Pathogenic Immune Cells Research Articles

Metabolic regulation and function of T helper cells in neuroinflammation

Neuroinflammatory conditions such as multiple sclerosis (MS) are initiated by pathogenic immune cells invading the central nervous system (CNS). Autoreactive CD4+ T helper cells are critical players that orchestrate the immune response both in MS and in other neuroinflammatory autoimmune diseases including animal models that have been developed for MS. T helper cells are classically categorized into different subsets, but heterogeneity exists within these subsets. Untangling the more complex regulation of these subsets will clarify their functional roles in neuroinflammation. Here, we will discuss how differentiation, immune checkpoint pathways, transcriptional regulation and metabolic factors determine the function of CD4+ T cell subsets in CNS autoimmunity. T cells rely on metabolic reprogramming for their activation and proliferation to meet bioenergetic demands. This includes changes in glycolysis, glutamine metabolism and polyamine metabolism. Importantly, these pathways were recently also implicated in the fine tuning of T cell fate decisions during neuroinflammation. A particular focus of this review will be on the Th17/Treg balance and intra-subset functional states that can either promote or dampen autoimmune responses in the CNS and thus affect disease outcome. An increased understanding of factors that could tip CD4+ T cell subsets and populations towards an anti-inflammatory phenotype will be critical to better understand neuroinflammatory diseases and pave the way for novel treatment paradigms.

Effect of hyaluronic acid on cytokines and immune cells change in patients of knee osteoarthritis

PurposeTo evaluate the changes of cytokines and immune cells after Intra-articular hyaluronic acid(IAHA)injections in patients with knee osteoarthritis (KOA).Patients and MethodsSixteen patients were included in the study, with a total of 65 IAHA injections. The Numeric Rating Scale (NRS) and Lysholm scores were evaluated at each visit. The immune cells and 14 cytokines of synovial fluid were analyzed at each visit. The association between immune cells and cytokines were examined.ResultsIL-6 and IL-8 were the most common cytokines in the synovial fluid of KOA patients. The synovial fluid was orchestrated by macrophages (69%) and Lymphocytes (18%). Neutrophils were less to count of the total cell population (< 2%). The cytokines decreased significantly after the first injection and then tended to be stable. Lymphocytes increased a lot, while Macrophages decreased in the early stage, then increased after multiple injections. The proposition of M1 decreased in the early stage, then increased after multiple injections, while M2 increased consistently. M1 and M2 were positively associated with IL-6 and IL-8.ConclusionThe synovial fluid of KOA patients was orchestrated by macrophages (69%) and Lymphocytes (18%) and cytokines like IL-6 and IL-8. IAHA may play an anti-inflammatory functional role through the decreased production of IL-6 and IL-8 by macrophages through polarization. The results from this study partially revealed the effect of IAHA on cytokines and immune cells change in KOA patients, and therapies targeting pathogenic cytokines and immune cells might be used to attenuate the knee joint inflammation and release pain.Trial registrationChiCTR2100050133; date registered 17 August 2021.

Identification of Pathogenic Immune Cell Subsets Associated With Checkpoint Inhibitor-Induced Myocarditis.

