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Background Interleukin-2 (IL-2) and the high-affinity IL-2 receptor (IL-2R) are essential for the survival of regulatory T cells (Tregs) which are the main players in immune tolerance and prevention of autoimmune diseases. Sjögren’s syndrome (SS) is a chronic autoimmune disease predominantly affecting women and is characterised by sicca symptoms including oral and ocular dryness. The aim of this study was to investigate an association between IL-2R and Treg function in patients with SS of different severity defined by the salivary flow rate. Methods In a cross-sectional study, we determined plasma soluble IL-2R (sIL-2R) levels in women with SS ( n =97) and healthy females ( n =50) using ELISA. A subset of those ( n =51) was screened for Treg function measured by the STAT5 signalling response to IL-2 using phospho-flow cytometry. Results We found that elevated plasma levels of sIL-2R were positively associated with the severity of SS reflected by a pathologically low salivary flow. Phospho-flow analysis revealed that patients with SS have a significantly lower frequency of pSTAT5 + Tregs upon IL-2 stimulation compared with healthy individuals, while the frequency of Tregs and pSTAT5 in conventional T cells remained unchanged. In addition, we observed more pSTAT5 + Tregs at baseline in patients with SS, which is significantly associated with seropositivity and elevated sIL-2R. Conclusions Our data indicates that Tregs have a weakened immunosuppressive function in patients with SS due to impaired IL-2/IL-2R signalling capacity. This could mediate lymphocytic infiltration into salivary glands inducing sicca symptoms. We believe that sIL-2R could act as a useful indicator for SS and disease severity.

Monocyte-derived dendritic cells (moDC) are an important scientific and clinical source of functional dendritic cells (DC). However, the optimization of the generation process has to date mainly been limited to the variation of soluble factors. In this study, we investigated the impact of the cell culture dish surface on phenotype and cytokine profile. We compared a standard cell culture dish to a non-adherent culture dish for two immunogenic maturation conditions, two tolerogenic conditions, and an unstimulated control. Phenotype, cytokine profile and T cell stimulatory capacity were determined after a 3-day culture. Light microscopy revealed an increase in homotypic cluster formation correlated with the use of non-adherent surfaces, which could be reduced by using blocking antibodies against CD18. All surface markers analyzed showed moderate to strong differences depending on the culture dish surface, including significantly decreased expression of key maturation markers such as CD80, CD86, and CCR7 as well as PD-L1 on cells stimulated with the Jonuleit cytokine cocktail cultured on a non-adherent surface. Significant differences in the secretion of many cytokines were observed, especially for cells stimulated with LPS, with over 10-fold decreased secretion of IL-10, IL12-p40, and TNF-α from the cells cultured on the non-adherent surface. All immunogenic moDC populations showed similar capacity to induce antigen-specific T cells. These results provide evidence that the DC phenotype depends on the surface used during moDC generation. This has important implications for the optimization of DC-based immunotherapy development and underlines that the local surrounding can interfere with the final DC population beyond the soluble factors.

BackgroundPrimary Sjögren’s syndrome (pSS) is a systemic autoimmune disease, characterized by mononuclear cell infiltrates in the salivary and lacrimal glands, leading to glandular atrophy and dryness. Patient heterogeneity and lack of knowledge regarding its pathogenesis makes pSS a difficult disease to manage.MethodsAn exploratory analysis using mass cytometry was conducted of MAPK/ERK and JAK/STAT signaling pathways in peripheral blood mononuclear cells (PBMC) from 16 female medication free pSS patients (8 anti-Sjögren’s syndrome-related antigen A negative/SSA- and 8 SSA+) and 8 female age-matched healthy donors after stimulation with interferons (IFNs).ResultsWe found significant differences in the frequencies of memory B cells, CD8+ T central and effector memory cells and terminally differentiated CD4+ T cells among the healthy donors and patient subgroups. In addition, we observed an upregulation of HLA-DR and CD38 in many cell subsets in the patients. Upon IFNα2b stimulation, slightly increased signaling through pSTAT1 Y701 was observed in most cell types in pSS patients compared to controls, while phosphorylation of STAT3 Y705 and STAT5 Y694 were slightly reduced. IFNγ stimulation resulted in significantly increased pSTAT1 Y701 induction in conventional dendritic cells (cDCs) and classical and non-classical monocytes in the patients. Most of the observed differences were more prominent in the SSA+ subgroup, indicating greater disease severity in them.ConclusionsAugmented activation status of certain cell types along with potentiated pSTAT1 Y701 signaling and reduced pSTAT3 Y705 and pSTAT5 Y694 induction may predispose pSS patients, especially the SSA+ subgroup, to upregulated expression of IFN-induced genes and production of autoantibodies. These patients may benefit from therapies targeting these pathways.

