Prolactin promotes proliferation of germinal center B cells, formation of plasma cells, and elevated levels of IgG3 anti-dsDNA autoantibodies.

Systemic lupus erythematosus (SLE) mainly affects females at reproductive age, which has been associated with hormones, such as prolactin (PRL). Different studies suggest that PRL exacerbates the clinical manifestations of SLE both in patients and in mouse models (e.g., the MRL/lpr strain), increasing the production of autoantibodies, which can be deposited as immune complexes and trigger inflammation and damage to different tissues. The objective of this work was to explore the potential mechanisms by which PRL increases the concentration of self-reactive antibodies in the MRL/lpr SLE model. To this end, we determined the role of PRL on the activation and proliferation of germinal center B cells (B-GCs) and their differentiation into antibody-secreting cells (ASCs). We show that the absolute number and percentage of B-GCs were significantly increased by PRL in vivo or upon in vitro treatment with anti-IgM and anti-CD40 antibodies and PRL. The augmented B-GC numbers correlated with enhanced proliferation, but we did not observe enhanced expression of CD80 and CD86 activation markers or the BCL6 transcription factor, arguing against a more effective differentiation. Nevertheless, we observed enhanced phosphorylation of STAT1, secretion of IL-6, expression of IRF4, numbers of ASCs, and levels of IgG3 antibodies directed against dsDNA. Altogether, these results support the hypothesis that a PRL-mediated expansion of B-GCs yields more self-reactive ASCs, potentially explaining the pathogenic immune complexes that steadily lead to tissue damage during SLE.

Could SARS-CoV-2 blocking of ACE2 in endothelial cells result in upregulation of CX3CL1, promoting thrombosis in COVID-19 patients?

SARS-CoV-2 is the causal agent of COVID-19 disease. Currently, infection with SARS-CoV-2 has been the cause of death of over 2.5 million people globally, and there is still no effective curative treatment. Clinically, the severe symptoms caused by COVID-19, in addition to pneumonia, are associated with the development of hyperinflammatory syndrome and thrombosis. It is urgent to expand our understanding of the molecular mechanisms involved in the pathophysiology of COVID-19. This article discusses the potential role that the chemokine CX3CL1 could have in the development of COVID-19-associated thrombosis. CX3CL1 is abundantly expressed by activated endothelium and is an important regulator of many aspects of endothelial function and dysfunction, including thrombosis. The generation of hypotheses about molecules that could be relevant in well-defined aspects of the pathophysiology of COVID-19 encourages the development of basic and clinical studies, that could help find effective and much needed treatments.

Regulation and biological functions of the CX3CL1-CX3CR1 axis and its relevance in solid cancer: A mini-review.

CX3CL1 is a transmembrane protein from which a soluble form can be generated by proteolytic shedding. Membranal and soluble forms of CX3CL1 exhibit different functions, although both bind to the CX3CR1 chemokine receptor. The CX3CL1-CX3CR1 axis mediates the adhesion of leukocytes and is also involved in cell survival and recruitment of immune cell subpopulations. The function of CX3CL1 is finely tuned by cytokines and transcription factors regulating its expression and post-translational modifications. On homeostasis, the CX3CL1-CX3CR1 axis participates in the removal of damaged neurons and neurogenesis, and it is also involved on several pathological contexts. The CX3CL1-CX3CR1 axis induces several cellular responses relevant to cancer such as proliferation, migration, invasion and apoptosis resistance. In this review, we address biological aspects of this molecular axis with important therapeutic potential, emphasizing its role in cancer, one of the most prevalent chronic diseases which significantly affect the quality of life and life expectancy of patients.

Application of chemoresistive gas sensors and chemometric analysis to differentiate the fingerprints of global volatile organic compounds from diseases. Preliminary results of COPD, lung cancer and breast cancer.

