Cathepsin D is essential for the degradomic shift of macrophages required to resolve liver fibrosis.

BACKGROUND AND OBJECTIVES: Fibrosis contributes to 45% of deaths in industrialized nations and is characterized by an abnormal accumulation of extracellular matrix (ECM). There are no specific anti-fibrotic treatments for liver fibrosis, and previous unsuccessful attempts at drug development have focused on preventing ECM deposition. Because liver fibrosis is largely acknowledged to be reversible, regulating fibrosis resolution could offer novel therapeutical options. However, little is known about the mechanisms controlling ECM remodeling during resolution. Changes in proteolytic activity are essential for ECM homeostasis and macrophages are an important source of proteases. Herein, in this study we evaluate the role of macrophage-derived cathepsin D (CtsD) during liver fibrosis. METHODS: CtsD expression and associated pathways were characterized in single-cell RNA sequencing and transcriptomic datasets in human cirrhosis. Liver fibrosis progression, reversion and functional characterization were assessed in novel myeloid-CtsD and hepatocyte-CtsD knock-out mice. RESULTS: Analysis of single-cell RNA sequencing datasets demonstrated CtsD was expressed in macrophages and hepatocytes in human cirrhosis. Liver fibrosis progression, reversion and functional characterization were assessed in novel myeloid-CtsD (CtsDΔMyel) and hepatocyte-CtsD knock-out mice. CtsD deletion in macrophages, but not in hepatocytes, resulted in enhanced liver fibrosis. Both inflammatory and matrisome proteomic signatures were enriched in fibrotic CtsDΔMyel livers. Besides, CtsDΔMyel liver macrophages displayed functional, phenotypical and secretomic changes, which resulted in a degradomic phenotypical shift, responsible for the defective proteolytic processing of collagen I in vitro and impaired collagen remodeling during fibrosis resolution in vivo. Finally, CtsD-expressing mononuclear phagocytes of cirrhotic human livers were enriched in lysosomal and ECM degradative signaling pathways. CONCLUSIONS: Our work describes for the first-time CtsD-driven lysosomal activity as a central hub for restorative macrophage function during fibrosis resolution and opens new avenues to explore their degradome landscape to inform drug development.

Genome-Wide Association Studies on Resistance to Pea Weevil: Identification of Novel Sources of Resistance and Associated Markers.

Little resistance to the pea weevil insect pest (Bruchus pisorum) is available in pea (Pisum sativum) cultivars, highlighting the need to search for sources of resistance in Pisum germplasm and to decipher the genetic basis of resistance. To address this need, we screened the response to pea weevil in a Pisum germplasm collection (324 accession, previously genotyped) under field conditions over four environments. Significant variation for weevil seed infestation (SI) was identified, with resistance being frequent in P. fulvum, followed by P. sativum ssp. elatius, P. abyssinicum, and P. sativum ssp. humile. SI tended to be higher in accessions with lighter seed color. SI was also affected by environmental factors, being favored by high humidity during flowering and hampered by warm winter temperatures and high evapotranspiration during and after flowering. Merging the phenotypic and genotypic data allowed genome-wide association studies (GWAS) yielding 73 markers significantly associated with SI. Through the GWAS models, 23 candidate genes were found associated with weevil resistance, highlighting the interest of five genes located on chromosome 6. These included gene 127136761 encoding squalene epoxidase; gene 127091639 encoding a transcription factor MYB SRM1; gene 127097033 encoding a 60S ribosomal protein L14; gene 127092211, encoding a BolA-like family protein, which, interestingly, was located within QTL BpLD.I, earlier described as conferring resistance to weevil in pea; and gene 127096593 encoding a methyltransferase. These associated genes offer valuable potential for developing pea varieties resistant to Bruchus spp. and efficient utilization of genomic resources through marker-assisted selection (MAS).

Risk factors of death or chronic renal replacement therapy requirements in patients with thrombotic microangiopathies without ADAMTS-13 deficiency.

