The linker of T cells to B cells: Tfc cells and Autoimmune Diseases

The linker of T cells to B cells: Tfc cells and Autoimmune Diseases | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 17 March 2025 V1 Latest version Share on The linker of T cells to B cells: Tfc cells and Autoimmune Diseases Authors : Shun-yu Yao , Yong Peng 0000-0001-8390-7668 [email protected] , Xiuli Zhang , Huan Yang , Sugimoto Kazuo , Jia Liu , Miao-qiao Du , Lan-xin Lin , Quan Chen , and Hong Jin Authors Info & Affiliations https://doi.org/10.22541/au.174221480.01747174/v1 276 views 206 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract The success efficacy of B cell clearance depletion therapy in multiple sclerosis (MS) highly suggests strongly indicates the role involvement of B cells in the pathogenesis of MSdisease’s pathogenesis, posing thereby presenting a serious significant challenge to the existing classical pathogenesis conventional understanding of MS (i.e. T cell-mediated autoimmune diseases). pathogenesis.Both of CXCR5+CD8++ T cells [(follicular cytotoxic T cells, Tfc) and CXCR5+CD4+ T cells (follicular helper T cells, Tfh) serve as pivotal immune cells that bridge B cell and T cell interactions. While Tfc cells significantly contribute to the development of tumors and viral infections, they have been infrequently documented in autoimmune diseases, particularly in MS. CXCL13/CXCR5 is an important signaling pathway in Tfc cells, closely related to various cellular events.Evidence indicates that the pathway involving CXCR5 dysregulation is linked to tumor development and viral infections; however, the CXCL13/CXCR5 axis signaling pathway has seldom been documented in autoimmune diseases, especially in multiple sclerosis. In current review, we summaried current publications from pubmed including Tfc, CXCL13/CXCR5 axis and autoimmune diseases, tried to final the best protocol to study the role of Tfc in MS. The linker of T cells to B cells: Tfc cells and Autoimmune Diseases Shun-yu Yao 1,2 , Yong Peng 1,2* , Xiuli Zhang 3 , Huan Yang 4 , Sugimoto Kazuo 5,6 , Jia Liu 5,6 , Miao-qiao Du 1,2 , Lan-xin Lin 1,2 , Quan Chen 1,2 , Hong Jin 1,2 1Department of Neurology, Affiliated First Hospital of Hunan Traditional Chinese Medical College, Zhuzhou, Hunan 412000, China. 2Department of Neurology, Affiliated Provincial Traditional Chinese Medical Hospital of Hunan University of Chinese Medicine, Zhuzhou, Hunan 412000, China. 3Innovation Center for Science and Technology Innovation CenterTechnology, Hunan University of Chinese Medicine, Changsha, China” 4Department Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China. 5Department of Neurology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China. 6Institute for Brain Disorders, Beijing University of Chinese Medicine, Beijing, China. *Correspondence: : [email protected] or [email protected] (Y.P.) (Tel: :(+86)731-28290233; Researcher Researcher ID: : G-9270-2018; ORCID identifier: :0000-0001-8390-7668. Keywords: Autoimmune diseases; Multiple sclerosis; ; Experimental autoimmune encephalomyelitis; CXCR5+CD8+T cells; ; CXCR5+CD4+T cells Abstract The success efficacy of B cell clearance depletion therapy in multiple sclerosis (MS) highly suggests strongly indicates the role involvement of B cells in the pathogenesis of MSdisease’s pathogenesis, posing thereby presenting a serious significant challenge to the existing classical pathogenesis conventional understanding of MS (i.e. T cell-mediated autoimmune diseases). pathogenesis.Both of CXCR5+CD8++ T cells [(follicular cytotoxic T cells, Tfc) and CXCR5+CD4+ T cells (follicular helper T cells, Tfh) serve as pivotal immune cells that bridge B cell and T cell interactions. While Tfc cells significantly contribute to the development of tumors and viral infections, they have been infrequently documented in autoimmune diseases, particularly in MS. CXCL13/CXCR5 is an important signaling pathway in Tfc cells, closely related to various cellular events.Evidence indicates that the pathway involving CXCR5 dysregulation is linked to tumor development and viral infections; however, the CXCL13/CXCR5 axis signaling pathway has seldom been documented in autoimmune diseases, especially in multiple sclerosis. In current review, we summaried current publications from pubmed including Tfc, CXCL13/CXCR5 axis and autoimmune diseases, tried to final the best protocol to study the role of Tfc in MS. 1 Introduction The effectiveness of B cell depletion therapy in multiple sclerosis (MS) strongly indicates the involvement of B cells in the disease’s pathogenesis, thereby presenting a significant challenge to the established classical understanding of MS(Hauser et al 2017). In T cell-mediated autoimmune diseases, CXCR5+CD8+ T cells, also known as follicular cytotoxic T cells (Tfc), serve as pivotal immune cells that bridge B cells and T cells. While Tfc cells are crucial in the development of tumors and viral infections, they ha ve been infrequently documented in the context of autoimmune diseases, particularly multiple sclerosis.The CXCL13/CXCR5 signaling pathway plays a crucial role in Tfc cells and is intricately involved in numerous cellular processes. Research indicates that dysregulation of CXCR5-mediated signaling is linked to tumor development and viral infections; however, the involvement of the CXCL13/CXCR5 axis in autoimmune diseases, especially multiple sclerosis, has been scarcely documented(Hemmer et al 2015, Hohlfeld & Meinl 2017, Hussain et al 2020, Longbrake et al 2018, Reich et al 2018). please see figure 1 Drawing from the established classical pathogenesis of multiple sclerosis (MS), we examined self-reactive T cells, including CD8+T cells and IL17+CD8+T cells (Tc17), within an animal model of MS—experimental autoimmune encephalomyelitis (EAE). Our findings indicated that both CD8+T cells and Tc17 cells contribute to the development of EAE(Peng et al 2022, Peng Y 2021, Peng et al 2024b, Peng et al 2019); however, these observations alone are inadequate to fully elucidate the intricate pathogenesis of MS/EAE. Additionally, there is growing evidence supporting