Immune checkpoint inhibitors (ICIs) are monoclonal antibodies used to activate the immune system against tumor cells. Despite therapeutic benefits, ICIs have the potential to cause immune-related adverse events such as myocarditis, a rare but serious side effect with up to 50% mortality in affected patients. Histologically, patients with ICI myocarditis have lymphocytic infiltrates in the heart, implicating T cell-mediated mechanisms. However, the precise pathological immune subsets and molecular changes in ICI myocarditis are unknown. To identify immune subset(s) associated with ICI myocarditis, we performed time-of-flight mass cytometry on peripheral blood mononuclear cells from 52 individuals: 29 patients with autoimmune adverse events (immune-related adverse events) on ICI, including 8 patients with ICI myocarditis, and 23 healthy control subjects. We also used multiomics single-cell technology to immunophenotype 30 patients/control subjects using single-cell RNA sequencing, single-cell T-cell receptor sequencing, and cellular indexing of transcriptomes and epitopes by sequencing with feature barcoding for surface marker expression confirmation. To correlate between the blood and the heart, we performed single-cell RNA sequencing/T-cell receptor sequencing/cellular indexing of transcriptomes and epitopes by sequencing on MRL/Pdcd1-/- (Murphy Roths large/programmed death-1-deficient) mice with spontaneous myocarditis. Using these complementary approaches, we found an expansion of cytotoxic CD8+ T effector cells re-expressing CD45RA (Temra CD8+ cells) in patients with ICI myocarditis compared with control subjects. T-cell receptor sequencing demonstrated that these CD8+ Temra cells were clonally expanded in patients with myocarditis compared with control subjects. Transcriptomic analysis of these Temra CD8+ clones confirmed a highly activated and cytotoxic phenotype. Longitudinal study demonstrated progression of these Temra CD8+ cells into an exhausted phenotype 2 months after treatment with glucocorticoids. Differential expression analysis demonstrated elevated expression levels of proinflammatory chemokines (CCL5/CCL4/CCL4L2) in the clonally expanded Temra CD8+ cells, and ligand receptor analysis demonstrated their interactions with innate immune cells, including monocytes/macrophages, dendritic cells, and neutrophils, as well as the absence of key anti-inflammatory signals. To complement the human study, we performed single-cell RNA sequencing/T-cell receptor sequencing/cellular indexing of transcriptomes and epitopes by sequencing in Pdcd1-/- mice with spontaneous myocarditis and found analogous expansions of cytotoxic clonal effector CD8+ cells in both blood and hearts of such mice compared with controls. Clonal cytotoxic Temra CD8+ cells are significantly increased in the blood of patients with ICI myocarditis, corresponding to an analogous increase in effector cytotoxic CD8+ cells in the blood/hearts of Pdcd1-/- mice with myocarditis. These expanded effector CD8+ cells have unique transcriptional changes, including upregulation of chemokines CCL5/CCL4/CCL4L2, which may serve as attractive diagnostic/therapeutic targets for reducing life-threatening cardiac immune-related adverse events in ICI-treated patients with cancer.

Increased Development of Th1, Th17, and Th1.17 Cells Under T1 Polarizing Conditions in Juvenile Idiopathic Arthritis.

In juvenile idiopathic arthritis (JIA) inflammatory T cells and their produced cytokines are drug targets and play a role in disease pathogenesis. Despite their clinical importance, the sources and types of inflammatory T cells involved remain unclear. T cells respond to polarizing factors to initiate types of immunity to fight infections, which include immunity types 1 (T1), 2 (T2), and 3 (T17). Polarizing factors drive CD4+ T cells towards T helper (Th) cell subtypes and CD8+ T cells towards cytotoxic T cell (Tc) subtypes. T1 and T17 polarization are associated with autoimmunity and production of the cytokines IFNγ and IL-17 respectively. We show that JIA and child healthy control (HC) peripheral blood mononuclear cells are remarkably similar, with the same frequencies of CD4+ and CD8+ naïve and memory T cell subsets, T cell proliferation, and CD4+ and CD8+ T cell subsets upon T1, T2, and T17 polarization. Yet, under T1 polarizing conditions JIA cells produced increased IFNγ and inappropriately produced IL-17. Under T17 polarizing conditions JIA T cells produced increased IL-17. Gene expression of IFNγ, IL-17, Tbet, and RORγT by quantitative PCR and RNA sequencing revealed activation of immune responses and inappropriate activation of IL-17 signaling pathways in JIA polarized T1 cells. The polarized JIA T1 cells were comprised of Th and Tc cells, with Th cells producing IFNγ (Th1), IL-17 (Th17), and both IFNγ-IL-17 (Th1.17) and Tc cells producing IFNγ (Tc1). The JIA polarized CD4+ T1 cells expressed both Tbet and RORγT, with higher expression of the transcription factors associated with higher frequency of IL-17 producing cells. T1 polarized naïve CD4+ cells from JIA also produced more IFNγ and more IL-17 than HC. We show that in JIA T1 polarization inappropriately generates Th1, Th17, and Th1.17 cells. Our data provides a tool for studying the development of heterogeneous inflammatory T cells in JIA under T1 polarizing conditions and for identifying pathogenic immune cells that are important as drug targets and diagnostic markers.