The transcription factor β-catenin is able to induce tolerogenic/anti-inflammatory features in different types of dendritic cells (DCs). Monocyte-derived dendritic cells (moDCs) have been widely used in dendritic cell-based cancer therapy, but so far with limited clinical efficacy. We wanted to investigate the hypothesis that aberrant differentiation or induction of dual pro- and anti-inflammatory features may be β-catenin dependent in moDCs. β-catenin was detectable in both immature and lipopolysaccharide (LPS)-stimulated DCs. The β-catenin inhibitor ICG-001 dose-dependently increased the pro-inflammatory signature cytokine IL-12p70 and decreased the anti-inflammatory signature molecule IL-10. The β-catenin activator 6-bromoindirubin-3'-oxime (6-BIO) dose-dependently increased total and nuclear β-catenin, and this was associated with decreased IL-12p70, increased IL-10, and reduced surface expression of activation markers, such as CD80 and CD86, and increased expression of inhibitory markers, such as PD-L1. 6-BIO and ICG-001 competed dose-dependently regarding these features. Genome-wide mRNA expression analyses further underscored the dual development of pro- and anti-inflammatory features of LPS-matured moDCs and suggest a role for β-catenin inhibition in production of more potent therapeutic moDCs.

There is a critical need to deconvolute the heterogeneity displayed by the minor salivary glands of primary Sjögren’s syndrome (pSS) patients. This is challenging primarily because the disease etiology remains unknown. The hypothesis includes that initial events in the disease pathogenesis target the salivary glands, thereby triggering the development of focal infiltrates (≥50 mononuclear cells) and finally germinal center-like structures. However, the proportion of key mononuclear immune cells residing at these sites, in combination with the overall ratio of morphometric tissue atrophy and adipose infiltration within the minor salivary glands (MSG) parenchyma at distinct phases of inflammatory disease establishment and progression have not been quantified in detail. In this cross-sectional study, we intended to address this problem by stratifying 85 patients into mild (S1), moderate (S2), and severe (S3) stages using the Inflammatory severity index. We found that mild (<3%) and marked (≥3%) levels of atrophy were accompanied by the respective levels of adipose infiltration in the non-SS sicca controls ( p < 0.01), but not in pSS patients. The percentage of adipose infiltration significantly correlated with the age of patients ( r = 0.458, p < 0.0001) and controls ( r = 0.515, p < 0.0001). The CD4 + T helper cell incidence was reduced in the focal infiltrates of the MSG of S2 patients compared to S1 ( p < 0.01), and in S2 compared to S1 and S3 combined ( p < 0.05). CD20 + B cells increased from S1 to S3 ( p < 0.01) and S2 to S3 ( p < 0.01), meanwhile CD138 + plasma cells diminished in S3 patients compared to both S1 and S2 groups combined ( p < 0.01). The proportion of patients with anti-Ro/SSA + , anti-La/SSB + , and RF + increased over the course of inflammatory disease progression and they were significantly more common in the S3 group relative to S1 ( p < 0.05). On the other hand, S2 patients measured a higher mean salivary flow relative to S1 and S3 patients combined ( p < 0.05). Our results demonstrate how the proposed Inflammatory severity index stratification revealed pathological cell and tissue-associated aberrations in the salivary component over the course of inflammatory progression, and their correlations to clinical outcomes. This could be directly transferred to the optimization of available diagnostic strategies applied for pSS patients.