the role of B cells in the pathogenesis of MS/EAE. Presently, the subsets of CD8+ T cells encompass Tc1 cells, Tc2 cells, Tc17 cells (IL17+ CD8+), CD8+ T regulatory cells (CD8 Tregs), memory CD8 T cells, and CXCR5+ CD8+ T cells (C-X-C chemokine receptor type 5+ CD8+ T cells)(Valentine & Hoyer 2019). Tc1 cells are classical cytotoxic CD8 T cells (CTL). Tc1 cells producing IFNγ, perforin, and granzymes to kill targeted cell(Chowdhury & Lieberman 2008).Tc1 cells consistently fulfill a vital function in viral and intracellular infections, as well as in certain autoimmune disorders, including multiple sclerosis (MS), uveitis, type I diabetes (T1D), immune thrombocytopenia, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and thyroiditis. Tc2 cells are responded to specific allergens and typically exhibit reduced CTL function and produce IL-4 and IL-5(Valentine & Hoyer 2019) . Tc17 cells can express cytokines IL-5, IL-13, IL-17, IL-21, IL-22, IFN-γ, TNF-α, and GM-CSF(Han et al 2007, Liang et al 2015, Peng et al 2007a).Tc17 cells are stimulated by TGF-β in conjunction with IL-6, IL-21, and IL-1, and their maintenance is supported by IL-23. CD8 Treg have multiple phenotypes, including CD122(Kim et al 2011), and foxp3(Han et al 2007, Kim et al 2015, Peng et al 2007c).Additionally, three types of memory CD8 T cells have been identified: T effector memory (characterized by CD28− CD95+ markers, Tem), tissue-resident memory, and central memory (marked by CD28+ CD95+, Tcm)(Kaech & Cui 2012, Mylvaganam et al 2018). The profiles and functions of CD8 subsets, please see figure 2 and table 1. Although we have conducted long-term research on T cells and their subsets in MS/EAE, the above ideas have been based on the existing classic mechanism that MS is an autoimmune disease mainly mediated by T cells(Amato et al 2013, Arneth 2016, Arneth 2024, Dörries 2001, Dubik et al 2024, Höftberger et al 2020).Presently, various immune therapies directed at T and B cells have demonstrated success in MS(Häusser-Kinzel & Weber 2019), particularly the notable achievements of B cell depletion therapy in MS, which strongly indicates the involvement of B cells in its pathogenesis(Hauser et al 2017). While the precise mechanism remains uncertain, this poses a significant challenge to the established classical theories of MS pathogenesis(Hohlfeld & Meinl 2017).Therefore, it is crucial to identify the key connection points between T and B cells.Recent studies have identified that the immune cells bridging B and T cells are CXCR5+CD8+ T cells, also known as follicular cytotoxic T cells (Tfc), and CXCR5+CD4+ T cells, referred to as follicular helper T cells (Tfh). 2 Brief introduction of Tfh role in autoimmune diseases Tfh cells have been documented in a variety of autoimmune conditions, including multiple sclerosis. Tfh cells and mature B cells highly express the chemokine receptor CXCR5, which binds to its ligand CXCL13 to form B cell aggregates. Tfh cells are closely related to MS, CXCR5 is an important genetic risk locus for MS.Approximately 20% of T cells within the cerebrospinal fluid (CSF) express CXCR5, and the prevalence of activated Tfh cells correlates with disease progression in individuals with secondary progressive multiple sclerosis (SPMS).In EAE, mice deficient in CXCL13 expression exhibit only mild disease, and treatment with anti-CXCL13 blocking antibodies can mitigate EAE symptoms(Romme Christensen et al 2013). Tfh cells are crucial for the function and structure of follicles within lymphoid tissues(Bagaeva et al 2006), and follicle-like aggregates have been observed in the meninges, correlating with cortical pathology in MS(Crotty 2014, Magliozzi et al 2007). Tfc cells have been rarely reported in autoimmune diseases, especially in MS.The sole existing research indicates that, while Fingolimo significantly and unevenly decreases the frequency of Tfh cells, regulatory cell subsets, and Tfc cells in the peripheral blood of MS patients, the relative proportion of CXCR5 memory Th cells, regulatory T cells, and B cells rises(Huber et al 2020).2) Compared to untreated MS patients, dimethyl fumarate moderately reduced the absolute number of Tfh cells, but there was no change in Tfc cells(Turner et al 2022). please see figure 3 3 Phenotypes of Tfc cells Recently, a new subset of CD8 T cells, characterized by the expression of CXCR5 and also referred to as T follicular cytotoxic (Tfc) cells, has been recognized(Turner et al 2022, Valentine & Hoyer 2019, Valentine et al 2021, Yu & Ye 2018).Tfc cells have been observed infiltrating the B cell follicle in response to various diseases, including viral infections such as simian immunodeficiency virus (SIV) or human immunodeficiency virus (HIV)(Haran et al 2018, He et al 2016, Mylvaganam et al 2018, Mylvaganam et al 2017, Mylvaganam et al 2014), lymphocytic choriomeningitis virus (LCMV)(He et al 2016, Huang et al 2019, Im et al 2020), hepatitis B virus (HBV)(Kumashie et al 2020, Li et al 2020, Tyllis et al 2021), polycythemia-inducing Friend virus complex (FV)(Knuschke et al 2021), influenza A virus (FluA)(Hoji & Rinaldo 2005, Tyllis et al 2021), herpes simplex virus (HSV)(Stanfield et al 2017), and dengue virus 2(DENV2)(Qiu et al 2019, Rivino et al 2013).severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)(Adam et al 2021, Kudryavtsev et al 2022, Zhou et al 2023), Epstein-Barr virus (EBV)(Chatterjee et al 2019); malignancies [colorectal carcinoma(E et al 2018, Shen et al 2018, Xing et al 2017), non-small cell lung cancer (NSCLC)(Brummelman et al 2018), hepatocellular carcinoma(Jin et al 2017, Ye et al 2019), hematological cancers(Hofland et al 2021), pancreatic neoplasms(Bai et al 2017), gastric carcinoma(Wang et al 2021), breast carcinoma(Bassez et al 2021), thyroid carcinoma(Zhou et al 2018), melanoma(Gangaev et al 2021), lymphoma(Tang et al 2017);”’bacteria [Escherichia coli, Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Staphylococcus aureus(Shen et al 2019). immunodeficiency disease [CVID(de Lollo et al 2016); autoimmune diseases[rheumatoid arthritis (RA)(Anang et al 2022, Higashioka et al 2021, Pan