Cell-mediated Autoimmune Disease Research Articles

Naringin as a natural candidate for anti-autoimmune hepatitis: Inhibitory potency and hepatoprotective mechanism

BackgroundAutoimmune hepatitis (AIH), primarily mediated by T cells, is characterized by liver inflammation. Despite the advancements in understanding its pathogenesis, effective therapeutic options are limited. Naringin, a flavonoid abundant in citrus fruits, is recognized for its anti-inflammatory properties and ability to protect against various inflammatory diseases, including drug-induced liver injury. However, the exact effects of naringin on AIH and the mechanisms involved remain poorly understood. PurposeWe aim to determine the role of naringin in AIH, exploring its targets and actions in this disease. MethodsNetwork pharmacology, molecular docking, and molecular dynamics simulations were utilized to predict the HUB targets connecting naringin, T cell-mediated autoimmune disorders, and AIH. Cellular thermal shift assays were used to determine the binding abilities of naringin with the HUB targets. An in vivo experiment confirmed the impact of naringin treatment on AIH development and underlying mechanisms. ResultsNaringin demonstrated therapeutic effects on ConA-induced AIH. There were 455 shared targets between naringin, T cell-mediated autoimmune diseases, and AIH. Ten HUB genes (AKT1, ALB, IL-6, IL-1β, CTNNB1, TNF, TP53, MAPK3, VEGFA, and JUN) were identified through the PPI network. Gene ontology analysis revealed involvement in gene expression regulation, lipopolysaccharide-mediated signaling, and I-kappa kinase/NFκB signaling. Pathway analysis suggested TNF, Th1/Th2 cell differentiation, and Toll-like receptor pathways, with favorable naringin-HUB gene binding. Molecular docking confirmed albumin (ALB), IL-1β, IL-6, and TNF as primary targets for naringin. Molecular dynamics simulations showed stable binding in ALB-naringin, TNF-naringin, and IL-1β-naringin complexes. Naringin's hepatoprotective effect on AIH was supported by increased serum ALB and decreased hepatic inflammatory cytokines including IL-1β, IL-6, and TNF-α. ConclusionOur data underscore the potential of naringin as a preventive or therapeutical agent in T cell-mediated autoimmune diseases including AIH.

Repurposing of rituximab biosimilars to treat B cell mediated autoimmune diseases.

Rituximab, the first monoclonal antibody approved for the treatment of lymphoma, eventually became one of the most popular and versatile drugs ever in terms of clinical application and revenue. Since its patent expiration, and consequently, the loss of exclusivity of the original biologic, its repurposing as an off-label drug has increased dramatically, propelled by the development and commercialization of its many biosimilars. Currently, rituximab is prescribed worldwide to treat a vast range of autoimmune diseases mediated by B cells. Here, we present a comprehensive overview of rituximab repurposing in 115 autoimmune diseases across 17 medical specialties, sourced from over 1530 publications. Our work highlights the extent of its off-label use and clinical benefits, underlining the success of rituximab repurposing for both common and orphan immune-related diseases. We discuss the scientific mechanism associated with its clinical efficacy and provide additional indications for which rituximab could be investigated. Our study presents rituximab as a flagship example of drug repurposing owing to its central role in targeting cluster of differentiate 20 positive (CD20)B cells in 115 autoimmune diseases.

How persistent infection overcomes peripheral tolerance mechanisms to cause T cell-mediated autoimmune disease.

T cells help orchestrate immune responses to pathogens, and their aberrant regulation can trigger autoimmunity. Recent studies highlight that a threshold number of T cells (a quorum) must be activated in a tissue to mount a functional immune response. These collective effects allow the T cell repertoire to respond to pathogens while suppressing autoimmunity due to circulating autoreactive T cells. Our computational studies show that increasing numbers of pathogenic peptides targeted by T cells during persistent or severe viral infections increase the probability of activating T cells that are weakly reactive to self-antigens (molecular mimicry). These T cells are easily re-activated by the self-antigens and contribute to exceeding the quorum threshold required to mount autoimmune responses. Rare peptides that activate many T cells are sampled more readily during severe/persistent infections than in acute infections, which amplifies these effects. Experiments in mice to test predictions from these mechanistic insights are suggested.

