Annual documents on Treg cells in neurological diseases showed an overall upward trend, suggesting that this research field remains an active hotspot. Among 85 countries/regions publishing documents on this topic, the United States was the largest contributor, with double the number of documents and citations compared to China and far ahead of other countries/regions. Additionally, among the top 10 most productive organizations, seven were based in the United States, and among the top 15 most prolific authors, six were also from the United States, underscoring its substantial contributions to this research field. However, China has emerged as a potential contributor in this field, with its annual output overtaking other countries/regions and ranking first in 2022. Harvard Medical School was identified as the most important organization and a major driver of research on the role of Treg cells in neurological diseases. Nearly 25% of relevant research results were published in the top 11 journals, demonstrating their high quality and authoritative role as communication platforms for research related to Treg cells in neurological diseases. Notably, Frontier in Immunology was the most popular journal, playing an active role in promoting the development of Treg cells in neurological diseases.
Gendelman HE, currently affiliated with University of Nebraska Medical Center, has published the most documents on Treg cells in neurological diseases. These documents primarily focused on neuroimmunity, neuromodulatory, immunomodulation and neuroprotection. Among these documents, the document “Regulatory T cells attenuate Th17 cell-mediated nigrostriatal dopaminergic neurodegeneration in a model of Parkinson’s disease” has achieved the most citations. This study highlighted the potential of Treg cells in regulating neurodestructive immunity and laid the foundation for immunization strategies of PD [29]. However, Gendelman HE has collaborated less frequently with researchers from other organizations, possibly limiting academic exchanges between organizations and countries/regions and thereby impeding the development of research in this field. Therefore, we strongly recommend that researchers from different organizations and countries/regions engage in broader collaboration and communication to jointly advance the development of Treg cells in neurological diseases. Such collaborations can lead to more comprehensive research and better knowledge sharing.
Keywords are powerful tools for understanding the theme and research focus of scientific documents, and they can help identify hotspots and trends of Treg cells in neurological diseases. The most cited documents often signify important research directions and breakthroughs in the field. Co-cited references reflect the historical development and roots of the field, while references with citation bursts reveal the emerging hotspots within it. By combining keyword and citation analyses, we have identified the following aspects as current research hotspots and trends of Treg cells in neurological diseases:
Given their beneficial and protective properties, Treg cells are considered excellent candidates for immunomodulation. Treg cell-based therapeutic strategies have been actively developing in transplantation and autoimmune diseases [36]. The absence of Treg cells in the lymphoid aggregates of MS patients’ brain indicates that the reduction of Treg cells may play a role in the progression of the disease [37]. Thus, therapies based on Treg cells have the potential to ameliorate MS. A phase I clinical trial evaluating the adoptive transfer of Treg cells into patients with relapsing-remitting MS found it to be safe and well-tolerated, without adverse events [38]. Nonetheless, additional research is necessary to assess the efficacy and safety of Treg cell-based therapeutic strategies for patients with MS, given the limited knowledge about how Treg cells influence immune homeostasis and inflammation resolution. PD is a neurodegenerative disorder characterized by neuroinflammation that may be caused by an imbalance between Treg cells and Th17 cells. Treg cells have been shown to attenuate Th17 cell-mediated death of nigrostriatal dopaminergic neurons [39]. An in vitro study revealed that human adipose tissue-derived mesenchymal stem cells could inhibit the differentiation of CD4+ T cells isolated from patients with PD into Th17 cells. This inhibitory effect was mainly mediated by an increase in Treg cells and secretion of IL-10, indicating that Treg cells play an anti-inflammatory and neuroprotection role in PD [40]. Immunomodulation through Treg cell expansion was found to be an effective treatment for PD mice in a recent study, providing evidence that immunotherapy may offer a disease-modifying option for patients with PD [9]. Although the precise mechanism by which Treg cells facilitate post-stroke recovery remains unclear, studies have indicated that Treg cell-derived osteopontin contributes to a tissue-reparative microglial response, resulting in improved oligodendrocyte regeneration and remyelination during the chronic stages of stroke. As such, an increase in Treg cells could potentially improve long-term stroke recovery [36,41]. Recently, engineered Treg cells have been used for adoptive immunotherapy. Firstly, human Treg cells are isolated from human peripheral blood, umbilical cord blood or thymus. These Treg cells are then cultured in vitro to generate polyclonal Treg cells or antigen-specific Treg cells. Finally, qualified Treg cells are infused into patients to treat related diseases [42]. Therefore, immunomodulatory strategies based on Treg cells are novel and promising therapies for neurological diseases, and deserve continued research by scholars.
