Activation Of Th1 Cells Research Articles

Immunomodulatory Effects of Oxylipin 10-HOME Produced by Biofilm Results in Host-Biofilm Interaction in Breast Implant Illness

PURPOSE: The spread of biofilms on medical implants represents one of the principal triggers of persistent and chronic infections in clinical settings. Nearly 300,000 women annually have breast implant surgery in the United States, for reasons including post-mastectomy breast reconstruction, revision of prior augmentation/ reconstruction, cosmetic augmentation, and gender affirmation. There has been increased identification of patients experiencing a constellation of symptoms related to their implants termed as breast implant illness (BII). In this work, we report that bacterial biofilm associated with breast implant, metabolize fatty acid oleic acid present in the breast tissue milieu to oxylipins, one such oxylipin identified from this study is (E)-10-hydroxy-8-octadecenoic acid (10-HOME). We hypothesize that immunomodulatory effects of oxylipin 10-HOME produced by biofilm present on the implant could be a possible etiology for BII pathogenesis. METHOD: Implants, peri-prosthetic tissues and blood was collected from BII subjects (n=46) and two control groups, group I, (non-BII, n=34) patients with breast implants, no BII symptoms. Group II (normal tissue, n = 20), patients without an implant, whose breast tissue was removed due to surgical procedures. A questionnaire developed based on epidemiological studies on BII screened for the commonly reported symptoms associated with BII. Predictive variables included age, diabetes status, co-morbidities, type (smooth/textured) and duration of implant. Scanning electron microscopy (SEM), 16S rRNA (genomic) next generation sequencing (NGS) were used for bacterial biofilm identification. 10-HOME was quantitated through targeted and untargeted lipidomic analyses using LC-MS-MS. RNA-Seq analysis was performed on peri-prosthetic breast tissues. Flow cytometry and mass cytometry (CyToF) were conducted to investigate the role of immune cells. RESULTS: Bacterial biofilm was detected through SEM and 16SrRNA NGS. Bivariate analysis using cross-tabulation was performed between presence of biofilm and the study groups. Using the two-sample test of proportions with z-tests, Staphylococcus epidermidis colonization was observed to be higher in the BII group (73.33%) compared to non-BII group (16.67%, p=0.018) and the normal group (10%, p=0.036). The BII group was 2.4 times more likely to have S. epidermidis colonization compared to the non-BII group (Odds Ratio=2.4). Similarly, when comparing with normal group, the BII group was 3.4 times more likely to have S. epidermidis. Elevated levels of 10-HOME in BII compared to non-BII samples, (p<0.0001) were observed through mass spectrometry. Positive correlation was observed between bacterial abundance and concentration of 10-HOME in BII subjects (R2=0.88). RNA-Seq analysis on peri-prosthetic tissue and flow/ mass cytometry analyses from peripheral blood derived lymphocytes showed increased abundance of CD4+ Th1 cells. Th1 cells have been reported to be activated in auto-immune diseases. No significant difference was observed in the abundance of other Th subtypes (Th2, Th9 and Th22). Oxylipin 10-HOME polarized CD4+ naïve T cells to Th1 subtype in vitro. CONCLUSION: This study investigated the biofilm hypothesis of BII through a biofilm derived immunogenic metabolite. Through a systematic cause-effect based studies, the work shows activation of Th1 cells in presence of 10-HOME. The study provides the first evidence of a possible etiology of BII mediated via bacterial biofilm derived 10-HOME.

Plasma Extracellular Vesicles Play a Role in Immune System Modulation in Minimal Hepatic Encephalopathy.

Minimal hepatic encephalopathy (MHE) is associated with changes in the immune system including an increased pro-inflammatory environment and altered differentiation of CD4+ T lymphocytes. The mechanisms remain unknown. Changes in extracellular vesicle (EV) cargo including proteins and miRNAs could play a main role as mediators of immune system changes associated with MHE. The aim was to assess whether plasma EVs from MHE patients played a role in inducing the pro-inflammatory environment and altered differentiation of CD4+ T lymphocyte subtypes in MHE patients. We characterized the miRNA and protein cargo of plasma EVs from 50 cirrhotic patients (27 without and 23 with MHE) and 24 controls. CD4+ T cells from the controls were cultured with plasma EVs from the three groups of study, and the cytokine release and differentiation to CD4+ T-cell subtypes were assessed. Plasma EVs from MHE patients had altered miRNA and protein contents, and were enriched in inflammatory factors compared to the controls and patients without MHE. EVs from MHE patients modulated the expression of pro-inflammatory IL-17, IL-21, and TNF-α and anti-inflammatory TGF-β in cultured CD4+ T lymphocytes, and increased the proportion of Th follicular and Treg cells and the activation of Th17 cells. In conclusion, plasma EVs could play an important role in the induction of immune changes observed in MHE.