et al 2023), Sjögren syndrome (SS)(Hinrichs et al 2009, Zhai et al 2022), myasthenia gravis (MG)(Fan et al 2022), multiple sclerosis (MS)(Huber et al 2020, Longbrake et al 2018). Please see figure 4 and table 1. Previously, autoimmune diseases (AIDs) have been considered as rare diseases, however, recently AIDs are common with high prevalence (7%-9%), depended on significant progress in diagnosis and treatment on AIDs(Qi et al 2023, Wang et al 2015, Yu et al 2014). Typically, AIDs have different classifications. Tissue and organ damage can manifest as organ-specific conditions, such as type 1 diabetes (T1D), multiple sclerosis (MS), uveitis, and myasthenia gravis (MG), or as systemic diseases affecting multiple organs, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and Sjögren’s syndrome (SS)(Richard-Eaglin & Smallheer 2018). For dominated immune cells, there are autoreactive T cell dominated AIDs, such as T1D, MS(Peng et al 2022, Peng & Liu 2002, Peng Y 2021, Peng et al 2024b, Peng et al 2019), SS, uveitis(Peng et al 2007b, Peng et al 2007c, Peng et al 2006) and RA, and autoreactive B cell dominated AIDs, such as SLE, MG(Peng et al 2024a, Wang et al 2015). Currently, the classical mechanism of pathogenesis in T cell dominated AIDs, such as MS is challenged by great successful B cell-targeting therapies on MS(Hauser et al 2017, Hauser et al 2008, Häusser-Kinzel & Weber 2019, Hemmer et al 2015, Hohlfeld & Meinl 2017, Krumbholz & Meinl 2014, Montalban et al 2017). Therefore, it is crucial to identify the key connection points between T and B cells, and the best candidates are Tfc cells. Although not definitively established, Tfc exhibit distinctive phenotypes, including a variety of cell markers (CD11a, CD11b, CD20, CD25, CD27, CD28, CD38, CD39, CD40, CD43, CD44hi, CD45RA, CD45RO, CD57, CD62L, CD69, CD83, CD94, CD95, CD101, CD103, CXCR5, CD107, CD127, CD137, CD161, CD200, CD244, HLA-DR,41BBL, Slamf6, TCRVa7.2) and cytokines. Chemokines and their receptors, including CSF-1, IL-2, IL-4, IL-6, IL-7, IL-7R, IL-10, IL-17, IL-18Ra, IL-21, IL-21R, IL-22, IL-23, IL-27, IL-27R, IL-35, IFN-I, IFNAR1, IFN-γ, TGF-β, TNF-α, IL-4R (CD124), CCR2, CCR4, CCR5, CCR6, CCR7, CCR9, CCL5, CXCL1, CXCL5, CXCL10, CXCL12(SDF-1α), CXCL13, CXCR3, CXCR4, CXCR5, CX3CR1, and MIP-1β, have been extensively studied.(Adam et al 2021, Anang et al 2022, Bassez et al 2021, Brummelman et al 2018, Chatterjee et al 2019, de Lollo et al 2016, Hinrichs et al 2009, Hofland et al 2021, Hoji & Rinaldo 2005, Qiu et al 2019, Rivino et al 2013, Shen et al 2018, Stanfield et al 2017, Tyllis et al 2021, Valentine et al 2018, Wang et al 2021, Xing et al 2017, Yang et al 2021, Ye et al 2019, Zhou et al 2023), transcription factors [Bcl-6, CDCA7, CTLA-4, CULT1, E2A, pERK1/2, granulysin, granzyme B, Helios, ICOS, Id2, ISGs, molecules associated with the interferon pathway (MX1, MX2, GBP1, and ISG15), Ki-67, KLRG1, LAG-3, MAMU-DRA, MEF2C, NFATC1, NFATC2, PD-1, PD-L1, PD-L2, perforin, PRDM1, RANTES, SOX4, SPRY2, STAT2, STAT6, TCF4, TCF24, Tim-3](Cartwright et al 2022, He et al 2016, Martínez et al 2023, Mylvaganam et al 2018, Mylvaganam et al 2017, Olivo et al 2021, Perdomo-Celis et al 2019, Perdomo-Celis et al 2020, Perdomo-Celis et al 2018, Starke et al 2020).” Please see figure 4 and table 1. Even there are so many evidences in animal model and human studies indicated that Tfc cells share many aspects with CXCR5+ CD4+ T cells (T follicular helper, Tfh)(Yu & Ye 2018), such as localization in B cell follicles, expression in murine antigen-specific CD8+ T cells(He et al 2016, Im et al 2016, Leong et al 2016) and in secondary lymphoid organs(Im et al 2016, Miles et al 2016, Mylvaganam et al 2017, Petrovas et al 2017, Quigley et al 2007). Moreover, the expression level of CXCR5 is positively related with the localization level of Tfc cells in B cell follicles(Ayala et al 2017, Haran et al 2018, Huot et al 2021, Im et al 2016, Leong et al 2016). Furthermore, compared with naïve CD8+ T cells, Tfc cells expressed less CCR7(Ferrando-Martinez et al 2018, Miles et al 2016, Quigley et al 2007), which leads Tfc cells to the T cell zone(Vinuesa & Cyster 2011).Ultimately, the maturation and diversification of Tfc cells require mature B cells and follicular architecture. Tfh cells are present in various tissues and regions, including the T-B border or interfollicular zone(Bentebibel et al 2011, Kerfoot et al 2011, Lee et al 2011), within the bloodstream(He et al 2013, Morita et al 2011, Schmitt et al 2014), and in inflamed non-lymphoid tissues like the kidney(Liarski et al 2014), skin(Taylor et al 2018), lung(Vu Van et al 2016), synovium(Manzo et al 2008, Rao et al 2017), and tumors(Gu-Trantien et al 2013). Analogous to Tfh cells, Tfc cells encompass CXCR5+ CD8+ T cells both inside and outside B cell follicles(Vinuesa et al 2016), such as those found in T cell zones of the spleen(Li et al 2021), blood(Quigley et al 2007), and lung, pancreatic, and colorectal tumors(Bai et al 2017, Brummelman et al 2018, E et al 2018). Tfc cells expressed CXCR5, CCR7 and CXCR3(Im et al 2016, Leong et al 2016).Notably, Tfc cells exhibited elevated levels of CD62L and CD127 during chronic viral infection, a characteristic feature of memory CD8+ T cells(Im et al 2016, Leong et al 2016); however, the influence of IL-7 on Tfc cells remains uncertain, despite its critical role in memory CD8+ T cells(Yu & Ye 2018). In contrast to CXCR5-negative non-Tfc cells, Tfc cells demonstrated reduced cytotoxic activity, as evidenced by lower expression of granzymes and perforin during chronic viral infection(Im et al 2016, Leong et al 2016). 