BACKGROUND: Analysis of volatile organic compounds (VOCs) in exhaled breath has been proposed as a screening method that discriminates between disease and healthy subjects, few studies evaluate whether these chemical fingerprints are specific when compared between diseases. We evaluated global VOCs and their discrimination capacity in chronic obstructive pulmonary disease (COPD), lung cancer, breast cancer and healthy subjects by chemoresistive sensors and chemometric analysis. METHODS: A cross-sectional study was conducted with the participation of 30 patients with lung cancer, 50 with breast cancer, 50 with COPD and 50 control subjects. Each participant's exhaled breath was analyzed with the electronic nose. A multivariate analysis was carried: principal component analysis (PCA) and, canonical analysis of principal coordinates (CAP). Twenty single-blind samples from the 4 study groups were evaluated by CAP. RESULTS: A separation between the groups of patients to the controls was achieved through PCA with explanations of >90% of the data and with a correct classification of 100%. In the CAP of the 4 study groups, discrimination between the diseases was obtained with 2 canonical axes with a correct general classification of 91.35%. This model was used for the prediction of the single-blind samples resulting in correct classification of 100%. CONCLUSIONS: The application of chemoresistive gas sensors and chemometric analysis can be used as a useful tool for a screening test for lung cancer, breast cancer and COPD since this equipment detects the set of VOCs present in the exhaled breath to generate a characteristic chemical fingerprint of each disease.

Prolactin Rescues Immature B Cells from Apoptosis-Induced BCR-Aggregation through STAT3, Bcl2a1a, Bcl2l2, and Birc5 in Lupus-Prone MRL/lpr Mice.

Self-reactive immature B cells are eliminated through apoptosis by tolerance mechanisms, failing to eliminate these cells results in autoimmune diseases. Prolactin is known to rescue immature B cells from B cell receptor engagement-induced apoptosis in lupus-prone mice. The objective of this study was to characterize in vitro prolactin signaling in immature B cells, using sorting, PCR array, RT-PCR, flow cytometry, and chromatin immunoprecipitation. We found that all B cell maturation stages in bone marrow express the prolactin receptor long isoform, in both wild-type and MRL/lpr mice, but its expression increased only in the immature B cells of the latter, particularly at the onset of lupus. In these cells, activation of the prolactin receptor promoted STAT3 phosphorylation and upregulation of the antiapoptotic Bcl2a1a, Bcl2l2, and Birc5 genes. STAT3 binding to the promoter region of these genes was confirmed through chromatin immunoprecipitation. Furthermore, inhibitors of prolactin signaling and STAT3 activation abolished the prolactin rescue of self-engaged MRL/lpr immature B cells. These results support a mechanism in which prolactin participates in the emergence of lupus through the rescue of self-reactive immature B cell clones from central tolerance clonal deletion through the activation of STAT3 and transcriptional regulation of a complex network of genes related to apoptosis resistance.

Prolactin Increases the Frequency of Follicular T Helper Cells with Enhanced IL21 Secretion and OX40 Expression in Lupus-Prone MRL/lpr Mice.

Systemic lupus erythematosus is characterized by high levels of IgG class autoantibodies that contribute to the pathophysiology of the disease. The formation of these autoantibodies occurs in the germinal centers, where there is cooperation between follicular T helper cells (TFH) and autoreactive B cells. Prolactin has been reported to exacerbate the clinical manifestations of lupus by increasing autoantibody concentrations. The objective of this study was to characterize the participation of prolactin in the differentiation and activation of TFH cells, by performing in vivo and in vitro tests with lupus-prone mice, using flow cytometry and real-time PCR. We found that TFH cells express the long isoform of the prolactin receptor and promoted STAT3 phosphorylation. Receptor expression was higher in MRL/lpr mice and correlative with the manifestations of the disease. Although prolactin does not intervene in the differentiation of TFH cells, it does favor their activation by increasing the percentage of TFH OX40+ and TFH IL21+ cells, as well as leading to high serum concentrations of IL21. These results support a mechanism in which prolactin participates in the emergence of lupus by inducing overactive TFH cells and perhaps promoting dysfunctional germinal centers.

