Mesenchymal stem cell transplantation may be able to induce immunological tolerance in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a common, potentially fatal autoimmune disease involving a significant inflammatory response. SLE is characterised by failure of self-tolerance and activation of autoreactive lymphocytes, leading to persistent disease. Although current treatments achieve some improvement in patients, some SLE patients are refractory and others relapse after drug withdrawal. The toxicity of current drug regimens, with recurrent infections, together with ongoing inflammation, contribute significantly to the progressive decline in organ function. Therefore, the clinical management of SLE requires more effective and less toxic treatments, ideally inducing complete remission and self-tolerance. In this context, recently developed cell therapies based on mesenchymal stem cells (MSCs) represent a promising and safe strategy in SLE. MSCs inhibit the activation of B cells, prevent the differentiation of CD4⁺ T cells into autoreactive T cells, reprogram macrophages with anti-inflammatory effects and inhibit dendritic cells (DCs), limiting their activity as antigen-presenting cells. In addition, MSCs could induce antigen-specific tolerance by enhancing anergy processes in autoreactive cells - by inhibiting the maturation of antigen-presenting DCs, blocking the T cell receptor (TcR) pathway and secreting inhibitory molecules -, increasing apoptotic activity to eliminate them, and activating regulatory T cells (Tregs) to enhance their proliferation and induction of tolerogenic DCs. Thus, induction of self-tolerance leads to immune balance, keeping inflammation under control and reducing lupus flares.

Approaching Personalized Medicine: The Use of Machine Learning to Determine Predictors of Mortality in a Population with SARS-CoV-2 Infection.

The COVID-19 pandemic demonstrated the need to develop strategies to control a new viral infection. However, the different characteristics of the health system and population of each country and hospital would require the implementation of self-systems adapted to their characteristics. The objective of this work was to determine predictors that should identify the most severe patients with COVID-19 infection. Given the poor situation of the hospitals in the first wave, the analysis of the data from that period with an accurate and fast technique can be an important contribution. In this regard, machine learning is able to objectively analyze data in hourly sets and is used in many fields. This study included 291 patients admitted to a hospital in Spain during the first three months of the pandemic. After screening seventy-one features with machine learning methods, the variables with the greatest influence on predicting mortality in this population were lymphocyte count, urea, FiO2, potassium, and serum pH. The XGB method achieved the highest accuracy, with a precision of >95%. Our study shows that the machine learning-based system can identify patterns and, thus, create a tool to help hospitals classify patients according to their severity of illness in order to optimize admission.

Systemic Lupus Erythematosus: How Machine Learning Can Help Distinguish between Infections and Flares.

Systemic Lupus Erythematosus (SLE) is a multifaceted autoimmune ailment that impacts multiple bodily systems and manifests with varied clinical manifestations. Early detection is considered the most effective way to save patients' lives, but detecting severe SLE activity in its early stages is proving to be a formidable challenge. Consequently, this work advocates the use of Machine Learning (ML) algorithms for the diagnosis of SLE flares in the context of infections. In the pursuit of this research, the Random Forest (RF) method has been employed due to its performance attributes. With RF, our objective is to uncover patterns within the patient data. Multiple ML techniques have been scrutinized within this investigation. The proposed system exhibited around a 7.49% enhancement in accuracy when compared to k-Nearest Neighbors (KNN) algorithm. In contrast, the Support Vector Machine (SVM), Binary Linear Discriminant Analysis (BLDA), Decision Trees (DT) and Linear Regression (LR) methods demonstrated inferior performance, with respective values around 81%, 78%, 84% and 69%. It is noteworthy that the proposed method displayed a superior area under the curve (AUC) and balanced accuracy (both around 94%) in comparison to other ML approaches. These outcomes underscore the feasibility of crafting an automated diagnostic support method for SLE patients grounded in ML systems.