4. CXCR5 and CXCR5/CXCL13 Axis The influence of the CXCR5/CXCL13 axis on immune system function is complex and operates at multiple levels(Pan et al 2022):1) It significantly contributes to the regeneration, development, and immune response of secondary lymphoid tissues. Elevated CXCL13 expression on follicular dendritic cells correlates with increased levels of other chemokines, cytokines, and adhesion molecules(Krishnamurty & Turley 2020), while also facilitating B cell migration into B cell follicles.2) It modulates T cell positioning to enhance germinal center responses.CXCL13 facilitates the recruitment of Tfh cells to the interface between T cell and B cell follicles (T-B boundary), where they engage with activated B cells, thereby enhancing B cell activation and proliferation. The above two effects on T/B cell function were not found in CXCR5-/- mice.3) Modulating the migration of CXCR5+CD4+ T suppressor cells, also known as follicular T suppressor cells (TFr), thereby dampening the humoral immune responses of mature B cells and Tfh cells within the germinal center, is also associated with B1 cell responses.4) B cell trafficking and B cell receptor (BCR)-mediated B cell activation.5) By altering cellular dynamics to facilitate BCR-induced B cell activation, the aggregation of antigens at immune synapses is intensified.The proposed mechanism involves the CXCL13/CXCR5 axis facilitating membrane folding and adhesion, which is aided by lymphocyte function-associated antigen 1(LFA-1), and integrating B cell receptor (BCR) signaling activation through migration pathways supported by LFA-1. In conclusion, the CXCL13/CXCR5 axis plays a crucial role in modulating B cell homeostasis and various cellular processes, including migration, survival, proliferation, and gene transcription regulation(Hussain et al 2019).Although there have been many studies on the effects of CXCL13/CXCR5 axis on T/B cell function, there are few reports on the CXCR5+CD8+T cells that we are concerned about. Please see figure 5. Since Tfc is so important, understanding the origin and functionality of CXCR5 is crucial. The chemokine receptors CCR5, CCR9, CCR10, CXCR2, CXCR4, CXCR5, and CXCR7 are involved in the occurrence and development of tumors, autoimmune diseases, viral infections, and cytokine release syndrome (also known as cytokine storm).Among these, CXCR5 and its ligand CXCL13 are associated with the onset and progression of chronic inflammation, infections, immune responses, and autoimmune disorders(Skuhersky et al 2021). CXCR5, a G protein-coupled receptor of the A class, is predominantly found on B cells within secondary lymphoid tissues, including the spleen, lymph nodes, and Peyer’s patches, and is also present on specific T cell subsets, such as Tfh and Tfc cells. CXCL13 exerts a potent chemotactic influence on B cells and remains expressed in these secondary lymphoid tissues, particularly in follicular B cells, follicular dendritic cells (FDC), and Tfh cells(Pan et al 2022). CXCL13 expression is associated with different diseases, such as tumor, infectious diseases, primary pulmonary fibrosis (IPF), transplantation rejection and pathological neuralgia.CXCL13 is notably linked to a range of autoimmune conditions, including rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, primary Sjögren’s syndrome, and inflammatory bowel disease(Pan et al 2022). Please see figure 6. 4.1 CXCL13/CXCR5 axis signaling pathway The signaling pathways of CXCR5/CXCL13 axis are also multifaceted and multi-level.1) CXCR5 induced Ca2+ influx and chemotaxis without inhibitory G proteins.CXCR5 inhibits G proteins through the MAPK/extracellular signal-regulated kinase 1 and 2(ERK1/2) and G protein-coupled receptor 2(EBI2) pathway.3) CXCR5 linked to several human diseases, especially tumors, such as osteosarcoma cells via phospholipase C β(PLC β)/protein kinase C α(PKC)/NF κ B(Liu et al 2020), prostate cancer cell via PKC/PTEN to increase CXCL13 expression(Garg et al 2020).4) CXCR5 activates the NF-κB pathway and the mammalian target of rapamycin (mTOR) through the glycogen synthase kinase 3β(GSK-3β)/PI3K-Akt signaling cascade(Garg et al 2020, Zheng et al 2018).5) Additionally, CXCR5 stimulates the MAPK/p38 pathway via c-Jun N-terminal kinase (JNK) activation(El-Haibi et al 2011, Zhang et al 2017). Although there have been many studies on the CXCL13/CXCR5 axis signaling pathway in tumors, there are few reports on it in autoimmune diseases. Please see Figure 7. 4.2 CXCL13/CXCR5 Axis in Autoimmune Diseases The CXCL13/CXCR5 axis has been confirm to link to many autoimmune diseases, including RA, pSS, MS, SLE, MG, and more(Le Panse et al 2008, Serafini et al 2004, Steinmetz et al 2008). MS is the autoimmune disease that we are most concerned about.CXCL13 plays a significant role in the pathogenesis of MS/EAE. Elevated levels of CXCL13 are observed in the blood, cerebrospinal fluid, and demyelinating brain tissue of MS patients, correlating with higher recurrence rates, greater disease severity, increased intrathecal immunoglobulin production, the presence of oligoclonal bands (OCBs), and lymphocyte infiltration.2) The combination therapy of rituximab and fingolimod or methylprednisolone, dazumab and natalizumab alone can reduce CSF CXCL13 levels in MS patients(Le Panse et al 2008). To summarize, CXCL13 is regarded as a potential indicator of the severity, prognosis, and therapeutic response in MS.3) CXCL13-/- mice exhibit milder and self limiting forms of EAE: reduced clinical symptoms, inflammation, demyelination, reduced gliosis and white matter fibrosis, and more complete recovery.4) Blocking the LT-LT β R signaling pathway in EAE mice can inhibit the production of CXCL13 and the formation of ELSs in the meninges, as well as suppress EAE symptoms.3) Within the EAE mouse model mediated by Th17 cells, meningeal stromal cells exhibited CXCL13 expression in a manner dependent on LTβR(Pikor et al 2015).4) The administration of anti-CXCL13 antibodies in EAE induced by the adoptive transfer of myelin-specific Th17 cells is characterized by diminished Tfh cell infiltration in the CNS and reduced EAE severity, whereas the infiltration of Th17 cells and B cells remains largely unchanged.Nevertheless, treatment with anti-CXCL13 antibodies proved ineffective in B-cell-deficient EAE mice(Quinn et al 2018). In actively induced EAE, it was shown that CXCL13-/- mice exhibited no difference in CNS B cell infiltration compared to wild-type mice(Rainey-Barger et al 2011). However, in CXCL13-/- EAE mice, the Th1 and Th17 responses diminished two weeks following the peak of disease(Rainey-Barger