Repositioning the Early Pathology of Type 1 Diabetes to the Extraislet Vasculature.

Type 1 diabetes (T1D) is a prototypic T cell-mediated autoimmune disease. Because the islets of Langerhans are insulated from blood vessels by a double basement membrane and lack detectable lymphatic drainage, interactions between endocrine and circulating T cells are not permitted. Thus, we hypothesized that initiation and progression of anti-islet immunity required islet neolymphangiogenesis to allow T cell access to the islet. Combining microscopy and single cell approaches, the timing of this phenomenon in mice was situated between 5 and 8 wk of age when activated anti-insulin CD4 T cells became detectable in peripheral blood while peri-islet pathology developed. This "peri-insulitis," dominated by CD4 T cells, respected the islet basement membrane and was limited on the outside by lymphatic endothelial cells that gave it the attributes of a tertiary lymphoid structure. As in most tissues, lymphangiogenesis seemed to be secondary to local segmental endothelial inflammation at the collecting postcapillary venule. In addition to classic markers of inflammation such as CD29, V-CAM, and NOS, MHC class II molecules were expressed by nonhematopoietic cells in the same location both in mouse and human islets. This CD45- MHC class II+ cell population was capable of spontaneously presenting islet Ags to CD4 T cells. Altogether, these observations favor an alternative model for the initiation of T1D, outside of the islet, in which a vascular-associated cell appears to be an important MHC class II-expressing and -presenting cell.

A novel subpopulation of monocytes with a strong interferon signature indicated by SIGLEC-1 is present in patients with in recent-onset type 1 diabetes.

Type 1 diabetes is a T cell-mediated autoimmune disease characterised by pancreatic beta cell destruction. In this study, we explored the pathogenic immune responses in initiation of type 1 diabetes and new immunological targets for type 1 diabetes prevention and treatment. We obtained peripheral blood samples from four individuals with newly diagnosed latent autoimmune diabetes in adults (LADA) and from four healthy control participants. Single-cell RNA-sequencing (scRNA-seq) was performed on peripheral blood mononuclear cells to uncover transcriptomic profiles of early LADA. Validation was performed through flow cytometry in a cohort comprising 54 LADA, 17 adult-onset type 2 diabetes, and 26 healthy adults, matched using propensity score matching (PSM) based on age and sex. A similar PSM method matched 15 paediatric type 1 diabetes patients with 15 healthy children. Further flow cytometry analysis was performed in both peripheral blood and pancreatic tissues of non-obese diabetic (NOD) mice. Additionally, cell adoptive transfer and clearance assays were performed in NOD mice to explore the role of this monocyte subset in islet inflammation and onset of type 1 diabetes. The scRNA-seq data showed that upregulated genes in peripheral T cells and monocytes from early-onset LADA patients were primarily enriched in the IFN signalling pathway. A new cluster of classical monocytes (cluster4) was identified, and the proportion of this cluster was significantly increased in individuals with LADA compared with healthy control individuals (11.93% vs 5.93%, p=0.017) and that exhibited a strong IFN signature marked by SIGLEC-1 (encoding sialoadhesin). These SIGLEC-1+ monocytes expressed high levels of genes encoding C-C chemokine receptors 1 or 2, as well as genes for chemoattractants for T cells and natural killer cells. They also showed relatively low levels of genes for co-stimulatory and HLA molecules. Flow cytometry analysis verified the elevated levels of SIGLEC-1+ monocytes in the peripheral blood of participants with LADA and paediatric type 1 diabetes compared with healthy control participants and those with type 2 diabetes. Interestingly, the proportion of SIGLEC-1+ monocytes positively correlated with disease activity and negatively with disease duration in the LADA patients. In NOD mice, the proportion of SIGLEC-1+ monocytes in the peripheral blood was highest at the age of 6 weeks (16.88%), while the peak occurred at 12 weeks in pancreatic tissues (23.65%). Adoptive transfer experiments revealed a significant acceleration in diabetes onset in the SIGLEC-1+ group compared with the SIGLEC-1- or saline control group. Our study identified a novel group of SIGLEC-1+ monocytes that may serve as an important indicator for early diagnosis, activity assessment and monitoring of therapeutic efficacy in type 1 diabetes, and may also be a novel target for preventing and treating type 1 diabetes. RNA-seq data have been deposited in the GSA human database ( https://ngdc.cncb.ac.cn/gsa-human/ ) under accession number HRA003649.