Effects of anti-CD4 antibody treatment on calcium ions influx in peanut-sensitized C3H/HeJ mice

The precise mechanism underlying the effects of anti-CD4 antibody and calcium ions (Ca2+) in peanut allergy remains unknown. C3H/HeJ mice sensitized with peanut protein extract (PPE) were injected with anti-CD4 antibodies for 4 weeks. Stimulation with PPE increased the specific immunoglobulin (IgE), cytokine, histamine, and mMcp-1 levels, upregulated decorin (Dcn) expression, induced Ca2+ inflow in the spleen, and augmented the expression of the transcription factors GATA-3 and Foxp3, which resulted in Th2 and Treg cell activation. Notably, the Ca2+ levels were positively correlated with the histamine, interleukin (IL)-4, IL-5, and IL-13 levels, and negatively correlated with IL-10 levels. However, administration of anti-CD4 antibodies markedly alleviated allergic symptoms, activated T cells, and reduced Ca2+ inflow, cytokine, histamine, mMcp-1, and the IgHG3, CXCL12, MMP2 and FABP4 gene. Our results indicated that anti-CD4 antibodies can ameliorate PPE-induced allergy, which is probably related to the suppression of Ca2+ inflow, and inhibiting histamine, cytokine and IgHG3, CXCL12, MMP2, and FABP4, thus exerting a protective effect against PPE-sensitized food allergy.

Chitosan-coated PLGA nanoparticles for transcutaneous immunization: Skin distribution in lysozyme-sensitized mice

The effect of transcutaneous immunization was studied using a combined system of poly(DL-lactide-co-glycolide) (PLGA) nanoparticles and iontophoresis (IP). Both hen egg-white lysozyme (HEL)-loaded PLGA nanoparticles coated with chitosan hydroxypropyltrimonium chloride and their fluorescent nanoparticles were prepared using an antisolvent diffusion method. Their mean volume diameters were 87.6 ± 38.9 nm and 84.9 ± 27.6 nm, respectively. It was suggested from the results of the ex vivo skin accumulation study using fluorescent nanoparticles that the HEL released from the nanoparticles to the skin surface was efficiently delivered to antigen-presenting cells. HEL-specific IgG1 and IgG2a titers were determined in an in vivo percutaneous immunoreactivity study using lysozyme-sensitized mice. As results, the group using nanoparticles and IP showed 1.33 times higher HEL-specific IgG1 titer than a sham treatment group. The HEL-specific IgG2a titer was 1.36 times higher in the nanoparticles and IP group than in the HEL solution and IP group. It was suggested from the quantification results of total IgE in serum that the combined use of PLGA nanoparticles and IP reduced the total IgE concentration. The level of cytokines may have decreased due to Th1 cell activation and relative suppression of Th2 cells. The cytokine level is presumed to be reduced by activation of Th1 cells and relative suppression of Th2 cells. The histamine amount in plasma and rectal temperature after the induction of anaphylactic shock using lysozyme-sensitized mice were also studied, which indicates that the combined use of PLGA nanoparticles and IP may provide the same therapeutic effect as an injection.

Comprehensive immunophenotypic analysis reveals the pathological involvement of Th17 cells in Graves' disease

Graves' disease (GD) is an organ-specific autoimmune disease, but there are a few studies that have evaluated how immunophenotypes are related to clinical symptoms and intractable pathology, or the effects of treatment on immunophenotypes. We performed peripheral blood immunophenotyping in GD. We assessed the proportion of functional subsets of T helper cells (such as Th1, Th17, Treg and Tfh cells), B cells (Naïve, IgM memory, Class-switched, IgD−CD27− double negative and Plasmablasts cells), Monocytes, Dendritic cells and NK cells, and evaluated the relationship of immunophenotypes with clinical indices, disease activity, risk of relapse, and changes in immunophenotypes after treatment with antithyroid drugs. The activated Th17 cells, activated T follicular helper (Tfh) cells, and IgD−CD27− double-negative B cells were higher in newly onset GD compared with healthy participants. Th17 cells were associated with thyroid autoantibodies, thyroid function, thyroid enlargement, and Graves' Recurrent Events After Therapy (GREAT) score; while double-negative B cells were associated with thyroid autoantibodies. Treatment with antithyroid drugs decreased the activated Tfh cells in parallel with the improvement in thyroid function. However, activated Th17 cells were not associated with clinical improvement and remained unchanged. Peripheral blood immunophenotyping identified the differential involvement of T and B cell subsets in the pathogenesis of GD. Abnormalities in the differentiation of Th17, Tfh, and double-negative B cells reflected the clinical pathology associated with autoantibody production and excess thyroid hormones. And Th17 cells are significantly associated with the marker for resistance to treatment. These results suggest the involvement of Th17 cell activation in the intractable pathology associated with potential immune abnormalities in GD.Clinical trial registration: #UMIN000017726 (Date: June 1st, 2015).