Abstract 3539: IL-12 overcomes T-cell immune suppression by the B-ALL microenvironment

Abstract Leukemia remains one of the leading causes of disease-related deaths in children. Recent clinical advancements in both cell-directed and antibody therapies for B-cell leukemias demonstrate the importance of the immune system in eliciting anti-leukemia activity. Yet, there are still patients who suffer relapse with these treatments, which underscores the need to better understand immune evasion by leukemia cells and the need to develop more effective therapies. Although IL-12 has been well-studied in the context of pathogenic infections and immune cells, we previously published that IL-12 potently promotes B-ALL clearance in immune competent mice via increased T-cell activation. To further characterize the role of IL-12 in leukemia control, we examined the bone marrow of immune competent mice with B-ALL using an extensive flow cytometry panel. From these studies, we observed both an increase in T-cell and dendritic cell (DC) numbers and augmented DC activation in rIL-12p70 treated WT mice. Furthermore, rIL-12p70 treatment of WT mice with B-ALL exhibited increased GM-CSF, IL-2, IL-1β, CXCL2, CCL12, and IFN-gamma levels in the bone marrow microenvironment. In these experiments, we also analyzed gene expression profiles in T-cells. The expression of exhaustion-associated genes, including Lag3, Pcdc1, and Tigit, was higher in T-cells recovered from untreated mice with B-ALL relative to those from mice without leukemia. These data are consistent with observations made from single cell RNA-sequencing studies of children with B-ALL, where it was revealed that immune cell exhaustion was present at higher levels in those with measurable disease after induction therapy. Treatment of mice with IL-12 abrogated the leukemia induced increases in exhaustion-associated gene expression. Mechanistically, we observed that when T-cells are stimulated in vitro in B-ALL supernatant there is a reduction in the surface expression of the T-cell activation marker, CD44, and marker of degranulation, CD107b. Jurkat T-cells expressing NFAT or NF-kB reporter plasmids were used to assess activation of T-cell signaling pathways. In addition to suppressing CD44 and CD107b, we also found that B-ALL-secreted factors also suppress the activation of signaling pathways downstream of the TCR. Considering clinical implications of this discovery, we further explored IL-12 ex vivo in combination with the clinically approved bi-specific T-cell engager, blinatumomab. Notably, B-ALL-secreted factors reduced blinatumomab-mediated T-cell lysis of target cells, which was restored with recombinant IL-12 treatment. Overall, this data shows the potential for IL-12 to be used as an immunotherapeutic in conjunction with other current therapies to overcome T-cell suppression by B-ALL. Citation Format: Rae Hunter, Kathleen Imbach, Jodi Dougan, Priscilla Do, Ashley Townsel, Erik Dreaden, Gregory Gibson, Curtis Henry, Christopher Porter. IL-12 overcomes T-cell immune suppression by the B-ALL microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3539.

Proinflammatory signaling in islet β cells propagates invasion of pathogenic immune cells in autoimmune diabetes.

SUMMARYType 1 diabetes is a disorder of immune tolerance that leads to death of insulin-producing islet β cells. We hypothesize that inflammatory signaling within β cells promotes progression of autoimmunity within the islet microenvironment. To test this hypothesis, we deleted the proinflammatory gene encoding 12/15-lipoxygenase (Alox15) in β cells of non-obese diabetic mice at a pre-diabetic time point when islet inflammation is a feature. Deletion of Alox15 leads to preservation of β cell mass, reduces populations of infiltrating T cells, and protects against spontaneous autoimmune diabetes in both sexes. Mice lacking Alox15 in β cells exhibit an increase in a population of β cells expressing the gene encoding the protein programmed death ligand 1 (PD-L1), which engages receptors on immune cells to suppress autoimmunity. Delivery of a monoclonal antibody against PD-L1 recovers the diabetes phenotype in knockout animals. Our results support the contention that inflammatory signaling in β cells promotes autoimmunity during type 1 diabetes progression.

Identification of Biomarkers Associated With CD4+ T-Cell Infiltration With Gene Coexpression Network in Dermatomyositis.