Expression of lymphocyte activation gene-3 on CD4+T cells is regulated by cytokine interleukin-18 in myasthenia gravis

Myasthenia gravis (MG) is a T cell-dependent, B cell-mediated, and complement-dependent autoimmune disease. Lymphocyte activation gene-3 (LAG-3; CD223) is an immune checkpoint protein that plays an important role in maintaining autoimmune tolerance and homeostasis. To investigate the cytokine-regulated expression pattern of LAG-3, CD4+T cells were sorted from the peripheral blood of healthy volunteers by density gradient centrifugation and stimulated with various cytokines in vitro. The expression of membrane LAG-3 (mLAG-3), membrane a disintegrin and metallopeptidase domain10 (mADAM10) and membrane ADAM17 (mADAM17) on CD4+T cells was detected by flow cytometry; the concentration of soluble LAG-3 (sLAG-3) was detected by ELISA; and the relative expression of genes at the transcriptional level was detected by fluorescence quantitative RT-PCR (qRT-PCR). sLAG-3 levels were significantly increased in the peripheral plasma of AChR Ab-positive patients with MG compared to healthy volunteers, while the percentage of mLAG-3 expression on CD4+T lymphocytes in the peripheral blood of patients with MG was significantly reduced. IL-18 inhibited mLAG-3 levels on CD4+T cells in a concentration-dependent manner. Additionally, the concentration of sLAG-3 in the supernatant increased. After PHA and IL-18 stimulation, ADAM10 and ADAM17 also increased compared to those in the PHA-active group. Moreover, there were significant differences in the expression of mADAM10 and mADAM17 in CD4+T lymphocytes between patients with MG and healthy volunteers. These results suggest that IL-18 may regulate the expression pattern of mLAG-3 in CD4+T cells and sLAG-3 via ADAM10- and ADAM17-mediated pathways, thus affecting the immune effects of CD4+T cells. This study provides a preliminary exploration of the upstream regulatory molecules of the LAG-3 and IL-18/LAG-3 signalling pathways for potential targeted therapy of autoimmune diseases in the future.

VITAMIN D DEFICIENCY IN PATIENTS WITH ALOPECIA AERATA, AND RESPONSIVENESS TO VITAMIN D ANALOGUES: A SYSTEMATIC REVIEW

Background: Alopecia areata (AA) is a type of T cell-mediated autoimmune disease involving hair follicles (HF), which is manifested as round or oval non-cicatricial alopecia on the head, but also can occur anywhere in the body. The global morbidity of AA ranges from 0.1% to 0.2%, affecting the population of all ages without significant difference between genders. Vitamin D deficiency is common in alopecia aerata, but there is limited evidence to determine whether vitamin D supplementation improves alopecia aerata currently. The aim: This study aims to show vitamin D deficiency in patients with alopecia aerata, and responsiveness to vitamin D analogues. Methods: By comparing itself to the standards set by the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) 2020, this study was able to show that it met all of the requirements. So, the experts were able to make sure that the study was as up-to-date as it was possible to be. For this search approach, publications that came out between 2013 and 2023 were taken into account. Several different online reference sources, like Pubmed and SagePub, were used to do this. It was decided not to take into account review pieces, works that had already been published, or works that were only half done. Result: In the PubMed database, the results of our search brought up 46 articles, whereas the results of our search on SagePub brought up 74 articles. The results of the search conducted for the last year of 2013 yielded a total 43 articles for PubMed and 20 articles for SagePub. The result from title screening, a total 20 articles for PubMed and 3 articles for SagePub. In the end, we compiled a total of 10 papers. We included five research that met the criteria. Conclusion: Vitamin D deficiency in alopecia aerata correlates inversely with disease severity and duration. Vitamin D receptor expression is reduced in alopecia aerata and inversely correlate with inflammation histologically but does not correlates with serum vitamin D levels, severity, pattern, or duration of illness.