Biomarkers of systemic treatment response in people with psoriasis: a scoping review.

Responses to the systemic treatments commonly used to treat psoriasis vary. Biomarkers that accurately predict effectiveness and safety would enable targeted treatment selection, improved patient outcomes and more cost-effective healthcare. To perform a scoping review to identify and catalogue candidate biomarkers of systemic treatment response in psoriasis for the translational research community. A systematic search of CENTRAL, Embase, LILACS and MEDLINE was performed for relevant articles published between 1990 and December 2021. Eligibility criteria were studies involving patients with psoriasis (any age, n ≥ 50) reporting biomarkers associated with systemic treatment response. The main outcomes were any measure of systemic treatment efficacy or safety. Data were extracted by one reviewer and checked by a second; studies meeting minimal quality criteria (use of methods to control for confounding) were formally assessed for bias. Candidate biomarkers were identified by an expert multistakeholder group using a majority voting consensus exercise and mapped to relevant cellular and molecular pathways. Of 71 included studies (67 studying effectiveness outcomes and eight safety outcomes; four studied both), most reported genomic or proteomic biomarkers associated with response to biologics (48 studies). Methodological or reporting limitations frequently compromised the interpretation of findings, including inadequate control for key covariates, lack of adjustment for multiple testing, and selective outcome reporting. We identified candidate biomarkers of efficacy to tumour necrosis factor inhibitors [variation in CARD14, CDKAL1, IL1B, IL12B and IL17RA loci, and lipopolysaccharide-induced phosphorylation of nuclear factor (NF)-κB in type 2 dendritic cells] and ustekinumab (HLA-C*06:02 and variation in an IL1B locus). None were supported by sufficient evidence for clinical use without further validation studies. Candidate biomarkers were found to be involved in the immune cellular crosstalk implicated in psoriasis pathogenesis, most notably antigen presentation, T helper (Th)17 cell differentiation, positive regulation of NF-κB, and Th17 cell activation. This comprehensive catalogue provides a key resource for researchers and reveals a diverse range of biomarker types and outcomes in the included studies. The candidate biomarkers identified require further evaluation in methodologically robust studies to establish potential clinical utility. Future studies should aim to address the common methodological limitations highlighted in this review to expedite discovery and validation of biomarkers for clinical use. What is already known about this topic? Responses to the systemic treatments commonly used to treat psoriasis vary. Biomarkers that accurately predict effectiveness and safety would enable targeted treatment selection, improved patient outcomes and more cost-effective healthcare. What does this study add? This review provides a comprehensive catalogue of investigated biomarkers of systemic treatment response in psoriasis. A diverse range of biomarker types and outcomes was found in the included studies, serving as a key resource for the translational research community.

Moonlighting glyceraldehyde-3-phosphate dehydrogenase (GAPDH) protein of Lactobacillus gasseri attenuates allergic asthma via immunometabolic change in macrophages

BackgroundThe extra-intestinal effects of probiotics for preventing allergic diseases are well known. However, the probiotic components that interact with host target molecules and have a beneficial effect on allergic asthma remain unknown. Lactobacillus gasseri attenuates allergic airway inflammation through the activation of peroxisome proliferator- activated receptor γ (PPARγ) in dendritic cells. Therefore, we aimed to isolate and investigate the immunomodulatory effect of the PPARγ activation component from L. gasseri.MethodsCulture supernatants of L. gasseri were fractionated and screened for the active component for allergic asthma. The isolated component was subjected to in vitro functional assays and then cloned. The crystal structure of this component protein was determined using X-ray crystallography. Intrarectal inoculation of the active component-overexpressing Clear coli (lipopolysaccharide-free Escherichia coli) and intraperitoneal injection of recombinant component protein were used in a house dust mite (HDM)-induced allergic asthma mouse model to investigate the protective effect. Recombinant mutant component proteins were assayed, and their structures were superimposed to identify the detailed mechanism of alleviating allergic inflammation.ResultsA moonlighting protein, glycolytic glyceraldehyde 3-phosphate dehydrogenase (GAPDH), LGp40, that has multifunctional effects was purified from cultured L. gasseri, and the crystal structure was determined. Both intrarectal inoculation of LGp40-overexpressing Clear coli and intraperitoneal administration of recombinant LGp40 protein attenuated allergic inflammation in a mouse model of allergic asthma. However, CDp40, GAPDH isolated from Clostridium difficile did not possess this anti-asthma effect. LGp40 redirected allergic M2 macrophages toward the M1 phenotype and impeded M2-prompted Th2 cell activation through glycolytic activity that induced immunometabolic changes. Recombinant mutant LGp40, without enzyme activity, showed no protective effect against HDM-induced airway inflammation.ConclusionsWe found a novel mechanism of moonlighting LGp40 in the reversal of M2-prompted Th2 cell activation through glycolytic activity, which has an important immunoregulatory role in preventing allergic asthma. Our results provide a new strategy for probiotics application in alleviating allergic asthma.