Thrombotic microangiopathy (TMA), characterized by microangiopathic hemolytic anemia, thrombocytopenia, and multisystem organ dysfunction, is a life-threatening disease. Patients with TMA who do not exhibit a severe ADAMTS-13 deficiency (defined as a disintegrin-like and metalloprotease with thrombospondin type 1 motif no. 13 activity ≥10%: TMA-13n) continue to experience elevated mortality rates. This study explores the prognostic indicators for augmented mortality risk or necessitating chronic renal replacement therapy (composite outcome: CO) in TMA-13n patients. We included 42 TMA-13n patients from January 2008 to May 2018. Median age of 41 years and 60% were female. At presentation, 62% required dialysis, and 57% warranted intensive care unit admission. CO was observed in 45% of patients, including a 9-patient mortality subset. Multivariate logistic regression revealed three independent prognostic factors for CO: early administration of eculizumab (median time from hospitalization to eculizumab initiation: 5 days, range 0-19 days; odds ratio [OR], 0.14; 95% confidence interval [CI], 0.02-0.94), presence of neuroradiological lesions (OR, 6.67; 95% CI, 1.12-39.80), and a PLASMIC score ≤4 (OR, 7.39; 95% CI, 1.18-46.11). In conclusion, TMA-13n patients exhibit a heightened risk of CO in the presence of low PLASMIC scores and neuroradiological lesions, while early eculizumab therapy was the only protective factor.

The association of inflammatory biomarkers and long-term clinical outcomes in older adults with non-ST elevation acute coronary syndrome.

BACKGROUND: The prognostic significance of inflammatory markers on the long-term risk of major adverse cardiovascular and cerebrovascular events (MACCE) in older NSTEACS patients remains unclear. METHODS: NSTEACS patients aged 75 and older were recruited to the multicentre cohort study Improve Cardiovascular Outcomes in High-Risk PatieNts with Acute Coronary Syndrome (ICON1). Inflammatory markers including interleukin-6 (IL-6), myeloperoxidase (MPO), high-sensitivity C-reactive protein (hsCRP), fibrinogen and tumor necrosis factor-alpha (TNF-α) were collected at baseline. Primary outcome was MACCE consisting of all-cause mortality, reinfarction, stroke/transient ischaemic attack, urgent revascularization, and significant bleeding at 5-year follow-up. RESULTS: There were 230 patients with baseline IL-6 (median age 80.9 [interquartile range (IQR):78.2-83.9] years). High IL-6 was not associated with MACCE, but it was independently associated with all-cause mortality (adjusted hazard ratio [aHR]: 2.26 [95% Confidence Interval (CI):1.34-3.82]; P = 0.002). For patients with hsCRP (n = 260, median age 80.9 [IQR:77.9-84.1] years), higher levels were significantly associated with increased risk of MACCE (aHR:1.77 [95% CI:1.26-2.49], P = 0.001). In the cohort with MPO (230 patients, median age 80.9 [IQR:78.2-83.9] years), lower MPO was independently associated with the risk of MACCE (aHR: 0.67 [95%CI:0.46-0.96]; P = 0.029). There was no prognostic significance with fibrinogen and TNF-α. CONCLUSION: Among older NSTEACS patients, elevated IL-6 and hsCRP were associated with increased risk of all-cause mortality and MACCE, respectively. Low MPO levels were associated with higher MACCE. Further studies are required to determine how these biomarkers should influence treatment strategy in this understudied subset. CLINICAL TRIAL REGISTRATION: NCT01933581.

Impact of Minimally Invasive Intra-Capsular Metatarsal Osteotomy on Plantar Pressure Decrease: A Cross-Sectional Study.