BackgroundDermatomyositis is an autoimmune disease characterized by damage to the skin and muscles. CD4+ T cells are of crucial importance in the occurrence and development of dermatomyositis (DM). However, there are few bioinformatics studies on potential pathogenic genes and immune cell infiltration of DM. Therefore, this study intended to explore CD4+ T-cell infiltration–associated key genes in DM and construct a new model to predict the level of CD4+ T-cell infiltration in DM.MethodsGSE46239, GSE142807, GSE1551, and GSE193276 datasets were downloaded. The WGCNA and CIBERSORT algorithms were performed to identify the most correlated gene module with CD4+ T cells. Matascape was used for GO enrichment and KEGG pathway analysis of the key gene module. LASSO regression analysis was used to identify the key genes and construct the prediction model. The correlation between the key genes and CD4+ T-cell infiltration was investigated. GSEA was performed to research the underlying signaling pathways of the key genes. The key gene-correlated transcription factors were identified through the RcisTarget and Gene-motif rankings databases. The miRcode and DIANA-LncBase databases were used to build the lncRNA-miRNA-mRNA network.ResultsIn the brown module, 5 key genes (chromosome 1 open reading frame 106 (C1orf106), component of oligomeric Golgi complex 8 (COG8), envoplakin (EVPL), GTPases of immunity-associated protein family member 6 (GIMAP6), and interferon-alpha inducible protein 6 (IFI6)) highly associated with CD4+ T-cell infiltration were identified. The prediction model was constructed and showed better predictive performance in the training set, and this satisfactory model performance was validated in another skin biopsy dataset and a muscle biopsy dataset. The expression levels of the key genes promoted the CD4+ T-cell infiltration. GSEA results revealed that the key genes were remarkably enriched in many immunity-associated pathways, such as JAK/STAT signaling pathway. The cisbp_M2205, transcription factor-binding site, was enriched in C1orf106, EVPL, and IF16. Finally, 3,835 lncRNAs and 52 miRNAs significantly correlated with key genes were used to build a ceRNA network.ConclusionThe C1orf106, COG8, EVPL, GIMAP6, and IFI6 genes are associated with CD4+ T-cell infiltration. The prediction model constructed based on the 5 key genes may better predict the level of CD4+ T-cell infiltration in damaged muscle and lesional skin of DM. These key genes could be recognized as potential biomarkers and immunotherapeutic targets of DM.

Neurosteroid Role in the Integration of Olfactory Immune Responses in Rainbow Trout (Oncorhynchus Mykiss)

The objective of this study is to unravel the integration of olfactory signals involved in the nasal detection of pathogens and the activation of associated physiological responses in Rainbow trout.The infectious pathogen Yersinia ruckeri causes enteric redmouth disease in aquaculture farms worldwide. Recent research shows that olfactory organ of rainbow trout is highly susceptible external tissue like gills or skin due to direct contact with the microbiome‐rich environment. Recent findings have demonstrated that olfactory sensory cells play a key role in early pathogen detection and immune cell activation along with their primary role in detecting environmental stimuli.We hypothesize that olfactory immune responses elicited by Y ruckeri are modulated by neurosteroids. To test our hypothesis, we nasally exposed rainbow trout to Y. ruckeri vaccine or saline and took nose and brain samples at four different time periods (4 hours, 24 hours, 7 days, and 14 days) after exposure. We analyzed fish neurosteroids (cortisol, estradiol, and progesterone) and gene expression of steroidogenic enzymes (p450, 3β HSD, 11β HSD, and 17 β HSD) in nose, olfactory bulb, and rest of the brain. Exposure to Y. rukeri vaccine caused significant changes in tissue neurosteroid production and steroidogenic enzyme expression at different times after exposure.Within the olfactory epithelium (OE), we detected a significant decrease (p = 0.003) in estradiol after 15 min exposure with 26.1 pg/mg tissue and 391.0 pg/mg tissue in treated and control individual respectively. Progesterone (174.83 pg/mg tissue) was significantly (p = 0.004) higher after 4 hours compared to the control (26.5 pg/mg of tissue) and cortisol (10.95 pg/mg of tissue) was significantly lower (p = 0.003) after 14 days in Y. ruckeri‐treated fish compared to the control (78.76 pg/mg of tissue). Within the olfactory bulb (OB), lower concentrations of cortisol and progesterone (5.65 pg/mg tissue and 1.6 pg/mg tissue respectively) were observed after 15 minutes in the Y. ruckeri‐treated fish compared to the control (22.8 pg/mg of tissue and 1.9 pg/mg of tissue, respectively). There was also a higher concentration of estradiol after 15 minutes and 4 hours compared to the control. Lastly, within the rest of brain cortisol (9.1 pg/mg tissue) was significantly higher after 4 hours in vaccine treated fish compared to the control (4.9 pg/mg tissue) and estradiol was significantly lower after 15 minutes in the vaccine group (5.5 pg/mg of tissue), compared to the control (55.9 pg/mg of tissue). However, neurosteroid concentration in the rest of brain was relatively low compared to the OE and OB. The neurosteroids: cortisol, estradiol, and progesterone play many important roles in fish physiology including stress response, cognitive behavioral modulation, and immunological response. Our preliminary results also show a significant differential expression of steroidogenic enzymes after exposure to the vaccine. Altogether, our results demonstrate that neurosteroids play a critical role in the integration of immune olfactory responses in vertebrates.