et al 2011).These findings indicate that CXCL13 might draw Tfh cells into the CNS, consequently sustaining the immune response facilitated by B cells, Th1 cells, and Th17 cells in EAE. PSS usually occurs before the activation, somatic hypersensitivity, and maturation of self reactive T cells and B cells, mainly in GC(Zhai et al 2022).Throughout these processes, Tfh cells exhibit PD-1 and ICOS expression and facilitate the development of germinal centers within secondary lymphoid organs by secreting IL-21 and CXCL13. While follicular T cells are predominantly confined to secondary lymphoid organs, CXCR5+/- T cells have also been detected in peripheral blood. The study revealed a notable increase in CD8+CXCR5− PD-1+ T cells in pSS patients compared to the healthy control group, whereas CD8+ Treg cells were markedly reduced.The proportion of CD8+CXCR5+PD-1+ T cells relative to CD8+ Tregs serves as a significant marker for differentiating pSS from healthy controls. The count of CD8+CXCR5+PD-1+ T cells exhibits a strong correlation with CD4+CXCR5+ T cells and B cells, and is elevated in pSS patients exhibiting lung involvement(Zhai et al 2022). Ulcerative colitis (UC) is a chronic autoimmune inflammatory condition that cycles between periods of activity and remission, posing a long-term risk for colitis-associated cancers. The disease is characterized pathologically by the infiltration of numerous neutrophils into the colonic and rectal mucosa, and there are currently no dependable biomarkers for tracking active UC(Pararasa et al 2019, Uo et al 2013). The development of UC involves the proliferation of activated B cells and the generation of pathogenic antibodies(Long et al 2020). In Balb/c mice with DSS-induced colitis, a notable rise in Tfh and Tfr cell populations was detected in the colon. Moreover, the percentage of Tfr and Tfc cells increased in peripheral blood, whereas the proportion of Tfc cells diminished in the colon.The counts of Tfr and Tfc cells diminish in the colon and peripheral blood, whereas the percentage of effector memory T cells rises. In the colon of DSS colitis mice, there is an increase in TIGIT+CD226 CD4+CXCR5+ T cells and Tfc cells. Additionally, PD-1+, ICOS+, and PD-1+ICOS+CD4+CXCR5+ T cells exhibit elevated levels. Fingolimo is an efficacious treatment for relapsing-remitting multiple sclerosis. It prevents CCR7+ lymphocytes from exiting lymphoid tissue into the bloodstream by inhibiting the sphingosine-1-phosphate pathway, thereby reducing peripheral blood lymphocyte levels. Present in both lymphoid tissue and peripheral blood, it supports B cell function and is essential for generating effective antibody responses. Fingolimo has also been implicated in the development of various autoimmune disorders.The study revealed that while Fingolimo significantly and unevenly decreased the frequency of peripheral blood Tfh cells, regulatory cell subsets, and Tfc cells, there was a corresponding increase in the relative frequency of CXCR5 memory Th cells, regulatory T cells, and B cells(Huber et al 2020). Dimethyl fumarate (DMF) is frequently employed as a treatment for relapsing multiple sclerosis (MS). Compared to untreated MS patients, dimethyl fumarate moderately reduced the absolute number of Tfh cells, but there was no change in Tfc cells(Longbrake et al 2018). In comparison to the lymphoid tissue of healthy individuals, that of RA patients and those at risk for RA exhibited a higher presence of CD19+B cells, Tfh, and Tfc cells(Anang et al 2022). In summary, there is little research on Tfc cells in autoimmune diseases, especially MS, but their importance cannot be ignored and deserves further investigation. 5.Tfh and Tfc in MS For example, typically, MS was a T cell-dominated autoimmune disease(Arneth 2016, Arneth 2024, Behan & Chaudhuri 2014, Dubik et al 2024, Li et al 2024, Xing et al 2024), which damage central nervous system (CNS)(Hemmer et al 2015, Reich et al 2018). Currently, the classical mechanism of pathogenesis in MS is challenged by great successful B cell-targeting therapies on MS(Hauser et al 2017, Häusser-Kinzel & Weber 2019, Hemmer et al 2015, Hohlfeld & Meinl 2017, Krumbholz & Meinl 2014, Krumbholz et al 2007, Montalban et al 2017).Thus, it is essential to pinpoint the primary interaction sites between T and B cells, with the most promising candidates being CXCR5+CD8+ T cells (follicular cytotoxic T cells, Tfc) and CXCR5+CD4+ T cells (follicular helper T cells, Tfh). Studies of Tfh cells have been well-done in MS(Crotty 2014, Quinn & Axtell 2018, Schmitt et al 2016, Ueno et al 2018). CXCR5, which is a genetic risk factor for MS, expressed on Tfh cells(Lill et al 2013, The International Multiple Sclerosis Genetics et al 2011).Tfh cells were detected in the cerebrospinal fluid (CSF) and linked to secondary progressive multiple sclerosis (SPMS) as well as the cortical pathology characteristic of MS. Both CXCR5 ligand-CXCL13-/- mice and anti CXCL13 antibody (Ab) were able to reduce the clinical symptoms in MS model-experimental autoimmune encephalomyelitis (EAE)(Bagaeva et al 2006). Until now, few studies of Tfc have published in autoimmune diseases, such as MS. For example, fengolimol significantly reduced Tfc cells in MS patients(Huber et al 2020). However, dimethyl fumarate moderately did not change in Tfc cells in MS(Longbrake et al 2018). Due to few evidences on Tfc in MS, we think that it will be a good target on MS future studies. In clinical trials, dimethyl fumarate (DMF) showed good effects on relapsing MS, such as improvements on clinical manifestation and imaging(Fox et al 2012, Gold et al 2012). The mechanisms of DMF on MS might be neuroprotection dependent or independent Nrf2 pathway(Ghoreschi et al 2010, Scannevin et al 2012, Schulze-Topphoff et al 2016), and effecting on lymphocytes(Fox et al 2016, Fox et al 2012, Gold et al 2012).In comparison to healthy controls, Longbrake et al. demonstrated that in MS patients, DMF decreased the frequencies of circulating CD8+ and CD4+ T cells, CD56dim natural killer (NK) cells, CD19+ B cells, plasmacytoid dendritic cells, circulating memory B cells, follicular T-helper cells (CD4+ CXCR5+), and mucosal invariant T cells (CD8+ CD161+). However, the frequencies of T-regulatory and CD8+CXCR5+ cells remained unchanged(Longbrake et al 2018, Longbrake et al 2016). 