Background: Metatarsalgia is a common pathology that is initially treated conservatively, but failure to do so requires surgery, such as the minimally invasive distal metatarsal osteotomy (DICMO). Methods: In this prospective study of 65 patients with primary metatarsalgia who underwent DICMO, plantar pressures, American Orthopaedic Foot and Ankle Society MetaTarsoPhalangeal-InterPhalangeal scale (AOFAS-MTP-IP) and Visual Analog Scale (VAS) were evaluated pre-operatively and post-operatively and there was a subgroup in which an inclinometer was used to observe the importance of the inclination of the osteotomy. Results: The results show a significant reduction in plantar pressures after DICMO surgery without overloading the adjacent radii, especially in the subgroup with an inclinometer to guide the osteotomy. The AOFAS-MTP-IP scale evidenced a marked improvement in metatarsal function and alignment with scores close to normal. The VAS scale showed a substantial decrease in pain after DICMO osteotomy. Conclusions: DICMO, with an inclinometer for a 45° osteotomy, proved to be a safe and effective procedure for primary metatarsalgia, although further comparative studies are needed to confirm its superiority.

S-Adenosyl-l-methionine restores brain mitochondrial membrane fluidity and GSH content improving Niemann-Pick type C disease.

Niemann-Pick type C (NPC) disease is a lysosomal storage disorder characterized by impaired motor coordination due to neurological defects and cerebellar dysfunction caused by the accumulation of cholesterol in endolysosomes. Besides the increase in lysosomal cholesterol, mitochondria are also enriched in cholesterol, which leads to decreased membrane fluidity, impaired mitochondrial function and loss of GSH, and has been shown to contribute to the progression of NPC disease. S-Adenosyl-l-methionine (SAM) regulates membrane physical properties through the generation of phosphatidylcholine (PC) from phosphatidylethanolamine (PE) methylation and functions as a GSH precursor by providing cysteine in the transsulfuration pathway. However, the role of SAM in NPC disease has not been investigated. Here we report that Npc1-/- mice exhibit decreased brain SAM levels but unchanged S-adenosyl-l-homocysteine content and lower expression of Mat2a. Brain mitochondria from Npc1-/- mice display decreased mitochondrial GSH levels and liquid chromatography-high resolution mass spectrometry analysis reveal a lower PC/PE ratio in mitochondria, contributing to increased mitochondrial membrane order. In vivo treatment of Npc1-/- mice with SAM restores SAM levels in mitochondria, resulting in increased PC/PE ratio, mitochondrial membrane fluidity and subsequent replenishment of mitochondrial GSH levels. In vivo SAM treatment improves the decline of locomotor activity, increases Purkinje cell survival in the cerebellum and extends the average and maximal life spam of Npc1-/- mice. These findings identify SAM as a potential therapeutic approach for the treatment of NPC disease.

The perception of healthcare professionals, through their own personal experiences, of the use of music therapy in hospitalised children and adolescents.

BACKGROUND: Music therapy is an emerging and useful methodology for improving patient environments within healthcare fields. However, although it has been shown that music therapy interventions with hospitalised children and adolescents have been used for decades with positive effects, there are currently very few studies that specifically describe the perspectives of healthcare professionals regarding the value of music therapy when applied in these patients. OBJECTIVES: To describe the insights of healthcare professionals regarding music therapy, both on a personal level and in terms of its usefulness in the care of hospitalised children and adolescents. DESIGN: This was a qualitative descriptive-exploratory study with focus groups. PARTICIPANTS: Eighteen healthcare professionals. METHODS: In January 2023, two focus groups, containing nine healthcare professionals each, were created to collect data regarding their experiences concerning the effect of music therapy on hospitalised children and adolescents. Before recording their opinions, all these professionals participated in an interactive music therapy session. The thematic analysis in this work was performed using MAXQDA® software. RESULTS: Two main categories emerged: (a) the effects of music therapy on healthcare professionals, and (b) the benefits of music therapy to patients (children and adolescents). CONCLUSIONS: Music therapy was valued positively by healthcare professionals who described the benefits its use has for hospitalised children and adolescents. They also expressed positive viewpoints regarding the use of music therapy to improve their own self-knowledge and self-care. IMPLICATIONS TO PRACTICE: Healthcare professionals may utilise music therapists to improve patient outcomes and reduce the negative effects of hospitalisation.