Clinical Evaluation of Vitamin A Supplementation on Disease Development, Progression and Treatment of Multiple Sclerosis: Current Evidence and Future Perspectives

Vitamin A constitutes an essential nutrient with important actions in immunological responses and the Central Nervous System (CNS). Neuroimmunological functions of vitamin A are mediated through its active metabolite, Retinoic Acid (RA). RA contributes to the regeneration and plasticity of the CNS, exerting also a key role in enhancing tolerance and reducing inflammatory responses by regulating T- and B- cells, as well dendritic cells’ populations. Several important studies have documented low plasma vitamin A levels in patients suffering from Multiple Sclerosis (MS). Vitamin A deficiency also leads to dysregulation of immune tolerance and pathogenic immune cell production in MS. In view of the above, the present review aims to critically summarize and discuss the currently available clinical studies, focusing on the potential beneficial effects of vitamin A on controlling MS pathophysiology. Cochrane Register of Controlled Trials (CENTRAL), BioMed Central, and MEDLINE databases database was thoroughly searched, using relative keywords, in order to identify clinical trials published in English. According to the existing clinical studies, the role of vitamin A in MS could be dual: it may decrease inflammation, while, at the same time, it may increase autoimmunity tolerance, also contributing to brain protection of MS patients. However, it must be stated that, at the present time, there is no clear clinical indication for using vitamin A as a complimentary treatment for MS. Further clinical trials with vitamin A supplementation as a potential cotreatment agent or as an add-on option are strongly recommended.

Periodontal connection with intestinal inflammation: Microbiological and immunological mechanisms.

Humans have coevolved with the trillions of resident microbes that populate every nook and cranny of the body. At each site, the resident microbiota creates a unique ecosystem specialized to its environment, benefiting the development and maintenance of human physiology through harmonious symbiotic relationships with the host. However, when the resident microbiota is perturbed, significant complications may arise with disastrous consequences that affect the local and distant ecosystems. In this context, periodontal disease results in inflammation beyond the oral cavity, such as in the gastrointestinal tract. Accumulating evidence indicates that potentially harmful oral resident bacteria (referred to as pathobionts) and pathogenic immune cells in the oral mucosa can migrate to the lower gastrointestinal tract and contribute to intestinal inflammation. We will review the most recent advances concerning the periodontal connection with intestinal inflammation from microbiological and immunological perspectives. Potential therapeutic approaches that target the connection between the mouth and the gut to treat gastrointestinal diseases, such as inflammatory bowel disease, will be examined. Deciphering the complex interplay between microbes and immunity along the mouth–gut axis will provide a better understanding of the pathogenesis of both oral and gut pathologies and present therapeutic opportunities.

Control of CD4+ T Cell Differentiation and Function by PI3K Isoforms.

The phosphoinositide-3-kinase (PI3K) pathway is a highly conserved intracellular signaling pathway involving numerous key effectors which, in response to diverse extracellular stimuli, modulate the phenotype and function of most mammalian cell types in a pleiotropic manner. PI3K signaling plays a critical role in the development, activation, and differentiation of lymphocytes. In particular, the PI3Kδ and PI3Kγ isoforms have been shown to carry out essential, non-redundant roles in T cells, and therefore, tight regulation of the PI3K pathway is important to maintain the balance between immune tolerance and inflammation. Recent and ongoing efforts to manipulate the biology of T helper cell subsets in the treatment of autoimmune conditions, inflammatory disorders, as well as cancer have shown promising results, and targeting the PI3K pathway may be beneficial in these contexts. However, more insight as to the precise function of individual PI3K isoforms in pathogenic and protective immune cell subsets is still required, and how exactly PI3K signaling is regulated and integrated with classical immune pathways. This chapter provides an overview of the role of PI3K isoforms in the differentiation and function of T helper cell subsets, within the broader context of targeting this pathway to potentially alleviate immunopathology.