Primary Sjögren's syndrome (pSS) is associated with polymorphisms and mRNA expression profiles that are indicative of an exaggerated innate and type I IFN immune response. Excessive activation potential of signaling pathways may play a role in this profile, but the intracellular signaling profile of the disease is not well characterized. To gain insights into potentially dysfunctional intracellular signaling profiles of pSS patients we conducted an exploratory analysis of MAPK/ERK and JAK/STAT signaling networks in peripheral blood mononuclear cells (PBMC) from 25 female pSS patients and 25 female age-matched healthy donors using phospho-specific flow cytometry. We analyzed unstimulated samples, as well as samples during a 4 h time period following activation of Toll-like receptor (TLR) 7 and 9. Expression levels of , and in PBMC were analyzed by real-time PCR. Cytokine levels in plasma were determined using a 25-plex Luminex-assay. Principal component analysis (PCA) showed that basal phosphorylation profiles could be used to differentiate pSS patients from healthy donor samples by stronger intracellular signaling pathway activation in NK and T cells relative to B cells. Stimulation of PBMC with TLR7 and -9 ligands showed significant differences in the phosphorylation profiles between samples from pSS patients and healthy donors. Including clinical parameters such as extraglandular manifestations (EGM), we observed stronger responses of NF-κB and STAT3 S727 in B cells from EGM-negative patients compared to EGM-positive patients and healthy controls. Plasma cytokine levels were correlated to the basal phosphorylation levels in these patients. In addition, 70% of the patients had a positive IFN score. These patients differed from the IFN score negative patients regarding their phosphorylation profiles and their plasma cytokine levels. In conclusion, we here report increased signaling potentials in peripheral B cells of pSS patients in response to TLR7 and -9 stimulation through STAT3 S727 and NF-κB that correlate with a type I IFN signature. Induction of these pathways could contribute to the generation of a type I IFN signature in pSS. Patients displaying elevated potentiation of STAT3 S727 and NF-κB signaling could therefore benefit from therapies targeting these pathways.

BackgroundPsoriasis is a chronic immune-mediated skin disease with systemic inflammation and comorbidities. Although the disease severity may vary over time, many patients suffer from mild to moderate disease. Often local treatment will be sufficient to control the symptoms, but they may have several side effects. ω-3 polyunsaturated fatty acids have shown promising results in clinical trials with mild-to-moderate psoriasis.MethodsWe explored the impact of phospholipid bound docosahexaenoic acid and eicosapentaenoic acid in a 3:1 ratio on immune cells and cytokine networks in peripheral blood of patients with psoriasis. We investigated the inter-relation of plasma cytokine levels and disease severity in 58 patients, and explored the status of circulating immune cell activity in 18 patients with non-severe psoriasis before and during herring roe oil supplementation. Plasma concentration of 22 cytokines was measured by Luminex technology and circulating immune cells were analyzed by multicolor flow cytometry.ResultsCCL2 levels decreased over time, and IFN-γR1 increased, possibly related to the action of ω-3 polyunsaturated fatty acids. We observed a shift from naïve to effector CD4+ T cells and decreases of CD38 expression on CD4+ and CD8+ T cells, CD56bright NK cells and CD14+CD16- classical monocytes.ConclusionsThese findings support the beneficial effect of herring roe oil supplementation.