The lncRNA Malat1 inhibits miR-15/16 to enhance cytotoxic T cell activation and memory cell formation.

Proper activation of cytotoxic T cells via the T cell receptor and the costimulatory receptor CD28 is essential for adaptive immunity against viruses, intracellular bacteria, and cancers. Through biochemical analysis of RNA:protein interactions, we uncovered a non-coding RNA circuit regulating activation and differentiation of cytotoxic T cells composed of the long non-coding RNA Malat1 (Metastasis Associated Lung Adenocarcinoma Transcript 1) and the microRNA family miR-15/16. miR-15/16 is a widely and highly expressed tumor suppressor miRNA family important for cell proliferation and survival. miR-15/16 play important roles in T cell responses to viral infection, including the regulation of antigen-specific T cell expansion and memory. Comparative Argonaute-2 high-throughput sequencing of crosslinking immunoprecipitation (AHC) combined with gene expression profiling in normal and miR-15/16-deficient mouse T cells revealed a large network of hundreds of direct miR-15/16 target mRNAs, many with functional relevance for T cell activation, survival and memory formation. Among these targets, Malat1 contained the largest absolute magnitude miR-15/16-dependent AHC peak. This binding site was among the strongest lncRNA:miRNA interactions detected in the T cell transcriptome. We used CRISPR targeting with homology directed repair to generate mice with a 5-nucleotide mutation in the miR-15/16-binding site in Malat1. This mutation interrupted Malat1:miR-15/16 interaction, and enhanced the repression of other miR-15/16 target genes, including CD28. Interrupting Malat1 interaction with miR-15/16 decreased cytotoxic T cell activation, including the expression of interleukin 2 (IL-2) and a broader CD28-responsive gene program. Accordingly, Malat1 mutation diminished memory cell persistence in mice following LCMV Armstrong and Listeria monocytogenes infection. This study marks a significant advance in the study of long non-coding RNAs in the immune system by ascribing cell-intrinsic, sequence-specific in vivo function to Malat1. These findings have implications for T cell-mediated autoimmune diseases, antiviral and anti-tumor immunity, as well as lung adenocarcinoma and other malignancies where Malat1 is overexpressed.

The lncRNA Malat1 inhibits miR-15/16 to enhance cytotoxic T cell activation and memory cell formation

Proper activation of cytotoxic T cells via the T cell receptor and the costimulatory receptor CD28 is essential for adaptive immunity against viruses, intracellular bacteria, and cancers. Through biochemical analysis of RNA:protein interactions, we uncovered a non-coding RNA circuit regulating activation and differentiation of cytotoxic T cells composed of the long non-coding RNA Malat1 (Metastasis Associated Lung Adenocarcinoma Transcript 1) and the microRNA family miR-15/16. miR-15/16 is a widely and highly expressed tumor suppressor miRNA family important for cell proliferation and survival. miR-15/16 play important roles in T cell responses to viral infection, including the regulation of antigen-specific T cell expansion and memory. Comparative Argonaute-2 high-throughput sequencing of crosslinking immunoprecipitation (AHC) combined with gene expression profiling in normal and miR-15/16-deficient mouse T cells revealed a large network of hundreds of direct miR-15/16 target mRNAs, many with functional relevance for T cell activation, survival and memory formation. Among these targets, Malat1 contained the largest absolute magnitude miR-15/16-dependent AHC peak. This binding site was among the strongest lncRNA:miRNA interactions detected in the T cell transcriptome. We used CRISPR targeting with homology directed repair to generate mice with a 5-nucleotide mutation in the miR-15/16-binding site in Malat1. This mutation interrupted Malat1:miR-15/16 interaction, and enhanced the repression of other miR-15/16 target genes, including CD28. Interrupting Malat1 interaction with miR-15/16 decreased cytotoxic T cell activation, including the expression of interleukin 2 (IL-2) and a broader CD28-responsive gene program. Accordingly, Malat1 mutation diminished memory cell persistence in mice following LCMV Armstrong and Listeria monocytogenes infection. This study marks a significant advance in the study of long non-coding RNAs in the immune system by ascribing cell-intrinsic, sequence-specific in vivo function to Malat1. These findings have implications for T cell-mediated autoimmune diseases, antiviral and anti-tumor immunity, as well as lung adenocarcinoma and other malignancies where Malat1 is overexpressed.