Machine learning, a new tool for the detection of immunodeficiency patterns in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease that affects several organs and causes variable clinical symptoms. Early diagnosis is currently the most effective way to save the lives of patients with SLE. But it is very difficult to detect in the early stages of the disease. Because of this, this study proposes a machine learning system to help diagnose patients with SLE. To carry out the research, the extreme gradient boosting method has been implemented due to its performance characteristics, as it allows high performance, scalability, accuracy, and low computational load. From this method we try to recognize patterns in the data obtained from patients, which allow the classification of SLE patients with high accuracy and differentiate these patients from controls. Several machine learning methods have been analyzed in this study. The proposed method achieves a higher prediction value of patients who may suffer from SLE than the rest of the compared systems. The proposed algorithm achieved an improvement in accuracy of 4.49% over k-Nearest Neighbors. As for the Support Vector Machine and Gaussian Naive Bayes (GNB) methods, they achieved a lower performance than the proposed one, reaching values of 83% and 81%, respectively. It should be noted that the proposed system showed a higher area under the curve (90%) and a balanced accuracy (90%) than the other machine learning methods. This study shows the usefulness of ML techniques for identifying and predicting SLE patients. These results demonstrate the possibility of developing automatic diagnostic support systems for SLE patients based on machine learning techniques.

Posterior reversible encephalopathy syndrome as presenting form of very early systemic sclerosis.

Introduction. Posterior Reversible Encephalopathy Syndrome (PRES) is an increasingly recognized clinical and radiological entity with a wide spectrum of symptoms. Its mechanism depends on failure of the blood-brain barrier due to high systemic blood pressure (BP) and loss of integrity of vascular endothelium related with different triggers. Methods. We aim to report a case of PRES induced by arterial hypertension and very early systemic sclerosis (SSc) not previously known. Results. A 64-year-old female was admitted due to 1-week pulsating headache more prominent on frontal scalp, accompanied by phonophobia, photophobia, and facial flushing. Neurological exam revealed brisk deep tendon reflex. Brain magnetic resonance imaging (MRI) showed subcortical lesions mainly located in posterior regions. BP was monitored and episodic arterial hypertension was detected. In laboratory tests positive anti-topoisomerase I antibodies were detected. BP was controlled with angiotensin-converting-enzyme inhibitors and headache improved. In a new MRI a month later improvement of white matter lesions was observed. Capillaroscopy showed "active pattern," considered typical of SSc. Conclusion. In SSc anti-endothelial cell antibodies impair vascular endothelium and liberation of vasoconstrictors leads to BP increasing and disruption of blood-brain barrier autoregulation mechanisms. PRES can be the first manifestation of very early SSc and this entity should be considered even in absence of skin lesions or Raynaud phenomenon.

Critical COPD respiratory illness is linked to increased transcriptomic activity of neutrophil proteases genes.

BACKGROUND: Gene expression profiling (GEP) in cells obtained from peripheral blood has shown that this is a very useful approach for biomarker discovery and for studying molecular pathogenesis of prevalent diseases. While there is limited literature available on gene expression markers associated with Chronic Obstructive Pulmonary Disease (COPD), the transcriptomic picture associated with critical respiratory illness in this disease is not known at the present moment. FINDINGS: By using Agilent microarray chips, we have profiled gene expression signatures in the whole blood of 28 COPD patients hospitalized with different degrees of respiratory compromise.12 of them needed of admission to the ICU, whilst 16 were admitted to the Respiratory Medicine Service. GeneSpring GX 11.0 software was used for performing statistical comparisons of transcript levels between ICU and non-ICU patients. Ingenuity pathway analysis 8.5 (IPA) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to select, annotate and visualize genes by function and pathway (gene ontology). T-test showed evidence of 1501 genes differentially expressed between ICU and non-ICU patients. IPA and KEGG analysis of the most representative biological functions revealed that ICU patients had increased levels of neutrophil gene transcripts, being [cathepsin G (CTSG)], [elastase, neutrophil expressed (ELANE)], [proteinase 3 (PRTN3)], [myeloperoxidase (MPO)], [cathepsin D (CTSD)], [defensin, alpha 3, neutrophil-specific (DEFA3)], azurocidin 1 (AZU1)], and [bactericidal/permeability-increasing protein (BPI)] the most representative ones. Proteins codified by these genes form part of the azurophilic granules of neutrophils and are involved in both antimicrobial defence and tissue damage. This "neutrophil signature" was paralleled by the necessity of advanced respiratory and vital support, and the presence of bacterial infection. CONCLUSION: Study of transcriptomic signatures in blood suggests an essential role of neutrophil proteases in COPD patients with critical respiratory illness. Measurement and modulation of the expression of these genes could present an option for clinical monitoring and treatment of severe COPD exacerbations.