Identification of breath-prints for the COPD detection associated with smoking and household air pollution by electronic nose.

PURPOSE: The analysis of breath-print, has been proposed as an attractive alternative to investigate possible biomarkers of Chronic Obstructive Pulmonary Disease (COPD). The aim of the present study was to discriminate between healthy subjects, patients with COPD associated with smoking (COPD-S) and patients with COPD associated with household air pollution (COPD-HAP). METHODS: A cross-sectional study of 294 participants was conducted, 88 with smoking associated COPD, 28 associated with HAP and 178 healthy subjects. Breath-print analysis was performed by using the Cyranose 320 electronic nose. Group data were evaluated by Principal Component Analysis (PCA), Canonical Discriminant Analysis (CDA) and Support Vector Machine (SVM) and the test's diagnostic power by means of ROC (Receiver Operating Characteristic) curves. RESULTS: The results indicated that the breath-print of patients with COPD is different from the one of healthy subjects explaining a variability of 93.8% with a correct prediction of 97.8% and correct classification of 100%,also positive and negative predictive value of 96.5 and 100% respectively. Furthermore, the breath-print of exhaled breath from patients with COPD-S and COPD-HAP does not present any difference. CONCLUSIONS: The breath-print of exhaled breath from patients with COPD-S and COPD-HAP does not present any difference, which demonstrates that the breath-print is related to the disease and not to causality. With these results, the analysis of the breath-print of COPD is proposed as an alternative for a screening method in future clinical applications.

Identification of profiles of volatile organic compounds in exhaled breath by means of an electronic nose as a proposal for a screening method for breast cancer: a case-control study.

The objective of the present study was to identify volatile prints from exhaled breath, termed breath-print, from breast cancer (BC) patients and healthy women by means of an electronic nose and to evaluate its potential use as a screening method. A cross-sectional study was performed on 443 exhaled breath samples from women, of whom 262 had been diagnosed with BC by biopsy and 181 were healthy women (control group). Breath-print analysis was performed utilizing the Cyranose 320 electronic nose. Group data were evaluated by principal component analysis (PCA), canonical discriminant analysis (CDA), and support vector machine (SVM), and the test's diagnostic power was evaluated by means of receiver operating characteristic (ROC) curves. The results obtained using the model generated from the CDA, which best describes the behavior of the assessed groups, indicated that the breath-print of BC patients was different from that of healthy women and that they presented with a variability of up to 98.8% and a correct classification of 98%. The sensitivity, specificity, negative predictive value, and positive predictive value reached 100% according to the ROC curve. The present study demonstrates the capability of the electronic nose to separate between healthy subjects and BC patients. This research could have a beneficial impact on clinical practice as we consider that this test could probably be used at the first point before the application of established gold tests (mammography, ultrasound, and biopsy) and substantially improve screening tests in the general population.

Prolactin Rescues Immature B-Cells from Apoptosis Induced by B-Cell Receptor Cross-Linking.

Prolactin has an immunomodulatory effect and has been associated with B-cell-triggered autoimmune diseases, such as systemic lupus erythematosus (SLE). In mice that develop SLE, the PRL receptor is expressed in early bone marrow B-cells, and increased levels of PRL hasten disease manifestations, which are correlated with a reduction in the absolute number of immature B-cells. The aim of this work was to determine the effect of PRL in an in vitro system of B-cell tolerance using WEHI-231 cells and immature B-cells from lupus prone MRL/lpr mice. WEHI-231 cells express the long isoform of the PRL receptor, and PRL rescued the cells from cell death by decreasing the apoptosis induced by the cross-linking of the B-cell antigen receptor (BCR) as measured by Annexin V and active caspase-3. This decrease in apoptosis may have been due to the PRL and receptor interaction, which increased the relative expression of antiapoptotic Bcl-xL and decreased the relative expression of proapoptotic Bad. In immature B-cells from MRL/lpr mice, PRL increased the viability and decreased the apoptosis induced by the cross-linking of BCR, which may favor the maturation of self-reactive B-cells and contribute to the onset of disease.