Long-term surveillance of the feline leukemia virus in the endangered Iberian lynx (Lynx pardinus) in Andalusia, Spain (2008-2021).

Feline leukemia virus (FeLV) infection is considered one of the most serious disease threats for the endangered Iberian lynx (Lynx pardinus) Over 14 years (2008-2021), we investigated FeLV infection using point-of-care antigen test and quantitative real-time TaqMan qPCR for provirus detection in blood and tissues in lynxes from Andalusia (Southern Spain). A total of 776 samples from 586 individuals were included in this study. The overall prevalence for FeLV antigen in blood/serum samples was 1.4% (5/360) (95% CI: 0.2-2.6), FeLV proviral DNA prevalence in blood samples was 6.2% (31/503) (95% CI: 4.1-8.6), and FeLV proviral DNA in tissues samples was 10.2% (34/333) (95% CI: 7-13.5). From a subset of 129 longitudinally sampled individuals, 9.3% (12/129) PCR-converted during the study period. Our results suggest that FeLV infection in the Andalusian population is enzootic, with circulation of the virus at low levels in almost all the sampling years. Moreover, since only one viremic individual succumbed to the infection, this study suggests that lynxes may therefore control the infection decreasing the possibility of developing a more aggressive outcome. Although our results indicate that the FeLV infection in the Iberian lynx from Andalusia tends to stay within the regressive stage, continuous FeLV surveillance is paramount to predict potential outbreaks and ensure the survival of this population.

Elevated cholesterol in ATAD3 mutants is a compensatory mechanism that leads to membrane cholesterol aggregation.

Aberrant cholesterol metabolism causes neurological disease and neurodegeneration, and mitochondria have been linked to perturbed cholesterol homeostasis via the study of pathological mutations in the ATAD3 gene cluster. However, whether the cholesterol changes were compensatory or contributory to the disorder was unclear, and the effects on cell membranes and the wider cell were also unknown. Using patient-derived cells, we show that cholesterol perturbation is a conserved feature of pathological ATAD3 variants that is accompanied by an expanded lysosome population containing membrane whorls characteristic of lysosomal storage diseases. Lysosomes are also more numerous in Drosophila neural progenitor cells expressing mutant Atad3, which exhibit abundant membrane-bound cholesterol aggregates, many of which co-localize with lysosomes. By subjecting the Drosophila Atad3 mutant to nutrient restriction and cholesterol supplementation, we show that the mutant displays heightened cholesterol dependence. Collectively, these findings suggest that elevated cholesterol enhances tolerance to pathological ATAD3 variants; however, this comes at the cost of inducing cholesterol aggregation in membranes, which lysosomal clearance only partly mitigates.

Selenium status and its determinants in very old adults: insights from the Newcastle 85+ Study.

There is a dearth of data on Se status in very old adults. The aims of this study were to assess Se status and its determinants in 85-year-olds living in the Northeast of England by measuring serum Se and selenoprotein P (SELENOP) concentrations and glutathione peroxidase 3 (GPx3) activity. A secondary aim was to examine the interrelationships between each of the biomarkers. In total, 757 participants (463 women, 293 men) from the Newcastle 85+ Study were included. Biomarker concentrations were compared with selected cut-offs (serum Se: suboptimal 70 µg/l and deficient 45 µg/l; SELENOP: suboptimal 4·5 mg/l and deficient 2·6 mg/l). Determinants were assessed using linear regressions, and interrelationships were assessed using restricted cubic splines. Median (inter-quartile range) concentrations of serum Se, SELENOP and of GPx3 activity were 53·6 (23·6) µg/l, 2·9 (1·9) mg/l and 142·1 (50·7) U/l, respectively. Eighty-two percentage and 83 % of participants had suboptimal serum Se (< 70 µg/l) and SELENOP (< 4·5 mg/l), and 31 % and 40 % of participants had deficient serum Se (< 45 µg/l) and SELENOP (< 2·6 mg/l), respectively. Protein intake was a significant determinant of Se status. Additional determinants of serum Se were sex, waist:hip ratio, self-rated health and disease, while sex, BMI and physical activity were determinants of GPx3 activity. There was a linear association between serum Se and SELENOP, and nonlinear associations between serum Se and GPx3 activity and between SELENOP and GPx3 activity. These findings indicate that most participants had suboptimal Se status to saturate circulating SELENOP.