MCP-1 in urine as biomarker of disease activity in Systemic Lupus Erythematosus.

Conventional clinical parameters are not sensitive or specific enough for detecting ongoing disease activity in the Systemic Lupus Erythematosus (SLE). Measurement of cytokines in urine is an encouraging approach to detection of early flares in this disease. Here we have profiled 27 different cytokines, chemokines and celular growth factors in the urine of 48 patients previously diagnosed of SLE as potential biomarkers of disease activity. Correlation analysis with Bonferroni correction showed that MCP-1 was the only immune mediator which levels in urine correlated directly with the SLE Disease Activity Index 2000 (SLEDAI-2K) score (correlation coefficient, p): MCP-1 (0.45,0.003). MCP-1 correlated inversely with levels of C3 complement protein in serum (-0.50,0.001). MCP-1 showed significant higher levels in patients with severe disease activity in comparison with those exhibiting mild activity. Levels of this chemokine were also higher in patients with severe disease activity in comparison with patients with inactive disease and healthy controls. Areas under receiver operating characteristic curves (AUROC) for detection of severe disease (SLEDAI⩾8) was as follows for MCP-1: [AUROC, (IC95%), p]: [0.81 (0.65-0.96) 0.003]. In addition, MCP-1 showed a good result in the AUROC analysis for detecting renal involvement [0.70 (0.52-0.87) 0.050]. When correlation analysis were repeated excluding those patients with active renal disease (n=14), levels of MCP-1 in urine kept on showing a significant positive association with SLEDAI-2K score. In conclusion, multiplex-based cytokine profiling in urine demonstrated the superiority of MCP-1 over a wide range of cytokines as biomarker of disease activity in SLE.

Host response cytokine signatures in viral and nonviral acute exacerbations of chronic obstructive pulmonary disease.

Viruses are strongly associated with acute exacerbations of chronic obstructive pulmonary disease (AECOPD). Interferon-inducible protein-10 has been recently described as a biomarker of human rhinovirus infection, but there are no reports on the role of other immune mediators in AECOPD of viral origin. As an attempt to evaluate the differences in the systemic immune mediators profiles between AECOPD patients with presence/absence of viral infection, we measured 27 cytokines, chemokines, and cellular growth factors in the plasma of 40 patients with AECOPD needing of hospitalization by using a Luminex-based assay. These patients were screened for the presence of 16 different respiratory viruses in pharyngeal swabs. Ten healthy controls were recruited for comparison purposes. Both the group of patients with an associated viral infection (n = 11) and those with no viral infection (n = 29) showed high levels of vascular endothelial growth factor, interleukin-13 (IL-13), and IL-2. On the other hand, viral infection in AECOPD induced a coordinated response of innate immunity chemokines (eotaxin, interferon-inducible protein-10, IL-8), Th1 cytokines (IL-12p70, IL-15), and the immunomodulatory IL-10. This profile corresponds to a typical antiviral response signature previously documented for other viral infections. The identification of early cytokine signatures associated with viral infection in AECOPD could contribute to design better treatment strategies for this disease.

MCP-1 en orina como biomarcador de lupus renal en ausencia de citoquinas, interferón-gamma y factores de crecimiento / MCP-1 in urine as biomarker of renal lupus in absence of cytokines, interferon-gamma and growth factors