Abstract 12876: Identification of Pathogenic Immune Cell Subsets in Immunotherapy-Induced Myocarditis

Introduction: Immune checkpoint inhibitors (ICIs) are monoclonal antibodies used to activate the immune system against tumor cells. Despite therapeutic benefits, ICIs have the potential to cause immune related adverse events (irAE) such as myocarditis, a rare but serious side effect with up to 50% mortality in affected patients. Histologically, patients with ICI myocarditis have lymphocytic infiltrates in the heart, implicating T-cell-mediated mechanisms. However, the precise pathologic immune subsets and molecular changes in ICI myocarditis are unknown. Hypothesis: We hypothesize that ICI myocarditis is associated with significant quantitative and molecular changes in pathogenic immune cell subsets. Methods: To identify immune subset(s) associated with ICI myocarditis, we performed time-of-flight mass cytometry (CyTOF) on peripheral blood mononuclear cells from 40 patients and controls with autoimmune adverse events (irAE) on ICI including four patients with ICI myocarditis. We also profiled 15 patients/controls using single cell T-cell receptor (TCR) sequencing and RNA sequencing (scRNA-seq) with feature barcoding for surface marker expression confirmation. Results: With both methods, we found expansion of cytotoxic CD8+ T effector cells re-expressing CD45RA (Temra CD8+ cells) in ICI myocarditis patients compared to controls. Using TCR sequencing, these CD8+ Temra cells were clonally expanded in myocarditis patients. Transcriptomic analysis of these Temra CD8+ clones confirmed a highly activated and cytotoxic phenotype with expression of granzyme/perforin. Longitudinal study demonstrated progression of these Temra CD8+ cells into an exhausted phenotype two months after treatment with glucocorticoids. Differential expression of proinflammatory chemokines (CCL4/CCL4L2/CCL5) was uncovered in clonally expanded Temra CD8+ cells, and ligand-receptor analysis implicated their regulation of other inflammatory cells such as monocytes and NK cells. Conclusions: Clonal cytotoxic Temra CD8+ cells are significantly increased in patients with ICI myocarditis, and have unique transcriptional changes, including upregulation of chemokines CCL4/CCL4L2/CCL5, which may serve as attractive diagnostic/therapeutic targets.

CD47 antibody blockade suppresses microglia-dependent phagocytosis and monocyte transition to macrophages, impairing recovery in EAE.

Experimental autoimmune encephalomyelitis (EAE) is a well-characterized animal model of multiple sclerosis. During the early phase of EAE, infiltrating monocytes and monocyte-derived macrophages contribute to T cell recruitment, especially CD4+ T cells, into the CNS, resulting in neuronal demyelination; however, in later stages, they promote remyelination and recovery by removal of myelin debris by phagocytosis. Signal regulatory protein α and CD47 are abundantly expressed in the CNS, and deletion of either molecule is protective in myelin oligodendrocyte glycoprotein–induced EAE because of failed effector T cell expansion and trafficking. Here we report that treatment with the function blocking CD47 Ab Miap410 substantially reduced the infiltration of pathogenic immune cells but impaired recovery from paresis. The underlying mechanism was by blocking the emergence of CD11chiMHCIIhi microglia at peak disease that expressed receptors for phagocytosis, scavenging, and lipid catabolism, which mediated clearance of myelin debris and the transition of monocytes to macrophages in the CNS. In the recovery phase of EAE, Miap410 Ab–treated mice had worsening paresis with sustained inflammation and limited remyelination as compared with control Ab–treated mice. In summary, Ab blockade of CD47 impaired resolution of CNS inflammation, thus worsening EAE.

Fighting the uphill battle to cure type 1 diabetes.

Three complementary approaches for type 1 diabetes. Immunotherapy targets the pathogenic immune cells or inflammatory cytokines to revert type 1 diabetes. An artificial pancreas delivers insulin automatically using continuous glucose monitoring, a controlling algorithm, and an insulin pump. Beta cell replacement therapy varies depending on the cell sources: allogeneic, or xenogeneic islet; beta-like cells derived from ESCs or iPSCs.

Effect of switching glatiramer acetate formulation from 20 mg daily to 40 mg three times weekly on immune function in multiple sclerosis.

