentiation of Treg and Th17 cells in a ligand-specific manner, thereby establishing AHR as a discrete molecular switch for therapeutic immunomodulation. This finding not only underscores the pathogenic significance of Treg/Th17 imbalance in EAE but also positions the Th17/Treg axis as the central immunoregulatory hub of the disease. Th17 differentiation, mediated through the IL-6/STAT3/RORγt signaling cascade, drives neuroinflammation via IL-17-mediated BBB disruption and neutrophil recruitment. In contrast, Treg-mediated immunosuppression, achieved through IL-10 and TGF-β secretion, counterbalances effector T cell activity. This reciprocal regulation constitutes a fundamental immunopathological mechanism in both EAE and MS, wherein the Th17/Treg equilibrium dictates disease progression versus resolution. The precise modulation of this dynamic balance represents a promising therapeutic strategy for restoring immune homeostasis in neuroinflammatory disorders.

Multiple therapeutic interventions targeting the Th17/Treg axis have shown promising efficacy in EAE models. Pharmacological approaches include: (1) Rapamycin-fingolimod combination therapy, which restored immune balance by modulating splenic IL-17/TGF-β levels and RORγt/Foxp3 expression [28]; (2) Ginsenoside Rd, exhibiting dual immunomodulatory and microbiota-remodeling effects through cytokine profile alteration (IL-6/IL-17↓, TGF-β/IL-10↑) [29]; and (3) Pitavastatin-mediated Th17/Treg regulation [30]. Molecular interventions revealed microRNA-92a as a pathogenic regulator of T cell imbalance [31], while peroxynitrite was identified as exacerbating autoimmunity via IL-2R nitration and Treg suppression through RAS/JNK-AP-1 signaling [32]. These findings collectively validate the Th17/Treg axis as a critical therapeutic target and establish multiple mechanistic strategies, including pharmacological modulation and molecular interference, for restoring immune homeostasis in neuroinflammatory diseases.

Gut–Brain–Immune Axis: A Paradigm Shift in Microbiota Modulation for EAE/MS

Keyword co-occurrence mapping (Fig. 7) and reference co-citation clustering both underscore the recent ascendance of gut-centered research: during 2019–2024, the #6 cluster “Gut-Brain Axis and Microbiome” exhibits the strongest momentum among emerging themes, while Cluster #3 “gut microbiome” is prominently represented in the latest co-citation network, confirming this domain as a bona fide frontier. These convergent bibliometric signals dovetail with mechanistic evidence positioning the gut microbiota as a pivotal regulator of EAE pathogenesis through three principal axes: (1) SCFA-mediated immunomodulation, (2) tryptophan metabolic reprogramming, and (3) bile acid signaling through FXR/TGR5 receptors. These pathways collectively orchestrate neuroimmune homeostasis by fine-tuning Th17/Treg equilibrium, preserving BBB function, and influencing therapeutic responsiveness. These fundamental discoveries have propelled the development of precision microbiome interventions, including FMT protocols, genetically engineered probiotics, targeted prebiotic formulations, and synthetic microbial consortia, representing a paradigm shift in neuroinflammatory disease management.

Pathological dysbiosis demonstrates profound functional consequences in EAE pathogenesis: constipation-induced microbial imbalance in C57BL/6 mice significantly altered Treg/Th17 and Treg17/Teff17 ratios, disrupted cytokine networks, and aggravated disease severity [33]. Therapeutic interventions targeting the gut microbiota, including FMT, effectively restored microbial homeostasis while reducing systemic IL-17 and cortisol levels through HPA axis modulation [34]. Pharmacological approaches combining THC and CBD similarly attenuated EAE progression by preventing dysbiosis and promoting beneficial microbial communities [35]. Notably, microbiota-targeted therapies conferred comprehensive neuroprotection by mitigating glial activation, preserving BBB integrity, and maintaining myelin and axonal structure [36]. These findings collectively validate the gut-brain-immune axis as a promising therapeutic target, highlighting the need for future research to develop clinically translatable interventions, optimize treatment protocols, and establish personalized microbial biomarkers for precision medicine applications in MS.

Emerging Therapeutic Frontiers in EAE

Building upon the therapeutic insights targeting the Th17/Treg axis (Section 3.1) and gut-brain-immune axis modulation (Section 3.2), recent studies have unveiled a spectrum of innovative approaches for EAE/MS treatment through diverse molecular mechanisms. These advancements collectively highlight the expanding therapeutic landscape beyond conventional immunomodulation, offering new hope for precision medicine in MS. Research indicates that Mid1 regulates effector T cell migration to the CNS via the mTOR/microtubule pathway in EAE, positioning it as a potential therapeutic target for MS treatment [37]. Complementing this, AAV1.NT3 gene therapy demonstrates dual benefits—promoting remyelination and axonal protection while enhancing anti-inflammatory responses through IL-10/TGF-β upregulation and Treg expansion [38]. At the cellular level, betulin emerges as a neuroprotective agent by modulating microglial polarization via the AXL/SOCS3-JAK2/STAT1 signaling axis [39]. Furthermore, choroid plexus-targeted strategies have shown promise in preserving blood-CNS barrier integrity through SPAK kinase inhibition via the AP-1-MMP2/9-ZO-1 pathway or SPAK-NKCC1 antagonists [40].