Bronchus-associated macrophages efficiently capture and present soluble inhaled antigens and are capable of local Th2 cell activation.

In allergic asthma, allergen inhalation leads to local Th2 cell activation and peribronchial inflammation. However, the mechanisms for local antigen capture and presentation remain unclear. By two-photon microscopy of the mouse lung, we established that soluble antigens in the bronchial airway lumen were efficiently captured and presented by a population of CD11c+ interstitial macrophages with high CX3CR1-GFP and MHC class II expression. We refer to these cells as Bronchus-Associated Macrophages (BAMs) based on their localization underneath the bronchial epithelium. BAMs were enriched in collagen-rich regions near some airway branchpoints, where inhaled antigens are likely to deposit. BAMs engaged in extended interactions with effector Th2 cells and promoted Th2 cytokine production. BAMs were also often in contact with dendritic cells (DCs). After exposure to inflammatory stimuli, DCs migrated to draining lymph nodes, whereas BAMs remained lung resident. We propose that BAMs act as local antigen presenting cells in the lung and also transfer antigen to DCs.

Preeclampsia-Derived Exosomes Imbalance the Activity of Th17 and Treg in PBMCs from Healthy Pregnant Women.

The disturbance of maternofetal immune tolerance is identified as one of the important issues in the pathology of preeclampsia (PE). PE exosomes are believed to possess significant roles in immune abnormalities. In this study, to assess the possible effects of PE exosomes in the pathophysiology of preeclampsia patients, exosomes were isolated from the serum of PE patients and incubated with peripheral blood mononuclear cells (PBMCs) of healthy pregnant women. Also, exosomes from healthy pregnant women were utilized as the control. Th17/Treg ratio in PE and healthy pregnant women and the effects of PE exosomes on expression level of Th17 and Treg transcription factors, as well as their related cytokines in PBMCs of healthy pregnant women, were evaluated. A significant decrease in Treg cell number and increase in Th17 cells and Th17/Treg ratio were observed in PE patients. Following PE-exosome intervention, a significant increase in mRNA expression level of RORγt, IL-17, IL-23, IL-1β, and IL-6, and significant decrease in IL-10 and TGFβ were evident. On the other hand, no significant difference in FoxP3 level was detected. Additionally, increased IL-6, IL-17, IL-23, and IL-1β levels and decreased IL-10 level in the supernatant of cultured PBMCs from healthy pregnant women following PE-exosome intervention were exhibited. However, TGF-β level did not change significantly. Based on our findings, PE exosomes are able to alter the activity of Th17 and Treg cells as well as their related gene expression and cytokine profiles. These findings support the probable role of PE exosomes in PE pathogenesis.

Treatment with butyrate alleviates dextran sulfate sodium and Clostridium difficile-induced colitis by preventing activity of Th17 cells via regulation of SIRT1/mTOR in mice

Inflammatory bowel disease (IBD) patients are particularly vulnerable to infection with Clostridium difficile infection (CDI).Available treatments of IBD with CDI have not effective. Butyrate, the metabolites of microbiota, plays a vital role in maintaining immune homeostasis and potential drugs for treatment of IBD with CDI. The aim of this study was to investigate the effect of butyrate on IBD with CDI. Mice were given dextran sulfate sodium (DSS) and were infected with C. difficile (CD). Butyrate was treated during the study period. Butyrate protected from DSS+CD induced colitis by improving weight loss, survival, colon shorten, activity index score, and suppressing the expression of proinflammatory cytokines including IL-6, IL-17, TNF-α, IL-1β as well as regulating Th17/Treg balance through activation of SIRT1/mTOR. Besides, SR1001, an inhitor of the orphan nuclear receptors retinoic acid-related receptor γt, which is a transcription factor specific to the formation of Th17 cells can suppress the Th17 development and alleviate the DSS+CD induced colitis in mice. Notably, the therapeutic effect of butyrate was revered when disease mice treated with butyrate and Ex-527, a SIRT1 inhibitor. Taken together, we demonstrate that butyrate alleviates dextran sulfate sodium and clostridium difficile induced colitis by preventing Th17 through activation of SIRT1/mTOR.