BackgroundMany RRMS patients who had been treated for over 20 years with GA 20 mg/ml daily (GA20) switched to 40 mg/ml three times-a-week (GA40) to reduce injection-related adverse events. Although GA40 is as effective as GA20 in reducing annualized relapse rate and MRI activity, it remains unknown how switching to GA40 from GA20 affects the development of pathogenic and regulatory immune cells.ObjectiveTo investigate the difference in immunological parameters in response to GA20 and GA40 treatments.MethodsWe analyzed five pro-inflammatory cytokines (IL-1β, IL-23, IL-12, IL-18, TNF-α), and three anti-inflammatory/regulatory cytokines (IL-10, IL-13, and IL-27) in serum. In addition, we analyzed six cytokines (IFN-γ, IL-17A, GM-CSF, IL-10, IL-6, and IL-27) in cultured PBMC supernatants. The development of Th1, Th17, Foxp3 Tregs, M1-like, and M2-like macrophages were examined by flow cytometry. Samples were analyzed before and 12 months post switching to GA40 or GA20.ResultsPro- and anti-inflammatory cytokines were comparable between the GA40 and GA20 groups. Development of Th1, Th17, M1-like macrophages, M2-like macrophages, and Foxp3 Tregs was also comparable between the two groups.ConclusionsThe immunological parameters measured in RRMS patients treated with GA40 three times weekly are largely comparable to those given daily GA20 treatment.

The Interactions Between Candida albicans and Mucosal Immunity.

Mucosa protects the body against external pathogen invasion. However, pathogen colonies on the mucosa can invade the mucosa when the immunosurveillance is compromised, causing mucosal infection and subsequent diseases. Therefore, it is necessary to timely and effectively monitor and control pathogenic microorganisms through mucosal immunity. Candida albicans is the most prevalent fungi on the mucosa. The C. albicans colonies proliferate and increase their virulence, causing severe infectious diseases and even death, especially in immunocompromised patients. The normal host mucosal immune defense inhibits pathogenic C. albicans through stepwise processes, such as pathogen recognition, cytokine production, and immune cell phagocytosis. Herein, the current advances in the interactions between C. albicans and host mucosal immune defenses have been summarized to improve understanding on the immune mechanisms against fungal infections.

Glutamine metabolism is essential for the production of IL-17A in γδ T cells and skin inflammation

γδ T cell is one of the most important pathogenic immune cells in autoimmunity, especially in mucosal and epithelial diseases. Metabolism is essential for the maintenance of immune homeostasis. However, unlike αβ T cells, the metabolic regulation of γδ T cell activation still remain unclear. Here, we identified glutamine metabolism as a critical regulator for the generation of IL-17-producing γδ T cells. Metabolic screening uncovered that amino acids related to glutamine metabolism increased most obviously during γδ T cell activation. Pharmaceutical blocking of glutamine impaired IL-17 production in γδ T cells both in vitro and in vivo. Mechanism studies further revealed that genes downregulated upon glutamine deprivation enriched in IL-17 and IL-23/STAT3 signaling pathways. Consistent with this, the activation of STAT3 was suppressed after glutamine blocking. More importantly, application of glutamine antagonist in vivo alleviated the progression of IL-23 induced psoriatic mice model. In addition, both the glutamine level and the expression of glutamine related enzymes were found higher in psoriasis patients when compared with healthy controls. Therefore, our work identified an important metabolic regulatory pathway in γδ T cell activation and suggested that glutamine metabolism could be used as a target for the treatment of γδ T cell related diseases.

4-Ethylguaiacol modulates neuroinflammation and Th1/Th17 differentiation to ameliorate disease severity in experimental autoimmune encephalomyelitis

BackgroundMultiple sclerosis (MS) is a progressive autoimmune disease characterized by the accumulation of pathogenic inflammatory immune cells in the central nervous system (CNS) that subsequently causes focal inflammation, demyelination, axonal injury, and neuronal damage. Experimental autoimmune encephalomyelitis (EAE) is a well-established murine model that mimics the key features of MS. Presently, the dietary consumption of foods rich in phenols has been reported to offer numerous health benefits, including anti-inflammatory activity. One such compound, 4-ethylguaiacol (4-EG), found in various foods, is known to attenuate inflammatory immune responses. However, whether 4-EG exerts anti-inflammatory effects on modulating the CNS inflammatory immune responses remains unknown. Thus, in this study, we assessed the therapeutic effect of 4-EG in EAE using both chronic and relapsing-remitting animal models and investigated the immunomodulatory effects of 4-EG on neuroinflammation and Th1/Th17 differentiation in EAE.MethodsChronic C57BL/6 EAE and relapsing-remitting SJL/J EAE were induced followed by 4-EG treatment. The effects of 4-EG on disease progression, peripheral Th1/Th17 differentiation, CNS Th1/Th17 infiltration, microglia (MG) activation, and blood-brain barrier (BBB) disruption in EAE were evaluated. In addition, the expression of MMP9, MMP3, HO-1, and Nrf2 was assessed in the CNS of C57BL/6 EAE mice.ResultsOur results showed that 4-EG not only ameliorated disease severity in C57BL/6 chronic EAE but also mitigated disease progression in SJL/J relapsing-remitting EAE. Further investigations of the cellular and molecular mechanisms revealed that 4-EG suppressed MG activation, mitigated BBB disruption, repressed MMP3/MMP9 production, and inhibited Th1 and Th17 infiltration in the CNS of EAE. Furthermore, 4-EG suppressed Th1 and Th17 differentiation in the periphery of EAE and in vitro Th1 and Th17 cultures. Finally, we found 4-EG induced HO-1 expression in the CNS of EAE in vivo as well as in MG, BV2 cells, and macrophages in vitro.ConclusionsOur work demonstrates that 4-EG confers protection against autoimmune disease EAE through modulating neuroinflammation and inhibiting Th1 and Th17 differentiation, suggesting 4-EG, a natural compound, could be potentially developed as a therapeutic agent for the treatment of MS/EAE.