Graphene-Based Engineered Living Materials.

With the rise of engineered living materials (ELMs) as innovative, sustainable and smart systems for diverse engineering and biological applications, global interest in advancing ELMs is on the rise. Graphene-based nanostructures can serve as effective tools to fabricate ELMs. By using graphene-based materials as building units and microorganisms as the designers of the end materials, next-generation ELMs can be engineered with the structural properties of graphene-based materials and the inherent properties of the microorganisms. However, some challenges need to be addressed to fully take advantage of graphene-based nanostructures for the design of next-generation ELMs. This work covers the latest advances in the fabrication and application of graphene-based ELMs. Fabrication strategies of graphene-based ELMs are first categorized, followed by a systematic investigation of the advantages and disadvantages within each category. Next, the potential applications of graphene-based ELMs are covered. Moreover, the challenges associated with fabrication of next-generation graphene-based ELMs are identified and discussed. Based on a comprehensive overview of the literature, the primary challenge limiting the integration of graphene-based nanostructures in ELMs is nanotoxicity arising from synthetic and structural parameters. Finally, we present possible design principles to potentially address these challenges.

Botulinum toxin A versus platelet rich plasma ultrasound-guided injection in the treatment of plantar fasciitis: A randomised controlled trial.

BACKGROUND: Platelet-rich plasma (PRP) and botulinum toxin type A (BTX-A) injections have proven effective in clinical trials for plantar fasciitis treatment but have not been directly compared. We aimed to compare clinical outcomes in patients undergoing PRP or BTX-A injections. METHODS: We performed a randomised controlled trial (59 patients; 1-year follow-up) to assess efficacy, using pain and functional scales (VAS, AOFAS Hindfoot-scale and FAAM questionnaire) and fascia thickness reduction, in control and single ultrasound-guided BTX-A or PRP injection groups. RESULTS: The BTX-A group showed better results at 1-month after treatment. Conversely, the PRP injection was more effective in the long-term, with significant pain reduction and functional improvement. Plantar fascia thickness significantly reduced from months 1 and 3 in the PRP and BTX-A groups, respectively. CONCLUSION: PRP and BTX-A injections are effective in patients with plantar fasciitis with BTX-A achieving better short-term pain reduction and PRP better long-term results. LEVEL OF EVIDENCE: Level I; Randomised Controlled Trial.

Language and Cultural Barriers and Facilitators of Sexual and Reproductive Health Care for Migrant Women in High-Income European Countries: An Integrative Review.

INTRODUCTION: Dealing with intercultural communicative barriers in European countries' national health services is an increasing and necessary challenge to guarantee migrant women's right to health care. This integrative review describes the communication barriers and facilitators that migrant women encounter to access and use sexual and reproductive health (SRH) services in Europe. METHODS: A literature search was performed to identify original studies in PubMed, CINAHL, PsycINFO, Web of Science, and Scopus, using keywords associated with migrant women and SRH services. This was supplemented by scanning the reference lists from relevant studies and similar reviews. Studies exploring the perspective of migrant women about communication barriers and facilitators to the access and use of SRH services were included, whereas those that solely explored health professional's experiences were excluded. Findings were organized into 4 themes: (1) verbal-linguistic barriers, (2) nonverbal language barriers, (3) cultural barriers, and (4) communication facilitators. RESULTS: Nineteen studies met the inclusion criteria. Results showed that when women had problems understanding or being understood by health professionals, they experienced feelings of anxiety, fear, insecurity, and discrimination that discouraged them from using SRH services. The most requested facilitators by women were health education, access to professional interpreters and translation of written information, and increasing the practitioners' cultural competence. DISCUSSION: Communication barriers undermine migrant women's right to benefit from preventive SRH programs and to make informed decisions concerning their health. It is necessary to establish tailored plans in each health care center to improve intercultural communication that integrate facilitators proposed by women. Future research should provide solid evidence on the effectiveness of each facilitator implemented.