Substantial evidence has indicated that the gut-brain axis likely plays a crucial role in neurological diseases, with an altered gut microbiota potentially having significant implications on immune responses in both the gut and distal effector immune sites such as the central nervous system [43]. A study involving experimental autoimmune encephalomyelitis mice found that the gut microbiota greatly influenced the balance between pro- and anti-inflammatory immune responses. This discovery suggested that modulating gut microbiota could provide new targets for treating extraintestinal inflammatory diseases like MS [21]. Specific metabolites of gut microbiota, such as the tryptophan metabolite FICZ [6-formylindolo (3‐2b) carbazole], are associated with the production of pro-inflammatory cytokines and the generation of Th17 cells. Conversely, commensal bacteria and their metabolites, including Lactobacilli and Bacillus-derived poly-gamma-glutamic acid (gamma-PGA), can stimulate Treg cell generation to promote immune suppression. Therefore, the immunomodulatory effects of gut microbiota may be mediated primarily via the Th17/Treg axis [44]. Exposure to MS microbiota or MS-associated Acinetobacter calcoaceticus extract was shown to alter lymphocyte differentiation in healthy individuals, resulting in an increase in Th1 cells and a decrease in CD25+Foxp3+ Treg cells, while exposure to Parabacteroides distasonis extract increased Treg cell differentiation [45]. Patients with MS display a reduction in commensal microbiota levels compared to healthy individuals, and therapies targeting the microbiota have demonstrated to increase the microbiota and improve MS by decreasing Th1- and Th17-cell levels and increasing Treg cell levels [46]. Patients with neurological diseases often exhibit gut microbial dysbiosis and altered microbial metabolites, highlighting the potential of microbial components or commensal bacteria as immunomodulatory agents to correct Th17/Treg imbalances and then treat neurological diseases [47]. Therefore, developing therapeutic interventions targeting the gut microbiome could represent a promising strategy for managing neurological diseases.
Cytokines are under active investigation as immune modulators to boost the numbers and functions of Treg cells in neurological diseases. The development and function of CD4+CD25+ Treg cells are regulated by Foxp3, while peripheral CD4+CD25− T cells can acquire suppressor function through ectopic Foxp3 expression. This discovery opens up a new way for cell-based therapies for autoimmunity [32]. IL-2 is an essential factor for the development, survival, and function of Foxp3+ natural Treg cells, playing a critical role in maintaining Treg cells homeostasis [20,33]. Studies have revealed that low-dose IL-2 therapy can selectively promote the persistence and survival of Treg cells while limiting effects on other T cell subsets. The therapeutic efficacy of this approach has been demonstrated in both animal models and clinical trials, highlighting its potential as a promising treatment option [48,49]. The aberrant TGF-β signaling observed in individuals with MS is strongly associated with Treg cell dysfunction [50]. Consequently, targeting and modulating TGF-β signaling may hold promise for addressing this defect and potentially alleviating the symptoms of MS. IL-6 plays a pivotal role in regulating the balance between Th17 and Treg cells. Specifically, IL-6 supports the differentiation of Th17 cells from naive T cells together with TGF-β, and inhibits TGF-β-induced Treg differentiation [51]. Tocilizumab, an anti-IL-6 receptor monoclonal antibody, has been approved for treating inflammatory diseases [18]. Therefore, the utilization of cytokines as immune modulators to regulate the differentiation and function of Treg cells represents a significant therapeutic approach in the treatment of neurological diseases. Furthermore, relevant immunomodulatory agents have transformed recent clinical practice to prevent and reverse pathology of neurological diseases. However, a delivery system that can cross the blood-brain barrier to carry immunomodulatory agents is still the direction of scholars’ unremitting exploration.
Limitations
This study is the first bibliometric analysis to systematically analyze documents related to Treg cells in neurological diseases. Nevertheless, there are still some deficiencies here. Firstly, only English language articles and reviews published in the Web of Science Core Collection were collected, which may lead to language and publication bias. Furthermore, as bibliometric analysis is closely linked to timeliness, it is essential to continuously update the results and trends of research on Treg cells in neurological diseases to keep pace with ongoing scientific exploration. This will enable a more comprehensive understanding of the topic as well as provide more precise predictions of future trends. However, given the large enough number of documents in this analysis, we believe that this study provides an instructive perspective for the research of Treg cells in neurological diseases and guides future research in this field.