Role of Chemokines in Non-Small Cell Lung Cancer: Angiogenesis and Inflammation.

Non-small cell lung cancer (NSCLC) is one of the most common types of aggressive cancer. The tumor tissue, which shows an active angiogenesis, is composed of neoplastic and stromal cells, and an abundant inflammatory infiltrate. Angiogenesis is important to support tumor growth, while infiltrating cells contribute to the tumor microenvironment through the secretion of growth factors, cytokines and chemokines, important molecules in the progression of the disease. Chemokines are important in development, activation of the immune response, and physiological angiogenesis. Chemokines have emerged as important regulators in the pathophysiology of cancer. These molecules are involved in the angiogenesis/angiostasis balance and in the recruitment of tumor infiltrating hematopoietic cells. In addition, chemokines promote tumor cell survival, as well as the directing and establishment of tumor cells to metastasis sites. The findings summarized here emphasize the central role of chemokines as modulators of tumor angiogenesis and their potential role as therapeutic targets in the inflammatory process of NSCLC angiogenesis.

Aspectos inmunlóógicos del envejecimiento

La inmunosenescencia es un proceso complejo que involucra múltiples cambios en las poblaciones linfocitarias. Estos cambios en el adulto mayor incrementan la incidencia y severidad de las enfermedades infecciosas y algunos cánceres. En este artículo revisamos algunos de los cambios inmunológicos más relevantes que han sido descritos durante el envejecimiento y su asociación con algunas patologías.

Immunosenescence is a complex process involving multiple changes in lymphocyte subsets. In the elderly, these changes contribute to an increased incidence and severity of infectious diseases and some types of cancer. This paper reviews some of the immunological changes in the elderly and their association with certain diseases.

Oxido nítrico, una molécula multifuncional / Nitric oxide, a multifunctional molecule

El óxido nítrico es un regulador importante de diversas funciones fisiológicas y además, es un factor que contribuye a la respuesta inmune innata. Su efecto también puede estar relacionado a procesos patológicos como el asma o la inflamación crónica. Objetivo. En este trabajo se revisaron algunos aspectos bioquímicos, inmunológicos y fisiopatológicos del óxido nítrico

Moléculas de cooperación y regulación durante la migración celular en la respuesta inflamatoria / Molecules for cooperation and regulation during cell migration in the inflammatory response

En la superficie de todas las células existen estructuras sacarídicas, dentro de sus múltiples funciones fisiológicas se ha logrado identificar que funcionan como comunicadores intercelulares. En el caso de los leucocitos estas estructuras le permiten, por mecanismos de adherencia, identificar a los sitios de inflamación, este proceso se efectúa gracias a la interacción específica de diversas familias de glicoproteínas de superficie celular entre las que se considera a las denominadas "selectinas", las integrinas y las moléculas pertenecientes a la superfamilia de las inmunoglobulinas. En este Trabajo, se revisan las características moleculares de estas proteínas adhesivas y, los diversos procesos inflamatorios en los que están involucradas

Respuesta inmune en la tuberculosis / Immune response in tuberculosis

La tuberculosis es una de las enfermedades infecciosas más antiguas que han afectado al hombre. En la actualidad, representa uno de los padecimientos más importantes como causa de muerte. En este trabajo se pretende discutir algunos aspectos recientemente identificados relacionados con la fisiopatogenia de la enfermedad y que incluyen la respuesta inmune del individuo y a la capacidad que posee para reconocer, adecuadamente, al agente etiológico. El conocimiento de esta enfermedad en el contexto del sistema de histocompatibilidad, representa un avance importante en la identificación oportuna de individuos o poblaciontes de alto riesgo de enfermedades, lo que permitirá contemplar alternativas de pronósticos y/o tratamiento