Parkinson’s disease (PD) is more prevalent in men than women, and presents with different clinical features in each sex. Despite widespread recognition of these differences, females are under-represented in clinical and experimental studies of PD, and much remains to be elucidated regarding the biological underpinnings of sex differences in PD. In this review, we summarize known contributors to sex differences in PD etiology across the life course, with a focus on neurological development and gene regulation. Sex differences that are established at conception and heightened during adolescence and midlife may partially embed future PD risk, due to the complex interactions between gonadal hormones, gene regulation, lifestyle factors, and aging. While the neuroprotective properties of estrogen are strongly implicated in reduced prevalence of PD in women, interactions with genotype and gender-biased lifestyle factors are incompletely understood. Consideration of sex and gender-related factors in study design, data analysis, and interpretation have the power to expedite our knowledge of the etiology of PD in men and in women, and to inform prevention and therapeutic strategies tailored to each sex. Plain english summary Parkinson’s disease (PD) more commonly affects men, and is known to have different symptoms in men and women. While this is in part due to the protective effects of estrogen in women, our understanding of why there is a sex difference in PD, and how it develops in each sex, is currently incomplete. This article provides an overview of factors throughout the lifespan that contribute to the differences between men and women in brain health and risk for PD, with a focus on hormones, gene regulation, and their intersections with lifestyle factors. We also discuss how researchers can consider sex and gender in future studies to enhance our understanding of how PD develops, and potentially develop sex-tailored prevention and treatment strategies. Highlights Genetic risk for PD is similar between men and women. Transcriptomic and epigenetic differences in men and women with PD have been reported, particularly in substantia nigra tissue. Emerging evidence suggests interactions between gene regulation, sex hormones, and lifestyle factors contribute to disease pathogenesis in each sex. Statistical approaches can be used to balance sex ratios and explore sex as a contributor to PD etiology, rather than a confounder. Increasing representation of women in PD clinical studies is a priority for future research endeavors.

Sjögren's syndrome (SS) is a rheumatic autoimmune disease characterized by inflammation of exocrine glands. As autoantibodies are present in a majority of patients, B cells have been suggested to play an important role in onset and development of the disease. Toll-like receptors (TLRs) are pattern recognition receptors triggering innate immune responses. Since an increased expression of TLRs has been detected in other rheumatic diseases the purpose of this study was to explore TLRs in B cells of SS patients. The expression of TLR-7 and -9 in B cell subsets of 25 patients with primary SS (pSS) and 25 healthy controls was analysed in peripheral blood using flow cytometry and real time quantitative PCR. We detected similar levels of CD19+ B cells in pSS patients and healthy controls. An increased number of naïve B cells, as well as fewer pre-switched memory B cells were found in pSS patients. No significant differences were observed in TLR-7 and -9 expression in B cells between pSS patients and healthy controls. This study shows that pSS patients have an alteration in the B cell subpopulation composition compared to controls, with less pre-switched memory B cells and more naïve B cells. We did not detect any significant disparities in TLR-7 and -9 expression between the two groups.

Exercise is increasingly recognized as a beneficial intervention for Parkinson's disease (PD), yet the optimal type and intensity of exercise remain unclear. This study investigated the relationship between exercise intensity and neural responses in PD patients, using electroencephalography (EEG) to explore potential neural markers that could be ultimately used to guide exercise intensity. EEG data were collected from 14 PD patients (5 females) and 8 healthy controls (HC) performing stationary pedaling exercises at 60 RPM with resistance adjusted to target heart rates of 30, 40, 50, 60, and 70% of maximum heart rate. Subjects pedaled for 3 min at each intensity level in a counterbalanced order. Canonical Time-series Characteristics (Catch-22) features and Multi-set Canonical Correlation Analysis (MCCA) were utilized to identify common profiles of EEG features at increasing exercise intensity across subjects. We identified a statistically significant MCCA component demonstrating a monotonic relationship with pedaling intensity. We have discovered nine features which show significant trends across intensity ( -value<0.01), and the dominant feature in this component was Periodicity Wang ( -value<0.0001), related to the autocorrelation of the EEG. Analysis revealed a consistent trend across features: six features increased with intensity, indicating heightened rhythmic engagement and sustained neural activation, while three features decreased, suggesting reduced variability and enhanced predictability in neural responses. Notably, PD patients exhibited more rigid, consistent response patterns compared to healthy controls (HC), who showed greater flexibility and variability in their neural adaptation across intensities. This study highlights the feasibility of using EEG-derived features to track exercise intensity in PD patients, identifying specific neural markers correlating with varying intensity levels. PD subjects demonstrate less inter-subject variability in motor responses to increasing intensity. Our results suggest that EEG biomarkers can be used to assess differing brain involvement with the same exercise of increasing intensity, potentially useful for guiding targeted therapeutic strategies and maximizing the neurological benefits of exercise in PD.