Inhibition of SUMOylation promotes remyelination and reduces IL-17 mediated autoimmune inflammation: Novel approach toward treatment of inflammatory CNS demyelinating disease

Small ubiquitin like modifiers (SUMO) are reversible posttranslational modifiers of intracellular proteins. In the CNS, expression of myelin genes is regulated by state of SUMOylation of their respective transcription factors. In the immune system, deSUMOylation activates innate immune responses and promotes anti-viral immunity. However, the role played by SUMO in an adaptive immune response and in the development of T cell mediated autoimmune disease has not been previously described.TAK981 is a synthetic small molecule which by forming adducts with SUMO proteins prevents SUMOylation. We examined the expression of myelin genes and their transcription factors following culture with TAK981 in Oligodendrocyte Precursor Cells (OPC). We found that myelin basic protein (MBP), a key myelin protein, is upregulated in OPC in the presence of TAK981. We also found increased expression of transcription factors Sox10 and Myrf, which engage in the expression of MBP. In the Cuprizone model of demyelination/remyelination, animals which were treated with TAK981 showed increased remyelination in areas of demyelination and an increase in the number of maturing oligodendrocytes compared to vehicle treated controls. In in vitro cultures of lymphocytes, TAK981 reduced the expression of TH17 in T cells in mice immunized with MOGp35–55. Following in vivo treatment with TAK981, there was a significant reduction in the clinical and pathological severity in mice immunized to develop experimental allergic encephalitis (EAE).The dual effects of deSUMOylation on remyelination and in regulating an autoimmune adaptive response offers a novel approach to the management of human inflammatory demyelinating diseases such as multiple sclerosis.

LncRNA Neat1 targets NonO and miR-128-3p to promote antigen-specific Th17 cell responses and autoimmune inflammation

Long non-coding RNAs (lncRNAs) interaction with RNA-Binding proteins (RBPs) plays an important role in immunological processes. The generation of antigen-specific Th17 cells is closely associated with autoimmune pathogenesis. However, the function of lncRNA-RBP interactions in the regulation of pathogenic Th17 cell responses during autoimmunity remains poorly understood. Here, we found that lncRNA Neat1, highly expressed in Th17 cells, promoted antigen-specific Th17 cell responses. Both global and CD4+ T cell-specific knockdown of Neat1 protected mice against the development of experimental autoimmune uveitis (EAU). Mechanistically, Neat1 regulated RNA-Binding protein NonO, thus relieving IL-17 and IL-23R from NonO-mediated transcriptional repression and supporting antigen-specific Th17 cell responses. In addition, Neat1 also modulated miR-128-3p/NFAT5 axis to increase the expression of IL-17 and IL-23R, leading to augmented Th17 cell responses. Our findings elucidate a previously unrecognized mechanistic insight into the action of Neat1 in promoting antigen-specific Th17 responses and autoimmunity, and may facilitate the development of therapeutic targets for T cell-mediated autoimmune diseases.

MuSK-CAART: A novel precision cellular therapy for muscle-specific tyrosine kinase myasthenia gravis

Chimeric autoantibody receptor (CAAR) T cells are a novel genetically-engineered T cell immunotherapy that aims to durably eliminate antigen-specific B cells while sparing healthy B cells, ideally leading to safe and lasting remission of B cell-mediated autoimmune diseases with a one-time infusion. We describe the preclinical development of muscle-specific tyrosine kinase CAAR T cells (MuSK-CAART) for the treatment of MuSK myasthenia gravis, a debilitating autoantibody-mediated disease that causes potentially life-threatening muscle weakness.