4-Ethylguaiacol modulates neuroinflammation and Th1/Th17 differentiation to ameliorate disease severity in experimental autoimmune encephalomyelitis

Abstract Multiple sclerosis (MS) is a progressive autoimmune disease characterized by the accumulation of pathogenic inflammatory immune cells in the central nervous system (CNS) that subsequently causes focal inflammation, demyelination, and neuronal damage. Experimental Autoimmune Encephalomyelitis (EAE) is a well-established murine model of MS. Presently, growing evidences show that phenolic compounds exert anti-inflammatory effects by inhibiting the production of inflammatory molecules. 4-ethylguaiacol (4-EG), a phenolic compound, which was detected in foods, such as green bell peppers, corns, sesames, and coffee has been shown to possess anti-inflammatory effects through attenuating peripheral immune responses. However, whether 4-EG exerts anti-inflammatory effects on modulating the CNS inflammatory immune responses remains unexplored. In this study we assessed the therapeutic effect of 4-EG in EAE using both chronical and relapsing-remitting animal models. Our results showed that 4-EG not only ameliorated disease severity in chronic EAE but also mitigated disease progression in relapsing-remitting EAE. Further investigations revealed that 4-EG suppressed MG activation, inhibited Th1 and Th17 infiltration, and mitigated BBB disruption in the CNS of EAE. Furthermore, 4-EG suppressed Th1 and Th17 differentiation in the periphery of EAE. Finally, 4-EG induced HO-1 expression in the CNS of EAE as well as in MG and macrophages. In summary, our work demonstrates for the first time that 4-EG confers a protection against autoimmune disease EAE through modulating neuroinflammation and inhibiting Th1/Th17 differentiation, suggesting that 4-EG could be developed as a therapeutic agent for the treatment of MS/EAE.

Single-cell transcriptomics applied to emigrating cells from psoriasis elucidate pathogenic versus regulatory immune cell subsets

In previous human skin single-cell data, inflammatory cells constituted only a small fraction of the overall cell population, such that functional subsets were difficult to ascertain. Our aims were to overcome the aforesaid limitation by applying single-cell transcriptomics to emigrating cells from skin and elucidate exvivo gene expression profiles of pathogenic versus regulatory immune cell subsets in the skin of individuals with psoriasis. We harvested emigrating cells from human psoriasis skin after incubation in culture medium without enzyme digestion or cell sorting and analyzed cells with single-cell RNA sequencing and flow cytometry simultaneously. Unsupervised clustering of harvested cells from psoriasis skin and control skin identified natural killer cells, T-cell subsets, dendritic cell subsets, melanocytes, and keratinocytes in different layers. Comparison between psoriasis cells and control cells within each cluster revealed that (1) cutaneous type 17 T cells display highly differing transcriptome profiles depending on IL-17A versus IL-17F expression and IFN-γ versus IL-10 expression; (2) semimature dendritic cells are regulatory dendritic cells with high IL-10 expression, but a subset of semimature dendritic cells expresses IL-23A and IL-36G in psoriasis; and (3) CCL27-CCR10 interaction is potentially impaired in psoriasis because of decreased CCL27 expression in basal keratinocytes. We propose that single-cell transcriptomics applied to emigrating cells from human skin provides an innovative study platform to compare gene expression profiles of heterogenous immune cells in various inflammatory skin diseases.