8. Conclusion Now, we organized the latest information on Tfc of autoimmune diseases, However, the detail of, including their phenotypes and the pathogenesis mechanism underlying the role of Tfc in MS/EAE, MG are still unclear. In addition, it still has question should be answered. Even the signal transductionon of CXCR5/CXCL13 axis has been well-down on cancer, however they has been rarely reported on autoimmune diseases, especially on MS, it suggest this will be nice target for future studies. Declarations Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Availability of data and materials The evidence underpinning this article is detailed within the text. For further details, please reach out to the corresponding author. Competing interests The authors declare no conflict of interest. Funding This research was funded by the Key Projects of the Health and Family Planning Commission of Hunan Province, PR China (Grant No. C2023030765 to YP), the Key Projects of the Hunan Administration of Traditional Chinese Medicine (Grant No. A2023039 to YP), the University-Hospital Joint Fund of Hunan University of Chinese Medicine (Grant No.2022XYLH198 to YP), and the Fund for Creative Research Groups at the Affiliated First Hospital of Hunan Traditional Chinese Medical College, PR China (Grant No.”2021B-003 awarded to YP), and the Technology Plan Project of Zhuzhou City, Hunan Province, China (Grant No.2021-009 to YP).” Authors’ contributions Y.P. secured funding and formulated the research hypothesis. The main manuscript was written by Y.P., S.Y.Y., M.Q.D., L.X.L., H.Y., Q.C., and H.J., with S.Y.Y. responsible for creating all figures. The final manuscript reflects the collaborative writing efforts of all authors. Acknowledgements Not applicable. Figure legends Figure abstract: ”’Representation of the CXCL13/CXCR5 pathway in the development of multiple sclerosis (MS).”’ The central pathway represents the interaction between CXCL13 and CXCR5, which is critical in immune cell signaling.On the left, follicular cytotoxic T cells (Tfc, CXCR5+CD8+) are depicted engaging with B cells, underscoring their significance in immune regulation. Anomalies in the CXCL13/CXCR5 axis are suggested as a possible factor in the development of MS. Figure 1: ”’Representation of the CXCL13/CXCR5 pathway in the development of multiple sclerosis (MS).”’ The central part highlights the signaling pathway between CXCL13 and CXCR5, which is crucial for immune cell regulation. On the left, CXCR5+CD8+ T cells (follicular cytotoxic T cells, Tfc) are shown interacting with B cells, emphasizing their potential roles in tumors, viral infections, and autoimmune diseases. The bottom notes indicate that dysregulation of this pathway may be associated with the development of MS. Figure 2: Illustration of CD8+ T cell subsets and their functions. The diagram shows six main subsets branching from a central CD8+ T cell: Tc1 cells, which are conventional cytotoxic T lymphocytes that generate IFNγ, perforin, and granzymes, are involved in combating viral infections and contribute to autoimmune conditions such as multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus. 2.Tc2 cells: Respond to allergens, produce IL-4 and IL-5, with reduced cytotoxic function. Tc17 cells: Synthesize cytokines including IL-17, IL-22, and GM-CSF, which are implicated in inflammatory responses and are sustained by IL-23. 4.CD8+ Tregs: Regulatory T cells with phenotypes like CD122+ and Foxp3+, involved in immune suppression. Memory CD8+ T cells, which encompass effector memory (Tem), tissue-resident memory, and central memory (Tcm) subsets, play a vital role in immune memory. 6.CXCR5+ CD8+ T cells: Interact with B cells, implicated in immune regulation. This diagram provides an overview of the profiles and key functions of CD8+ T cell subsets. Figure 3: Impact of Fingolimod and Dimethyl Fumarate on T-cell and B-cell Subsets in Multiple Sclerosis (MS) Patients. Fingolimod therapy notably decreases the frequency of Tfh cells, regulatory cell populations, and Tfc cells in the peripheral blood, while concurrently elevating the proportion of CXCR5 memory Th cells, regulatory T cells, and B cells. In contrast, Dimethyl Fumarate moderately reduces the absolute number of Tfh cells with no observable change in Tfc cells.The direction of the arrows signifies alterations in frequency: a downward arrow denotes a decrease, an upward arrow signifies an increase, and an equal sign indicates no change. Figure 4: Phenotypic and Molecular Characteristics of Tfc Cells This figure delineates the essential markers, cytokines, chemokines, and transcription factors linked to Tfc cells. 1.Cell Markers: T-cell markers: CD11a, CD11b, CD20, CD27, etc. Activation markers: CD25, CD28, CD69, etc. Memory markers: CD45RA, CD45RO, CD62L, etc. 2.Cytokines and Chemokines: Cytokines: IL-2, IL-6, IL-21, IFN-γ, etc. Chemokines and Receptors: CCR5, CCR7, CXCL13, CXCR5, etc. 3.Transcription Factors: Key transcriptional regulators: Bcl-6, PD-1, STAT6, NFATC1, etc. Figure 5: The Impact of CXCR5/CXCL13 Axis on Immune System Function This diagram summarizes the multifaceted roles of the CXCR5/CXCL13 axis: Regeneration and immune responses in secondary lymphoid tissues are supported by CXCL13, which is expressed on follicular dendritic cells (FDCs) and aids in B cell migration into follicles while enhancing the expression of chemokines and cytokines. The regulation of T cell localization involves CXCL13 drawing Tfh cells to the T-B boundary, facilitating their interaction with activated B cells to augment B cell activation and proliferation. The regulation of CXCR5+CD4+ T suppressor cells (Tfr) involves inhibiting humoral immune responses within the germinal center and influencing B1 cell activities. B cell homing and activation, as well as antigen-specific immune responses, are orchestrated by CXCR5 and CXCL13 through BCR-induced processes. 