Increased SLAMF7+CD8+ T cells are associated with the pathogenesis of experimental autoimmune pancreatitis in mice

BackgroundIgG4-related autoimmune pancreatitis (AIP) is considered to be a T cell-mediated autoimmune disease. However, CD8+ T cells have only received brief mention, and have yet to be completely studied. The study aimed to investigate the expression of signaling lymphocytic activation molecule family 7 (SLAMF7) on CD8+ T cells and the features of SLAMF7+CD8+ T cells in MRL/Mp mice with AIP. MethodsA murine model of AIP was established by intraperitoneal injection with polyinosinic:polycytidylic acid (poly I:C) for 8 weeks. Dexamethasone treatment was daily administrated for the last 2 weeks during a 6-week course of poly I:C. SLAMF7 expression on CD8+ T cells in the spleen and pancreas was detected by flow cytometry. Granzyme B (GZMB) and cytokines including IFN-γ, TNF-α, and IL-2, were monitored in an in vitro T cell activation assay. Dexamethasone suppression assays were performed to downregulate SLAMF7 expression on T cells upon T cell receptor stimulation. ResultsAIP in MRL/Mp mice was induced by repeated intraperitoneal administration of poly I:C and CD8+ T cells were increased in the inflamed pancreas. SLAMF7+CD8+ T cells were elevated in the spleen and pancreas of AIP mice. SLAMF7+CD8+ T subsets produced more GZMB, IFN-γ, TNF-α and IL-2 than SLAMF7−CD8+ T subsets. Dexamethasone treatment ameliorated pancreatic inflammatory and fibrosis of AIP. Dexamethasone could downregulate SLAMF7+CD8+ T cells and reduce GZMB, IFN-γ and TNF-α levels both in vitro and in vivo. ConclusionsIncreased SLAMF7+CD8+ T cells exhibit enhanced cytotoxicity and cytokines secretion capacity, which may be involved in the pathogenesis of AIP.

ASCT2-mediated glutamine uptake promotes Th1 differentiation via ROS-EGR1-PAC1 pathway in oral lichen planus

Oral lichen planus (OLP) is a T cell-mediated autoimmune disease of oral mucosa concerning with the redox imbalance. Although glutamine uptake mediated by alanine-serine-cysteine transporter 2 (ASCT2) is critical to T cell differentiation, the exact mechanism remains ambiguous. Here, we elucidate a novel regulatory mechanism of ASCT2-mediated uptake in the differentiation and proliferation of T cells through maintaining redox balance in OLP. The results of immunohistochemistry (IHC) showed that both ASCT2 and glutaminase (GLS) were obviously upregulated compared to controls in OLP. Moreover, correlation analyses indicated that ASCT2 expression was significantly related to GLS level. Interestingly, the upregulation of glutamine metabolism in epithelial layer was consistent with that in lamina propria. Functional assays in vitro revealed the positive association between glutamine metabolism and lymphocytes infiltration. Additionally, multiplex immunohistochemistry (mIHC) uncovered a stronger colocalization among ASCT2 and CD4 and IFN-γ, which was further demonstrated by human Th1 differentiation assay in vitro. Mechanistically, targeting glutamine uptake through interference with ASCT2 using L-γ-Glutamyl-p-nitroanilide (GPNA) decreased the glutamine uptake of T cells and leaded to the accumulation of intracellular reactive oxygen species (ROS), which promoted dual specificity phosphatase 2 (DUSP2/PAC1) expression through activation of early growth response 1 (EGR1) to induce dephosphorylation of signal transducer and activator of transcription 3 (STAT3) and inhibit Th1 differentiation in turn. These results demonstrated that glutamine uptake mediated by ASCT2 induced Th1 differentiation by ROS-EGR1-PAC1 pathway, and restoring the redox dynamic balance through targeting ASCT2 may be a potential treatment for T cell-mediated autoimmune diseases.