Mathematical modeling for the combination treatment of IFN-[formula omitted] and anti-PD-1 in cancer immunotherapy

When the immune-checkpoint programmed death-1 (PD-1) binds to its ligand programmed death ligand 1 (PD-L1) to form the complex PD-1-PD-L1, this complex inactivates immune cells resulting in cell apoptosis, downregulation of immune reaction, and tumor evasion. The antibody, anti-PD-1 or anti-PD-L1, blocks the PD-1-PD-L1 complex formation to restore the functions of T cells. Combination of anti-PD-1 with other treatment shows promising in different types of cancer treatments. Interferon-gamma (IFN-γ) plays an important role in immune responses. It is mainly regarded as a pro-inflammatory cytokine that promotes the proliferation of CD8+ T cell and cytotoxic T cell, enhances the activation of Th1 cells and CD8+ T cells, and enhances tumor elimination. However, recent studies have been discovering many anti-inflammatory functions of IFN-γ, such as promotion of the PD-L1 expression, T cell apoptosis, and tumor metastasis, as well as inhibition of the immune recognition and the killing rates by T cells. In this work, we construct a mathematical model incorporating pro-inflammatory and anti-inflammatory functions of IFN-γ to capture tumor growth under anti-PD-1 treatment in the wild type and IFN-γ null mutant melanoma. Our simulation results qualitatively fit experimental data that IFN-γ null mutant with anti-PD-1 obtains the highest tumor reduction comparing to IFN-γ null mutant without anti-PD-1 and wild type tumor with anti-PD-1 therapy. Moreover, our synergy analysis indicates that, in the combination treatment, the tumor volume decreases as either the dosage of anti-PD-1 increases or the IFN-γ production efficiency decreases. Thus, the combination of anti-PD-1 and IFN-γ blockade improves the tumor reduction comparing to the monotherapy of anti-PD-1 or the monotherapy of IFN-γ blockade. We also find a threshold curve of the minimal dosage of anti-PD-1 corresponding to the IFN-γ production efficiency to ensure the tumor reduction under the presence of IFN-γ.

A Novel HDAC1-Selective Inhibitor Attenuates Autoimmune Arthritis by Inhibiting Inflammatory Cytokine Production.

Rheumatoid arthritis (RA) is systemic autoimmune arthritis that causes joint inflammation and destruction. Accumulating evidence has shown that inhibitors of class I histone deacetylases (HDACs) (i.e., HDAC1, 2, 3, and 8) are potential therapeutic candidates as targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs). Nevertheless, the inhibition of class I HDACs has severe adverse effects because of their broad spectrum. We evaluated the therapeutic effect of a novel selective HDAC1 inhibitor TTA03-107 for collagen-induced arthritis (CIA) and collagen antibody-induced arthritis (CAIA) models in mice. We also examined the effect of TTA03-107 in bone marrow-derived macrophages (BMDMs) and T helper 17 (Th17) cells in vitro. Here, we delineate that TTA03-107 reduced the severity of autoimmune arthritis without obvious adverse effects in CIA and CAIA models. Moreover, TTA03-107 suppressed the production of inflammatory cytokines, such as interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and IL-17A, in serum and joint tissue. In vitro treatment of BMDMs with TTA03-107 dampened the M1 differentiation and inflammatory cytokine production. TTA03-107 also suppressed the differentiation of Th17 cells. These results demonstrate that TTA03-107 can attenuate the development of arthritis in experimental RA models by inhibiting the differentiation and activation of macrophages and Th17 cells. Therefore, TTA03-107 is a potential tsDMARD candidate.

IL-25 contributes to development of chronic contact dermatitis in C57BL/6 mice, but not BALB/c mice

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by type 2 immune responses. Interleukin-25 (IL-25) is produced predominantly by epithelial cells. It can activate Th2 cells to produce type 2 cytokines such as IL-4, IL-5 and IL-13, contributing to host defense against nematodes. However, excessive/inappropriate production of IL-25 is considered to be involved in development of type 2 cytokine-associated allergic disorders such as asthma. On the other hand, the contribution of IL-25 to the pathogenesis of AD remains poorly understood. In the present study, we found that expression of Il25 mRNA was significantly increased in the skin of mice during oxazolone-induced chronic contact hypersensitivity (CHS), which is a mouse model of human AD. In addition, development of oxazolone-induced chronic CHS was significantly reduced in IL-25-deficient (Il25−/−) mice compared with wild-type mice on the C57BL/6, but not BALB/c, background, although IL-25 was not essential for IL-4 production by hapten-specific T cells. Therefore, IL-25 is crucial for development of chronic CHS, although that is partly dependent on the genetic background of the mice.