'It's always difficult for women': an analysis of the life stories of sub-Saharan migrant women.

The aim of this study was to understand the perspectives of female residents of Spain from West Africa in terms of the factors that condition their lives. Pierre Bourdieu's theory and the model of intersectionality formed the framework we used to qualitatively analyse the life stories of these women, which was complemented with life lines. The results showed us that traditional practices such as female genital mutilation and forced marriage are part of the social habitus of this group and they relate to each other through the several types of violence that occurs throughout their lives. In addition, in reference to the African community, these women were no longer African, while in terms of the Spanish community, they did not seem Spanish. At a health, political, and social level, this knowledge can help us to understand this group and to create personalised targeted interventions for them.

Psychometric Validation of the Tactical Assessment Instrument in Football for Use in Physical Education and with Youth Sport Teams.

Recently, the Tactical Assessment Instrument in Football (TAIS) was developed to address football's tactical requirements in terms of game phases, learners' roles, and organizational levels of play. In this study, we sought to evaluate the psychometric properties of this existing instrument in the Physical Education (PE) context and for youth sport teams (ages 8-12 years). Our research design involved: (a) participants playing 37 football games, (b) assessing participants via observation with the TAIS and (c) conducting psychometric analysis on the obtained assessment data. For the psychometric analysis, we carried out our work in four phases: (a) a statistical analysis of the evaluation criteria, (b) analysis of the instrument's structural dimensions, (c) internal item reliability analysis, and (d) provision of evidence for external validity. Participants were 592 children (156 girls, 436 boys; ages 8-12 years) from 74 PE classes or sport teams (from three institutional contexts - schools, community-based sports, and sports clubs) in Spain. We selected 12 tactical criteria and grouped them into four theoretical dimensions (appropriate attack, inappropriate attack, appropriate defense, inappropriate defense) to confirm the instrument's structural dimensions. The Cronbach alpha and Omega McDonald coefficients were greater than .70. The TAIS discriminated between participants from the three institutional contexts, offering evidence of the instrument's external validity. Thus, the TAIS now has sufficient psychometric support for assessing learning of football tactics in PE and youth sport teams. This instrument facilitates an ecological assessment of youth players' understanding of football tactics through four theoretical tactical dimensions and 12 criteria involving information about four learners' roles (both attack and defense, on- and off-the-ball) and three organizational tactical levels of play (whole team, small groups of learners, and individual learners).

Forensic analysis of biological fluid stains on substrates by spectroscopic approaches and chemometrics: A review.

BACKGROUND: Bodily fluid stains are one of the most relevant evidence that can be found at the crime scene as it provides a wealth of information to the investigators. They help to report on the individuals involved in the crime, to check alibis, or to determine the type of crime that has been committed. They appear as stains in different types of substrates, some of them porous, which can interfere in the analysis. The spectroscopy techniques combined with chemometrics are showing increasing potential for their use in the analysis of such samples due to them being fast, sensitive, and non-destructive. FINDINGS: This is a comprehensive review of the studies that used different spectroscopic techniques followed by chemometrics for analysing biological fluid stains on several surfaces, and under various conditions. It focuses on the bodily fluid stains and the most suitable spectroscopic techniques to study forensic scientific problems such as the substrate's characteristics, the influence of ambient conditions, the aging process of the bodily fluids, the presence of animal bodily fluids and non-biological fluids (interfering substances), and the bodily fluid mixtures. The most widely used techniques were Raman spectroscopy and attenuated total reflection Fourier transform infrared spectroscopy (ATR FTIR). Nonetheless, other non-destructive techniques have been also used, like near infrared hyperspectral imaging (HSI-NIR) or surface enhanced Raman spectroscopy (SERS), among others. This work provides the criteria for the selection of the most promising non-destructive techniques for the effective in situ detection of biological fluid stains at crime scene investigations. SIGNIFICANCE AND NOVELTY: The use of the proper spectroscopic and chemometric approaches on the crime scene is expected to improve the support of forensic sciences to criminal investigations. Evidence may be analysed in a non-destructive manner and kept intact for further analysis. They will also speed up forensic investigations by allowing the selection of relevant samples from occupational ones.