A mAb to SIRPα downregulates the priming of naive CD4 + T cell in Primary immune thrombocytopenia

SIRPα is a transmembrane protein that binds the protein tyrosine phosphatases SHP-1 and SHP-2 through its cytoplasmic region and is abundantly expressed on monocytes, dendritic cells, and macrophages. Studies recently showed that SIRPα is essential for priming of CD4 + T cells by DCs and for development of Th17 cell-mediated autoimmune diseases. We have now further evaluated the importance of SIRPα and that of its ligand CD47 in primary immune thrombocytopenia (ITP). In this study, we show that there was a low expression state of SIRPα on the surface of monocytes. Treatment of cells culture from ITP patients with a mAb to SIRPα that blocks the binding of SIRPα to CD47 downregulated the ITP response. The abilities of monocytes from ITP patients to stimulate an allogenic MLR were reduced. The proliferation of, and production of IL-2, by CD4 + T cells from ITP patients were inhibited, the Treg cell numbers and the production of IL-10 pairs were upregulated, and the production of TGF-β not was inhibited, by a mAb to SIRPα. Moreover, a mAb to SIRPα, the expression of HLA-DR and CD86 were markedly inhibited and the expression of CD80 was slightly upregulated, on the surface of CD14 + monocytes from ITP patients as compared with healthy subjects. However, blockade of SIRPα increased the secretion of TLR-dependent cytokines TNF-α, IL-6 and IL-1β by PBMCs, which may be considered as a reserve in response to danger signals. These results suggest that SIRPα on monocytes is essential for the priming of naive T cells and the development of ITP. Therefore, SIRPα is a potential therapeutic target for ITP and other autoimmune diseases.

Oral administration of procyanidin B2 3,3"-di-O-gallate ameliorates experimental autoimmune encephalomyelitis through immunosuppressive effects on CD4+ T cells by regulating glycolysis

Multiple Sclerosis (MS) is a chronic autoimmune disease of the central nervous system caused by the excessive activation of T cells. Procyanidins are polyphenols that exhibit anti-inflammatory activity. Procyanidin B2 (PCB2) gallate [specifically, PCB2 3,3″-di-O-gallate (PCB2DG)] inhibits cytokine production in T cells by suppressing the acceleration of glycolysis. In this study, we determined the effect of PCB2DG on T cell-mediated autoimmune disease in vivo. We examined the immunosuppressive effects of PCB2DG using an experimental autoimmune encephalomyelitis (EAE) model, which is a classic animal model for MS. Our results indicated that the clinical score for EAE symptoms improved significantly following the oral administration of PCB2DG. This effect was associated with the suppression of T cell-mediated cytokines (e.g., IFN-γ, TNF-α, and IL-17) and infiltrating T cells into the spinal cord, which ameliorated spinal cord injury. In addition, spleen cell culture experiments revealed that the increase of T cell-mediated pro-inflammatory cytokines in EAE mice was significantly decreased following PCB2DG treatment. We further analyzed the glycolytic activity of spleen cells to identify the mechanism of the immunosuppressive effects of PCB2DG. The production of lactate and the expression of glycolytic enzymes and transporters were increased following EAE induction, but not in PCB2DG-treated EAE mice. Collectively, our results indicate that a dietary polyphenol, which has a unique structure, improves the onset of EAE symptoms and inhibits the excessive activation of T cells by influencing glycolysis.

M6A mRNA modification potentiates Th17 functions to inflame autoimmunity.

N6-methyladenosine (m6A), the most common and abundant epigenetic RNA modification, governs mRNA metabolism to determine cell differentiation, proliferation and response to stimulation. m6A methyltransferase METTL3 has been reported to control T cell homeostasis and sustain the suppressive function of regulatory T cells (Tregs). However, the role of m6A methyltransferase in other subtypes of T cells remains unknown. T helper cells 17 (Th17) play a pivotal role in host defense and autoimmunity. Here, we found that the loss of METTL3 in T cells caused serious defect of Th17 cell differentiation, and impeded the development of experimental autoimmune encephalomyelitis (EAE). We generated Mettl3f/fIl17aCre mice and observed that METTL3 deficiency in Th17 cells significantly suppressed the development of EAE and displayed less Th17 cell infiltration into central nervous system (CNS). Importantly, we demonstrated that depletion of METTL3 attenuated IL-17A and CCR5 expression by facilitating SOCS3 mRNA stability in Th17 cells, leading to disrupted Th17 cell differentiation and infiltration, and eventually attenuating the process of EAE. Collectively, our results highlight that m6A modification sustains Th17 cell function, which provides new insights into the regulatory network of Th17 cells, and also implies a potential therapeutic target for Th17 cell mediated autoimmune disease.