5.Enhancement of Immune Synapse Formation: CXCL13 supports antigen aggregation via LFA-1-mediated adhesion and BCR signaling. 6.Research Gap: Limited studies focus on CXCR5+CD8+ T cells, highlighting an area for further investigation. Arrows and interactions in the diagram represent the relationships and mechanisms of action within the CXCR5/CXCL13 axis. Figure 6: XCR5 and CXCL13: Origin and Functionality This diagram illustrates the origin, expression, and functionality of CXCR5 and CXCL13: 1.CXCR5 as a G Protein-Coupled Receptor (GPCR): CXCR5 is classified as an A-class GPCR, structurally represented in the diagram. 2.CXCR5 Expression: CXCR5 is primarily expressed on: B cells are located in secondary lymphoid tissues, including the spleen, lymph nodes, and Peyer’s patches. T cell subsets: Including Tfh and Tfc cells, which play roles in immune regulation. 3.CXCL13 Chemotactic Function: CXCL13 is produced by follicular B cells, follicular dendritic cells (FDC), and Tfh cells within secondary lymphoid tissues. This molecule demonstrates significant chemotactic activity toward B cells and has been associated with various diseases, including: Autoimmune disorders, including rheumatoid arthritis (RA), multiple sclerosis (MS), systemic lupus erythematosus (SLE), primary Sjögren’s syndrome (pSS), and inflammatory bowel disease (IBD). Other conditions: Tumors, infectious diseases, primary pulmonary fibrosis (IPF), transplant rejection, and pathological neuralgia. Arrows and connections in the diagram represent the interactions and effects of CXCR5 and CXCL13 in immune responses and disease development. Figure 7: Signaling Pathways of CXCR5/CXCL13 Axis This diagram illustrates the multifaceted and multi-level signaling pathways mediated by the CXCR5/CXCL13 axis: 1.Calcium Influx and Chemotaxis: CXCR5 induces Ca²⁺ influx and chemotaxis without the involvement of inhibitory G proteins. 2.MAPK/ERK1/2/EBI2 Pathway: CXCR5 regulates the MAPK/ERK1/2/EBI2 pathway, which inhibits G proteins. 3.Tumor-Associated Pathways: In osteosarcoma cells, CXCR5 activates the PLCβ/PKCα/NF-κB pathway. In prostate cancer cells, CXCR5 regulates CXCL13 expression via the PKC/PTEN pathway. 4.GSK-3β/PI3K/Akt Pathway: CXCR5 activates NF-κB and the mTOR pathway through the GSK-3β/PI3K/Akt pathway. 5.JNK/MAPK/p38 Pathway: CXCR5 activates the MAPK/p38 pathway via the JNK signaling pathway. The diagram highlights the roles of these pathways in tumor progression and their potential links to other diseases, while noting the limited studies on autoimmune diseases. Abbreviations Alanine aminotransferase (ALT) African green monkeys (AGM) Antiretroviral therapy (ART) B cell lymphoma 6 protein (BCL6) Broadly neutralizing antibodies (bnAbs) C-C chemokine receptor type 7(CCR7) C-C chemokine ligand 5(CCL5) CD8 T regulatory cells (Tregs) Cell division cycle associated 7(CDCA7) Central memory (CD28+CD95+, Tcm) Chimeric Ag receptor (CAR) Chronic hepatitis B (CHB) Chronic lymphocytic leukemia (CLL) Combination antiretroviral therapy (cART) Common variable immunodeficiency (CVID) Community or hospital acquired pneumonia (CAP, HAP) Complete responders (CRs) Cutaneous leishmaniasis (CL) CXCR5+CD8 T cells (Tfc) C-X-C chemokine receptor type 5(CXCR5) Cytotoxic CD8 T cells (CTL) Cytotoxic T lymphocyte antigen (CTLA) Cysteine-X-cysteine chemokine ligand (CXCL) Dengue virus 2(DENV2) Down syndrome (DS) Engineered CD8 T cells expressing CXCR5(CD8hCXCR5) Eomesodermin (EOMES) Extracellular regulated kinase (ERK)Epstein-Barr virus (EBV) Follicular dendritic cells (FDCs) Follicular lymphoma (FL), The cohort from the Fudan University Shanghai Cancer Center (FUSCC) Follicular helper T cells (Tfh) Fork head-box -protein P3(Foxp3) Friend virus complex (FV) Germinal center (GC) Gastrointestinal (GI) Guanylate binding protein (GBP) HBV-infected HCC patients (HBV-HCC) Healthy donors (HDs) Hepatitis B virus (HBV) Herpes simplex virus (HSV) Hepatocellular carcinoma (HCC) Highly active antiretroviral therapy (HAART) HIV-unexposed uninfected healthy women(HU); HIV-unexposed seronegative women (UH), Hodgkin’s lymphoma (HL) Human cytomegalovirus (HCMV), Human immunodeficiency virus (HIV) Idiopathic pulmonary fibrosis (IPF) IFNα/β receptor 1(IFNAR1) IFN-stimulated genes (ISGs) Immune non-responders (INRs) Inducible T-cell costimulatory (ICOS) Influenza A virus (FluA) Inhibitor of DNA binding 2(Id2) Interferon type 1(IFN-I) Interleukin (IL) Interferon regulatory factor (IRF) Interferon-Stimulated Gene 15(ISG15) Killer-cell lectin like receptor G1(KLRG1) LTa1b2-lymphotoxin b receptor (LTbR) Lymphnode (LN) Lymph node mononuclear cells (LNMCs) Lymphocytic choriomeningitis virus (LCMV) Lymphoid tissue inducer (LTi) Lymphotoxin-a1b2(LTa1b2) Macrophage inflammatory protein-1β(MIP-1β) Macrophage inflammatory protein (MIP) Macrophage-colony stimulating factor (CSF-1) Mesenchymal lymphoid tissue organizer (mLTo) Microtubule-associated protein kinase (MAPK), Multiple sclerosis (MS) Multiple myeloma (MM) Myasthenia gravis (MG) Multiple Sclerosis (MS) Myocyte enhancer factor 2 C (MEF2C) Myxovirus (influenza virus) resistance 1(MX1) Non-small cell lung cancer (NSCLC) Non-Hodgkin’s lymphomas (NHL), ”Non-small cell lung carcinoma (NSCLC), Inhibitory antibodies (NAbs)” Nuclear factor of activated T-cells 1(NFATc1) Peripheral blood (PB) Phospho-ERK1/2(pERK1/2) Primary Sjögren syndrome (pSS) Procalcitonin (PCT) Programmed Death (PD)-1 Programmed cell death ligand 1(PD-L1) PR domain zinc finger protein 1(PRDM1) Purinergic receptor P2X7 Regulated upon activation, normal T cells express and presumably secrete (RANTES) Retinoic acid receptor-associated orphan nuclear receptor gamma (RORγ) Rheumatoid arthritis (RA) Seronegative female spouses of HIV-1 seropositive men (HESN) Severe Acute Respiratory Syndrome Coronavirus 2(SARS-CoV-2) Signal transducer and activator of transcription 6(STAT6) Simian immunodeficiency virus (SIV) Spontaneous HIV controllers (HICs) Sprouty2(SPRY2) SRY-related high-mobility-group box 4(SOX4) Stem-like memory T cells (Tscm) Systemic lupus erythematosus (SLE) T cell immunoglobulin and mucin domain 3(TIM-3) T effector