Basic quality indicators for clinical care of patients with major depression, schizophrenia, and bipolar disorder.

OBJECTIVE: To identify a set of indicators to monitor the quality of care for patients with major depression, schizophrenia, or bipolar disorder. METHODS: A group of 10 experts selected the most automatically applicable indicators from a total of 98 identified in a previous study. Five online sessions and 5 discussion meetings were performed to select the indicators that met theoretical feasibility criteria automatically. Subsequently, feasibility was tested in a pilot study conducted in two hospitals of the Spanish Health Service. RESULTS: After evaluating its measurement possibilities in the Spanish Health Service, and the fulfillment of all the quality premises defined, 16 indicators were selected. Three were indicators of major depression, 5 of schizophrenia, 3 of bipolar disorder, and 5 indicators common to all three pathologies. They included measures related to patient safety, maintenance and follow-up of treatment, therapeutic adherence, and adequacy of hospital admissions. After the pilot study, 5 indicators demonstrated potential in the automatic generation of results, with 3 of them related to treatments (clozapine in schizophrenia, lithium for bipolar disorder, and valproate in women of childbearing age). CONCLUSIONS: Indicators support the monitoring of the quality of treatment of patients with major depression, schizophrenia, or bipolar disorder. Based on this proposal, each care setting can draw up a balanced scorecard adjusted to its priorities and care objectives, which will allow for comparison between centers.

Decidualized human decidual stromal cells inhibit chemotaxis of activated T cells: a potential mechanism of maternal-fetal immune tolerance.

Background: Numerous lines of evidence confirm that decidual stromal cells (DSCs) play a key role in maternal-fetal immune tolerance. Under the influence of progesterone and other hormones, the DSCs go through a process of differentiation (decidualization) during normal pregnancy. In mice, DSCs inhibit the expression of chemokines that attract abortigenic Th1 and Tc cells to the decidua. We have studied this phenomenon in humans. Methods: We established human DSC lines and decidualized these cells in vitro with progesterone and cAMP. We determined the expression of the chemokines CXCL9, CXCL10 and CXCL11, whose receptor CXCR3 is expressed by Th1 and Tc cells, in undifferentiated DSCs and decidualized DSCs by qRT-PCR. Activated CD3+CXCR3+ cells, including CD4+ Th1 cells and CD8+ Tc cells, were induced in vitro. The migration capacity of these activated lymphocytes was investigated in Transwell chambers with conditioned media from undifferentiated and decidualized DSCs. Results: We demonstrated that CXCL9 was not expressed by DSCs, whereas the expression of CXCL10 and CXCL11 was inhibited in decidualized cells. Conditioned media from decidualized cells significantly inhibited the migration of Th1 and Tc cells. We found that decidualized cells secrete factors of MW less than 6000-8000 Da, which actively inhibit the chemotaxis of these lymphocytes. Discussion: These results confirm in humans that decidualization of DSCs inhibits the expression by these cells of chemokines that attract Th1 and Tc cells and induces the secretion by DSCs of factors that inhibit the chemotaxis of these lymphocytes, thus preventing the arrival of abortigenic T cells in the decidua.