JAK2/STAT5 inhibition protects mice from experimental autoimmune encephalomyelitis by modulating T cell polarization

Multiple sclerosis (MS) has been considered as a T cell-mediated autoimmune disease. However, the signaling pathways regulating effector T cells in MS have yet to be elucidated. Janus kinase 2 (JAK2) plays a crucial role in hematopoietic/immune cytokine receptor signal transduction. Here, we tested the mechanistic regulation of JAK2 and the therapeutic potential of pharmacological JAK2 inhibition in MS. Both inducible whole-body JAK2 knockout and T cell-specific JAK2 knockout completely prevented the onset of experimental autoimmune encephalomyelitis (EAE), a widely used MS animal model. Mice with JAK2 deficiency in T cells exhibited minimal demyelination and minimal CD45+ leukocyte infiltration in the spinal cord, accompanied by a remarkable reduction of T helper cell type 1 (TH1) and type 17 (TH17) in the draining lymph nodes and spinal cord. In vitro experiments showed that disruption of JAK2 markedly suppressed TH1 differentiation and IFNγ production. The phosphorylation of signal transducer and activator of transcription 5 (STAT5) was reduced in JAK2 deficient T cells, while STAT5 overexpression significantly increased TH1 and IFNγ production in STAT5 transgenic mice. Consistent with these results, JAK1/2 inhibitor baricitinib or selective JAK2 inhibitor fedratinib attenuated the frequencies of TH1 as well as TH17 in the draining lymph nodes and alleviated the EAE disease activity in mice. Our findings suggest that overactive JAK2 signaling in T lymphocytes is the culprit in EAE, which may serve as a potent therapeutic target for autoimmune disease.

Reactive oxygen species formation and its effect on CD4+ T cell-mediated inflammation.

Reactive oxygen species (ROS) are produced both enzymatically and non-enzymatically in vivo. Physiological concentrations of ROS act as signaling molecules that participate in various physiological and pathophysiological activities and play an important role in basic metabolic functions. Diseases related to metabolic disorders may be affected by changes in redox balance. This review details the common generation pathways of intracellular ROS and discusses the damage to physiological functions when the ROS concentration is too high to reach an oxidative stress state. We also summarize the main features and energy metabolism of CD4+ T-cell activation and differentiation and the effects of ROS produced during the oxidative metabolism of CD4+ T cells. Because the current treatment for autoimmune diseases damages other immune responses and functional cells in the body, inhibiting the activation and differentiation of autoreactive T cells by targeting oxidative metabolism or ROS production without damaging systemic immune function is a promising treatment option. Therefore, exploring the relationship between T-cell energy metabolism and ROS and the T-cell differentiation process provides theoretical support for discovering effective treatments for T cell-mediated autoimmune diseases.

The investigation of selective sphingosine-1 phosphate receptor 1&4 modulator to treat alopecia areata mouse model

Abstract Alopecia areata (AA) is a T cell mediated autoimmune disease characterized phenotypically by hair loss. NKG2D +CD8 +T cells is involved in the pathogenesis of AA. Sphingosine-1 phosphate (S1P) is a biologically active metabolite of cell membrane sphingolipids, which is essential for immune cell transport, and is known to be mainly involved in immune and inflammatory reactions. Due to involvement of S1P receptor (S1PR) in the immune system, S1PR modulator is being investigated for application in multiple sclerosis and other conditions. Among the five S1PRs, S1PRs 1&4 modulator (NXC736, Nextgen Bioscience, South Korea) was used to confirm its efficacy in the treatment of AA. AA lesion size measurement, disease-free ratio, immunohistochemistry and flow cytometry were used for analysis method. After oral administration of NXC736 for 84 days to AA mice, it was confirmed that the AA lesion area and disease-free ratio were significantly decreased compared to control group, and the infiltration of CD8 +T cells in the lesion skin was also significantly decreased. In addition, NKG2D level was decreased in effector CD8 +T cells. According to this result, we speculate that S1PR 1&4 modulator can be used as a promising treatment for AA. Supported by Nextgen Bioscience