Objetivo. Perfilar 17 medidores inmunológicos en la orina de pacientes con LES. Introducción. La nefritis lúpica es una enfermedad inflamatoria que afecta al parénquima renal. Citoquinas y quimiocinas son los mediadores inmunes dominantes relacionados con la patogénesis de la enfermedad. La obtención de marcadores de pronóstico no invasivos es un objetivo sumamente deseable para mejorar el manejo clínico de estos pacientes. Pacientes y métodos. En este estudio nosotros perfilamos 17 mediadores inmunológicos (citoquinas Th1, Th2, Th17 , quimiocinas y factores de crecimiento) en la orina de 25 pacientes con lupus y enfermedad renal activa usando un kit Biorad© 17-plex en plataforma Luminex©. Como grupo control se seleccionaron (n=10) voluntarios sanos con similar edad y sexo que los casos. Resultados. Los resultados evidenciaron que los únicos mediadores perceptibles en orina eran IL-8, MCP-1 y MIP-1β. Cuando los niveles de estos mediadores fueron comparados entre los pacientes y los controles, MCP-1 en la orina de los casos fue el único que aumentó de forma significativa (p<0,05) con respecto a los controles. Estos niveles de MCP-1 en orina se correlacionaron de forma positiva con la puntuación de SLEDAI y de forma negativa con los niveles en plasma de la proteína C4 del sistema de complemento. Conclusiones. Nuestros resultados refuerzan el papel de MCP-1 en orina como biomarcador no invasivo de actividad de enfermedad en el lupus renal, no evidenciando la detección de otros mediadores inmunológicos solubles, como son las citoquinas Th1, Th2, Th17 y factores de crecimiento (AU)

Objective. To characterize 17 immunological markers in the Urine of patients with SLE. Introduction. Lupus nephritis is an inflammatory disease affecting the renal parenchyma. Cytokines and chemokines are key immune mediators that have been related with the pathogenesis of the disease. Obtaining non invasive prognosis markers is a highly desirable objective in order to improve the clinical management of these patients. Patients and methods. In this study we profiled 17 immune mediators (Th1, Th2, Th17 cytokines, chemokines and growth factors) in the urine of 25 patients with systemic lupus erythematosus with active renal disease by using a Biorad© 17-plex kit on a Luminex© platform. A group of healthy volunteers of similar age and comparable sex distribution was recruited as control (n=10). Results. Results evidenced that the only detectable mediators in urine were IL-8, MCP-1 and MIP-1β. When levels of these mediators were compared between patients and controls, significantly higher levels of MCP-1 were observed in the urine of the patients. MCP-1 levels in urine correlated positively with the SLEDAI score in a significant way and negatively with plasma levels of complement C4. Conclusions. Our results reinforce the role of MCP-1 in urine as biomarker of disease activity in renal lupus, excluding the detection of other soluble immune mediators such as Th1, Th2 ,Th17 cytokines and growth factors as suitable markers in this non invasive sample (AU)

Prolonged standard treatment for systemic lupus erythematosus fails to normalize the secretion of innate immunity-related chemokines.

The pathogenesis of systemic lupus erythematosus (SLE) is far from having been elucidated at the molecular level. Using a multiplex system, we profiled 18 immune mediators in the plasma from 57 patients with SLE. Thirteen of them showed mild to moderate disease activity, and 29 showed severe activity, based upon the SLEDAI score. Fifteen patients were in complete clinical remission. Those patients with active disease, and those in clinical remission had been undergoing immunomodulatory treatment for an average of 10.7 months and 19.2 months respectively at the time of the visit. Samples obtained from 10 healthy volunteers were used as control. Patients with active disease and those with inactive disease showed elevated levels of the chemoattractant proteins MCP-1/CCL2, MIP1-beta/CCL4 and IL-8/CXCL8 as compared to the control (p < 0.05). This pattern of increased mediator levels was observed regardless of the immunomodulatory drug regimen received (non-steroidal anti-inflammatory, steroids or immunosuppressants), and of the degree of tissue damage. Patients with anticardiolipin antibodies (ACAs) showed significantly higher levels of IL-8 and MIP-1beta than those with no ACAs. Levels of MCP-1/CCL2, MIP1-beta/CCL4 and IL-8/CXCL8 correlated significantly, indicating a coordinated regulation of their secretion. Conversely, levels of Th1, Th2, Th17 cytokines, IFN-gamma and growth factors did not differ from those found in the healthy controls. IFN-alpha, IL-1beta, IL-6, IL-7 and IL-13 were undetectable. In conclusion, long term treatment of SLE with standard immunomodulatory drug regimens fails to normalize levels of key chemoattractant proteins linked to innate immunity. This might suggest the existence of a basal, pro-inflammatory state in patients with lupus, even in the absence of symptoms, which could serve as a "substratum" or initiator of the immunological events taking place during a flare-up of the disease.