MW‑9, a chalcones derivative bearing heterocyclic moieties, attenuates experimental autoimmune encephalomyelitis via suppressing pathogenic TH17 cells.

Previous studies have indicated that MW-9, a chalcones derivative bearing heterocyclic moieties, has considerable anti-inflammatory activity in vitro. Whether MW-9 may be used to treat inflammation-based diseases, such as multiple sclerosis, remains unknown. The present study was designed to determine the effect and underlying mechanism of MW-9 in experimental autoimmune encephalomyelitis (EAE). Female C57BL/6 mice immunized with MOG35-55 were treated with or without MW-9, then the clinical scores and other relevant parameters were investigated. Production of cytokines and specific antibodies were monitored by ELISA assays. Surface marker, Treg cell, and intracellular cytokines (IL-17A and IFN-γ) were detected by flow cytometry, and mRNA expression in the helper-T (TH)17 cell-related signaling pathway was examined by reverse transcription-quantitative (RT-q) PCR analysis. TH17 cell differentiation assay was performed. Herein, the present results demonstrated that oral administration of MW-9 reduced the severity of disease in EAE mice through slowing down infiltration process, inhibiting the demyelination, blocking anti-MOG35-55 IgG antibody production (IgG, IgG2a and IgG3), and decreasing accumulation of CD11b+Gr-1+ neutrophils from EAE mice. MW-9 treatments also led to significantly decreased IL-17A production and IL-17 expression in CD4+ T-cells, but had no detectable influence on development of TH1 and T-regulatory cells ex vivo. RT-qPCR analysis showed that within the spinal cords of the mice, MW-9 blocked transcriptional expression of TH17-associated genes, including Il17a, Il17f, Il6 and Ccr6. In TH17 cell differentiation assay, MW-9 inhibited differentiation of ‘naïve’ CD4+ T-cells into TH17 cells and reduced the IL-17A production. The data demonstrated that MW-9 could attenuate EAE in part through suppressing the formation and activities of pathogenic TH17 cells.

Rheumatologic manifestations with elevated levels of IL-6, IL-17A, and IL-23 in a patient with scurvy.

Symptomatic vitamin C deficiency, scurvy, is a relatively rare disease in developed countries, but it has been reported in patients with autism spectrum disorder or developmental delay who tend to have selective diets. Patients with scurvy often demonstrate musculoskeletal manifestations with unknown pathophysiology. Herein, we report a case of scurvy in an 11-year-old boy who presented with iron-deficiency anaemia, systemic osteomyelitis, myositis predominantly in the lower extremities, and right ventricular volume overload with mild pulmonary hypertension and was diagnosed with scurvy. He had a mild developmental disorder and a selective diet, which resulted in severe vitamin C deficiency. He received intravenous and oral vitamin C supplementation, which relieved his arthralgia and muscle pain in a week. Following 4 months of vitamin C supplementation, he demonstrated no abnormal manifestations on laboratory or imaging examination and recovered without sequelae. Inflammatory cytokine and chemokine evaluations demonstrated elevated levels of interleukin (IL)-6, IL-17A, and IL-23, which are associated with T-helper (Th) 17 cell activation. This study is the first to suggest the association between the inflammation seen in scurvy, rheumatic manifestations in the patient, and Th17 cell activation. Further analysis of the association between the inflammation and vitamin C supplementation may contribute to new insights for the comprehension and treatment of other inflammatory diseases, such as rheumatic diseases.

Abstract P3084: T Helper Cell Polarity Determines Salt-sensitivity And Development Of Hypertension