The therapeutic landscape for EAE/MS continues to expand with several innovative modalities currently under investigation. These include: (1) engineered nanoparticle platforms for CNS-targeted drug delivery, (2) CRISPR-based gene editing of disease-associated loci, and (3) metabolic modulators targeting immunometabolic checkpoints. These cutting-edge approaches highlight the critical need for: (i) systematic identification of novel biological targets, (ii) rigorous preclinical evaluation through multimodal validation, and (iii) development of optimized combinatorial therapeutic regimens. Such multidimensional research efforts are imperative to fully elucidate the complex pathogenesis of EAE/MS and facilitate the translation of these mechanistic insights into clinically viable therapeutic strategies.

Advantages and Limitations

The present study has several notable advantages. By analyzing 9,435 English-language articles and reviews from the Web of Science Core Collection (2000–2024), we established a large, high-quality dataset that accurately represents the global landscape of EAE research. Moreover, the combined use of VOSviewer and CiteSpace facilitated comprehensive visualization of co-authorship, co-citation, and keyword networks, enabling systematic identification of influential countries, institutions, journals, and thematic clusters. Additionally, temporal analyses—including citation bursts and keyword evolution—offered valuable insights into the dynamic shift in research priorities from classic immunopathology to neuroimmune–microbiome interactions.

However, several limitations must be considered. First, the exclusive reliance on Web of Science may have excluded relevant studies indexed in PubMed, Embase, or regional databases. Second, the restriction to English-language publications could have overlooked contributions from non-English-speaking regions. Third, the citation lag effect might have resulted in undervaluation of recently published studies with immature citation records. Finally, despite standardizing author keywords and conducting manual validation, the keyword-based thematic inference approach may not fully capture nuanced conceptual developments present in full-text content.

Conclusion

This bibliometric investigation delineates the conceptual trajectory of EAE research across a quarter-century, revealing a paradigm shift from T cell-dominated models to contemporary neuroimmune-microbiome frameworks. Geospatial mapping identifies the United States, Germany, and China as primary knowledge producers, with Harvard University and the University of California system demonstrating exceptional research influence. Periodical analysis establishes the Journal of Immunology and Journal of Neuroimmunology as core dissemination channels while documenting increasing cross-disciplinary integration spanning immunology, neurobiology, microbial ecology, and clinical translation. Current analytical foci—particularly reactive astrogliosis, gut-brain axis regulation, microglial dynamics, and neurovascular unit integrity—forecast the growing importance of multi-omics methodologies in elucidating MS pathobiology. These empirically derived insights offer strategic direction for target selection, international cooperation, and the development of mechanism-based therapeutics for neuroautoimmune disorders.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 38 KB) (38KB, docx)

Acknowledgements

HH and LS: conceptualization and supervision. ZHD, TY, XL, YH and KX: data management, data analysis, methodology, software application, and writing (initial manuscript). ZD, XL and YS: writing (review and editing).

Author Contributions

HXH and LJS: conceptualization and supervision. ZHD, TSY, XLL, YH and KX: data management, data analysis, methodology, software application, and writing (initial manuscript). ZBD, XYL and YBS: writing (review and editing).

Funding

This work was supported by the National Natural Science Foundation of China (No. 82301579), Shanxi Medical University Third Hospital Talent Introduction Research Fund Project (No. 2021RC033), Special Project for Science and Technology Cooperation and Exchange in Shanxi Province (No. 202304041101004), Shanxi University of Chinese Medicine Science and Technology Innovation Capability Cultivation Plan National Natural Science Foundation Cultivation Special Project (No. 2024PY-NS-012).

Data Availability

No datasets were generated or analysed during the current study.

Declarations

Disclosures

The authors report no conflicts of interest in this work.

Competing interests

The authors declare no competing interests.

Footnotes

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Zhihua Dong and Yu He contributed equally.

Contributor Information

Zhibin Ding, Email: zhibinding2013@163.com.

Xinyi Li, Email: xinyili2003@aliyun.com.

Yanbing Su, Email: suyanbing@sxbqeh.com.cn.

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Supplementary Materials

Supplementary file1 (DOCX 38 KB) (38KB, docx)

Data Availability Statement

No datasets were generated or analysed during the current study.

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