[MCP-1 in urine as biomarker of renal lupus in absence of cytokines, interferon-γ and growth factors]. / MCP-1 en orina como biomarcador de lupus renal en ausencia de citoquinas, interferón-γ y factores de crecimiento.

OBJECTIVE: To characterize 17 immunological markers in the Urine of patients with SLE. INTRODUCTION: Lupus nephritis is an inflammatory disease affecting the renal parenchyma. Cytokines and chemokines are key immune mediators that have been related with the pathogenesis of the disease. Obtaining non invasive prognosis markers is a highly desirable objective in order to improve the clinical management of these patients. PATIENTS AND METHODS: In this study we profiled 17 immune mediators (Th1, Th2, Th17 cytokines, chemokines and growth factors) in the urine of 25 patients with systemic lupus erythematosus with active renal disease by using a Biorad© 17-plex kit on a Luminex© platform. A group of healthy volunteers of similar age and comparable sex distribution was recruited as control (n=10). RESULTS: Results evidenced that the only detectable mediators in urine were IL-8, MCP-1 and MIP-1 ß. When levels of these mediators were compared between patients and controls, significantly higher levels of MCP-1 were observed in the urine of the patients. MCP-1 levels in urine correlated positively with the SLEDAI score in a significant way and negatively with plasma levels of complement C4. CONCLUSIONS: Our results reinforce the role of MCP-1 in urine as biomarker of disease activity in renal lupus, excluding the detection of other soluble immune mediators such as Th1, Th2 ,Th17 cytokines and growth factors as suitable markers in this non invasive sample.

Comparación de citocinas plasmáticas en pacientes con neumonía adquirida en la comunidad con y sin diagnóstico previo de EPOC por una técnica multiplex / Comparison of plasma cytokines using a multiplex technique in patients with community acquired pneumonia with or without COPD

La enfermedad pulmonar obstructiva crónica (EPOC) se asocia con una mayor mortalidad en pacientes con neumonía adquirida en la comunidad (NAC). En este trabajo se comparan los valores plasmáticos de 9 citocinas en 10 pacientes ingresados en nuestro hospital por NAC diagnosticados previamente de EPOC y 10 pacientes también ingresados por NAC pero sin EPOC. Para ello se utilizó el equipo Th1/Th2 para deteccio´n mu´ltiple de citocinas de Biorad sobre una plataforma Luminex. Al ingreso, los pacientes con EPOC mostraron unos valores significativamente menores de interleucina-2, GM-CSF e IFN-γ que los pacientes sin EPOC. Estos mediadores contribuyen en gran manera a la inmunidad adaptativa y a la activación de linfocitos T, por lo que su menor concentración en plasma sugiere la existencia de una respuesta inmune empeorada en los pacientes con EPOC que presentan una NAC. Esta respuesta empeorada podría contribuir a explicar el aumento de mortalidad en estos pacientes. Nuestros resultados muestran también la utilidad de las técnicas multiplex para la detección simultánea de varios mediadores en la misma muestra en estudios de investigación clínica(AU)

Chronic obstructive pulmonary disease (COPD) is associated with increased mortality in patients with community acquired pneumonia (CAP). In this work we have compared the plasma levels of 9 cytokines in 10 patients admitted to our hospital with CAP and a previous diagnosis of COPD against the levels of 10 patients with CAP and no COPD. For this we used the Biorad TM Th1/Th2 kit for multiple detection of cytokines on a Luminex platform. At admission, patients with COPD showed significantly lower levels of IL-2, GM-CSF and IFN-γ than patients with no COPD. These mediators are key contributors to adaptive immunity and to T cell activation. As a result, their concentration in plasma suggests an impaired immune response in those patients with COPD suffering from CAP. This impaired response could help to explain the increased mortality observed in these patients. Our results also show the usefulness of multiplex methods for simultaneous detection of several mediators in the same sample in clinical research studies(AU)