Background: Sodium chloride drives the stable induction of pathogenic T helper (Th) 17 cells and development of hypertension. However, high-salt intake induces hypertension in salt-sensitive persons but not in salt-resistant persons. Pathogenic Th17 cell plays an important role in the development of hypertension whereas suppressive Treg cell plays an important role in the prevention of hypertension. Objective: We tested the hypothesis that . Methods and Results: Eight-week-old male SS and SR rats were fed chow (NS, 0.4% NaCl) or high-salt (HS, 4% NaCl) diet for 4 weeks. Systolic blood pressure was measured by the tail-cuff method. Cultured splenic T cells from Dahl salt-sensitive (SS) and salt-resistant (SR) rats were exposed to hypertonic salt solution with or without IL-6 or TGFβ. T helper cell (Th17 and Treg) polarity was determined via flow cytometry. The expression of Th17-related genes such as interleukin (IL)-17A, IL-23R and retinoic acid receptor-related orphan receptor (ROR) γt) as well as Treg-related genes such as IL-10, CD25 and forkhead box (Fox) P3 were measured by ELISA or qRT-PCR. Adoptive transfer of Th17 cells isolated from SS or SR donors fed HS were performed intraperitoneally into SS and SR recipients. Upon chow diet, SR has higher Treg cells than SS does. HS intake induced hypertension and increased proinflammatory Th17 cells in SS but not in SR. Hypertonic salt solution induced differentiation of cultured splenic T cells preferentially into proinflammatory Th17 cells and anti-inflammatory Treg cells in SS and SR, respectively. Polarizing cytokine IL-6 also induced differentiation of cultured splenic T cells preferentially into proinflammatory Th17 cells and anti-inflammatory Treg cells in SS and SR, respectively, which were further potentiated by hypertonic salt solution. Adoptive transfer of activated Th17 cells isolated from hypertensive SS or normotensive SR, both of which had been fed HS diet, induced hypertension in SS recipients, but not SR recipients. Conclusions: These results indicate that T helper cell polarity after HS intake determines salt-sensitivity and development of hypertension in SS and SR rats. Th17 cell polarity predicts salt-sensitivity and development of hypertension, whereas Treg cell polarity predicts salt-resistance and maintenance of normotension. SR rats protect against hypertension after HS intake through anti-inflammatory Treg cell polarity.

Precision medicine based on the phenotypic differences in peripheral T helper cells in patients with psoriatic arthritis: One year follow-up outcomes.

PurposeWe validated the one-year effectiveness of strategic treatment with biological disease-modifying anti-rheumatic drugs (bDMARDs) based on peripheral T-lymphocytic phenotyping and explored the impact of treatment on T helper lymphocytic phenotypes.MethodsNinety-seven patients were registered in this study. One-year treatment response was compared between the two groups: the strategic bDMARDs treatment group (n = 41), in which bDMARDs were selected based on peripheral blood lymphocyte analysis, and the standard bDMARDs treatment group (n = 56), in which the patients underwent no strategic selection of bDMARDs and phenotyping. Changes in helper T lymphocytic phenotypes were evaluated after 1-year post-treatment.ResultsIn the standard bDMARDs treatment group, 23 patients (42.6%) achieved disease activity in psoriatic arthritis (DAPSA)-remission (REM), and 23 of 46 (50.0%) achieved PASI 90. In the strategic bDMARDs treatment group, 22 (53.7%) achieved DAPSA-REM, and 26 of 35 (74.2%) achieved PASI90. The rate of achieving minimal disease activity (MDA) and DAPSA-REM at month 6, DAPSA-low disease activity (LDA) at months 6 and 12, and PASI 90 at month 12 were significantly higher in the strategic bDMARDs treatment group. After treatment with ustekinumab, the proportion of aTh1/CD4 (%) significantly decreased. The percent reduction in activated Th17 cells was significantly higher in IL-17-i cells than in UST/TNF-i cells.ConclusionsThe results of this study demonstrate the 1-year effectiveness of precision medicine based on peripheral T-lymphocytic phenotyping in terms of DAPSA and MDA. Analysis of data from real-world clinical practice showed that the impact on the immune system varied among bDMARDs. However, because psoriatic arthritis has very high heterogeneity, it may be necessary to conduct studies with a larger sample size, perhaps drawing samples from multiple institutions.

Oral dextran sulfate sodium administration induces peripheral spondyloarthritis features in SKG mice accompanied by intestinal bacterial translocation and systemic Th1 and Th17 cell activation