memory (CD28- CD95+, Tem) Transcription 3(STAT3) Type I diabetes (T1D) Transforming Growth Factor (TGF) Transcription factor 4(TCF4) Viral loads (VLs) Viral suppressive capacity (VSC) Zhongshan Hospital cohort (ZSHS), Table 1 The profile of CXCR5+ CD8 T cells Note: not applicable (N/A), simian immunodeficiency virus (SIV) or human immunodeficiency virus (HIV), lymphocytic choriomeningitis virus (LCMV), hepatitis B virus (HBV), germinal center (GC), chimeric antigen receptor (CAR), not applicable (N/A), African green monkeys (AGM), antiretroviral therapy (ART), programmed death (PD)-1, programmed cell death ligand 1(PD-L1).”’”Inducible T-cell costimulatory (ICOS), interleukin (IL), Transforming Growth Factor (TGF), C-C chemokine receptor 7(CCR7), potent antiretroviral therapy (HAART), B cell lymphoma 6 protein (BCL6), PR domain zinc finger protein 1(PRDM1), cysteine-X-cysteine motif chemokine ligand (CXCL), Macrophage colony-stimulating factor (CSF-1), and C-C motif chemokine ligand 5(CCL5),””Nuclear factor of activated T-cells 1(NFATc1), cytotoxic T-lymphocyte-associated protein 4(CTLA-4), signal transducer and activator of transcription 6(STAT6), and transcription factor 4(TCF4)””’SRY-related high-mobility-group box 4(SOX4), myocyte enhancer factor 2C (MEF2C), cell division cycle-associated protein 7(CDCA7), Sprouty homolog 2(SPRY2), T cell immunoglobulin and mucin domain-containing protein 3(TIM-3), killer-cell lectin-like receptor subfamily G member 1(KLRG1), inhibitor of DNA binding 2(Id2), viral burden (VLs), HIV-1 group-specific antigen polyprotein (Gag), gastrointestinal (GI), macrophage inflammatory protein-1 beta (MIP-1β), and regulated upon activation, normal T cell expressed and presumably secreted protein (RANTES),”’combination antiretroviral therapy (cART), hepatitis B virus (HBV), alanine aminotransferase (ALT), chronic HBV infection (CHB), hepatocellular carcinoma (HCC), individuals with HCC associated with HBV infection (HBV-HCC), healthy controls (HDs), HIV-positive patients on antiretroviral treatment (ART), and spontaneous HIV controllers (HICs), central memory T cells (Tcm), effector memory T cells (Tem), and viral suppression ability (VSC)”extracellular signal-regulated kinase (ERK), microtubule-associated protein kinase (MAPK), phosphorylated ERK1/2(pERK1/2), engineered CD8 T cells that express CXCR5(CD8hCXCR5), and follicular helper T cells (TFH)””CXCR5+CD8 T cells (TFC), lymph node mononuclear cells (LNMCs), individuals with complete response (CRs), and immune non-responders (INRs), lymph nodes (LN), seronegative female partners of HIV-1 seropositive males (HESN); HIV-unexposed, uninfected healthy women (HU); HIV-infected women receiving antiretroviral therapy (HIV+ART+), and HIV-infected women not treated with antiretroviral therapy (HIV+ART−);””Macrophage inflammatory protein (MIP); follicular CD8-positive T cells (fCD8), broadly neutralizing antibodies (bnAbs), neutralizing antibodies (NAbs); stem-cell memory T cells (Tscm); individuals infected with HIV-2(HIV-2), HIV-1-infected individuals receiving antiretroviral therapy (HIV-1+ART+), HIV-1-infected individuals not exposed to antiretroviral therapy (HIV-1+ART-), and uninfected, HIV-unexposed healthy women (HU)”Friend virus complex (FV), lymph node (LN), HIV-1-seropositive men (HIV-discordant couples)(HESN), HIV-unexposed seronegative women (UH), interferon type 1(IFN-I), IFNα/β receptor 1(IFNAR1), transcription factor (TCF1), IFN-stimulated genes (ISGs),chronic hepatitis B (CHB), myxovirus (influenza virus) resistance 1(MX1), guanylate binding protein (GBP), Interferon-Stimulated Gene 15(ISG15), Follicular dendritic cells (FDCs),P2X7 purinergic receptor, dengue virus serotype 2(DENV2), severe acute respiratory syndrome coronavirus 2(SARS-CoV-2), Epstein-Barr virus (EBV), influenza A virus (FluA), human cytomegalovirus (HCMV), herpes simplex virus (HSV), common variable immunodeficiency (CVID), Down syndrome (DS), Hodgkin’s lymphoma (HL), non-Hodgkin’s lymphomas (NHL), diffuse large B-cell lymphoma (DLBCL), multiple myeloma (MM), and follicular lymphoma (FL) chronic lymphocytic leukemia (CLL), peripheral blood (PB), lymph nodes (LN), hepatocellular carcinoma (HCC), Cancer Genome Atlas (TCGA), Asian Cancer Research Group (ACRG), Zhongshan Hospital cohort (ZSHS), Fudan University Shanghai Cancer Center cohort (FUSCC), non-small cell lung cancer (NSCLC), Cutaneous leishmaniasis (CL), community or hospital acquired pneumonia (CAP, HAP), procalcitonin (PCT), rheumatoid arthritis (RA), primary Sjögren syndrome (pSS),Myasthenia gravis (MG), multiple sclerosis (MS), and dimethyl fumarate (DMF) References Adam L, Rosenbaum P, Quentric P, Parizot C, Bonduelle O, et al. 2021. 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Keyword autoimmunity Authors Affiliations Shun-yu Yao Affiliated First Hospital of Hunan Traditional Chinese Medical College View all articles by this author Yong Peng 0000-0001-8390-7668 [email protected] Affiliated First Hospital of Hunan Traditional Chinese Medical College View all articles by this author Xiuli Zhang Hunan University of Chinese Medicine View all articles by this author Huan Yang Xiangya Hospital Central South University View all articles by this author Sugimoto Kazuo Beijing University of Chinese Medicine Affiliated Dongzhimen Hospital View all articles by this author Jia Liu Beijing University of Chinese Medicine Affiliated Dongzhimen Hospital View all articles by this author Miao-qiao Du Affiliated First Hospital of Hunan Traditional Chinese Medical College View all articles by this author Lan-xin Lin Affiliated First Hospital of Hunan Traditional Chinese Medical College View all articles by this author Quan Chen Affiliated First Hospital of Hunan Traditional Chinese Medical College View all articles by this author Hong Jin Affiliated First Hospital of Hunan Traditional Chinese Medical College View all articles by this author Metrics & Citations Metrics Article Usage 276 views 206 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Shun-yu Yao, Yong Peng, Xiuli Zhang, et al. 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