BackgroundSpondyloarthritis (SpA) is an autoimmune and autoinflammatory musculoskeletal disease characterised by systemic enthesitis. Recent research has focused on subclinical inflammatory bowel disease (IBD) in SpA pathogenesis. SKG mice, harbouring the Zap70 W163C mutation, increase autoreactive Th17 cells intrinsically, and in a conventional environment, they exhibit spontaneous arthritis with fungal factors. Under SPF conditions, they show SpA features, including enteritis, after peritoneal injection of β-1,3-glucan. This study aimed to clarify whether oral dextran sulfate sodium (DSS) administration, utilised in IBD model mice, can provoke SpA features in SKG mice under SPF conditions, focusing on the relationship between gut microorganisms and SpA pathogenesis.MethodsBALB/c and SKG mice were administered oral DSS, and their body weights, arthritis, and enthesitis scores were recorded. In another cohort, antibiotics (meropenem and vancomycin) or an anti-fungal agent (amphotericin B) was administered orally before DSS administration. The splenic Th1 and Th17 cell populations were examined before and after DSS administration using flow cytometry. Furthermore, the amount of circulating bacterial DNA in whole blood was measured by absolute quantitative polymerase chain reaction (qPCR), and the number and characteristics of bacterial species corresponding to these circulating DNA were analysed by next-generation sequencing (NGS).ResultsAnkle enthesitis as a peripheral SpA feature was elicited in half of DSS-administered SKG mice, and none of the BALB/c mice. Pre-administration of antibiotics suppressed enthesitis, whilst an anti-fungal agent could not. Th1 and Th17 cell levels in the spleen increased after DSS administration, and this was suppressed by pre-administration of antibiotics. SKG mice have a larger amount of bacterial DNA in whole blood than BALB/c mice before and 1 day after the initiation of DSS administration. The number of bacterial species in whole blood increased after DSS administration in BALB/c and SKG mice. Some genera and species significantly specific to the DSS-treated SKG mouse group were also detected.ConclusionOral DSS administration alone elicited peripheral enthesitis in SKG mice with bacterial translocation accompanied by increased splenic Th1 and Th17 cell levels. Pre-administration of antibiotics ameliorated these DSS-induced SpA features. These findings suggest that intestinal bacterial leakage plays a pivotal role in SpA pathogenesis.

Inferred Causal Mechanisms of Persistent FMDV Infection in Cattle from Differential Gene Expression in the Nasopharyngeal Mucosa.

Foot-and-mouth disease virus (FMDV) can persistently infect pharyngeal epithelia in ruminants but not in pigs. Our previous studies demonstrated that persistent FMDV infection in cattle was associated with under-expression of several chemokines that recruit immune cells. This report focuses on the analysis of differentially expressed genes (DEG) identified during the transitional phase of infection, defined as the period when animals diverge between becoming carriers or terminators. During this phase, Th17-stimulating cytokines (IL6 and IL23A) and Th17-recruiting chemokines (CCL14 and CCL20) were upregulated in animals that were still infected (transitional carriers) compared to those that had recently cleared infection (terminators), whereas chemokines recruiting neutrophils and CD8+ T effector cells (CCL3 and ELR+CXCLs) were downregulated. Upregulated Th17-specific receptor, CCR6, and Th17-associated genes, CD146, MIR155, and ThPOK, suggested increased Th17 cell activity in transitional carriers. However, a complex interplay of the Th17 regulatory axis was indicated by non-significant upregulation of IL17A and downregulation of IL17F, two hallmarks of TH17 activity. Other DEG suggested that transitional carriers had upregulated aryl hydrocarbon receptor (AHR), non-canonical NFκB signaling, and downregulated canonical NFκB signaling. The results described herein provide novel insights into the mechanisms of establishment of FMDV persistence. Additionally, the fact that ruminants, unlike pigs, produce a large amount of AHR ligands suggests a plausible explanation of why FMDV persists in ruminants, but not in pigs.

Potential Natural Biomolecules Targeting JAK/STAT/SOCS Signaling in the Management of Atopic Dermatitis.

Atopic dermatitis (AD) is a chronic inflammatory skin disease caused by the dysregulation of cytokines and other immune mediators. JAK/STAT is a classical signal transduction pathway involved in various biological processes, and its dysregulation contributes to the key aspects of AD pathogenesis. Suppressor of cytokine signaling (SOCS) proteins negatively regulate the immune-related inflammatory responses mediated by the JAK/STAT pathway. JAK/STAT-mediated production of cytokines including IL-4, IL-13, IL-31, and TSLP inhibits the expression of important skin barrier proteins and triggers pruritus in AD. The expression of SOCS proteins regulates the JAK-mediated cytokines and facilitates maintaining the skin barrier disruptions seen in AD. STATs are crucial in dendritic-cell-activated Th2 cell differentiation in the skin, releasing inflammatory cytokines, indicating that AD is a Th2-mediated skin disorder. SOCS proteins aid in balancing Th1/Th2 cells and, moreover, regulate the onset and maintenance of Th2-mediated allergic responses by reducing the Th2 cell activation and differentiation. SOCS proteins play a pivotal role in inflammatory cytokine-signaling events that act via the JAK/STAT pathway. Therapies relying on natural products and derived biomolecules have proven beneficial in AD when compared with the synthetic regimen. In this review, we focused on the available literature on the potential natural-product-derived biomolecules targeting JAK/STAT/SOCS signaling, mainly emphasizing the SOCS family of proteins (SOCS1, SOCS3, and SOCS5) acting as negative regulators in modulating JAK/STAT-mediated responses in AD pathogenesis and other inflammatory disorders.