Post-cardioversion time Course of Atrial Remodeling Markers and their Association with Recurrence in Subjects with Long-standing, Persistent Atrial Fibrillation.

BACKGROUND: Activation of the renin-angiotensin-aldosterone axis with elevation of inflammatory markers and the resulting fibrosis play a very important role in atrial remodeling in patients with atrial fibrillation (AF), which is associated with post-cardioversion recurrence. AIM OF THE STUDY: The purpose of the study was to describe the time course of angiotensin II (AngII), aldosterone, and of the amino terminal pro-peptide of type III pro-collagen (PIIINP) following cardioversion, and their association with arrhythmia recurrence. METHODS: Ninety-nine subjects with long-standing, persistent, non-valvular atrial fibrillation who underwent successful electrical cardioversion were included, with a 6 month follow up. Angiotensin II (AngII), aldosterone and PIIINP concentrations were measured at 0, 1, 7, 30, and 180 d. Two groups were formed for the analysis: continuing sinus rhythm and recurrence of AF. RESULTS: 53% of the subjects experienced recurrence of AF. Subjects with recurrence had larger left atrial diameters and lower global peak atrial longitudinal strain (8.7 vs. 19.7%; p <0.001), higher levels of AngII (431.85 vs. 257.97 pg/mL; p = 0.003) at 180 d, higher pre-cardioversion levels of aldosterone, (11.42 vs. 5.46 pg/mL; p = 0.048) at 1 d (12.01 vs. 5.05 pg/mL; p = 0.004) and at 180 d (12.66 vs. 7.51 pg/mL; p = 0.011). There were no differences in PIIINP levels between both groups. CONCLUSIONS: Electrical post-cardioversion recurrence in subjects with long-standing, persistent AF is associated with elevated levels of AngII and aldosterone.

Increased expression of hypoxia-induced factor 1α mRNA and its related genes in myeloid blood cells from critically ill COVID-19 patients.

BACKGROUND: COVID-19 counts 46 million people infected and killed more than 1.2 million. Hypoxaemia is one of the main clinical manifestations, especially in severe cases. HIF1α is a master transcription factor involved in the cellular response to oxygen levels. The immunopathogenesis of this severe form of COVID-19 is poorly understood. METHODS: We performed scRNAseq from leukocytes from five critically ill COVID-19 patients and characterized the expression of hypoxia-inducible factor1α and its transcriptionally regulated genes. Also performed metanalysis from the publicly available RNAseq data from COVID-19 bronchoalveolar cells. RESULTS: Critically-ill COVID-19 patients show a shift towards an immature myeloid profile in peripheral blood cells, including band neutrophils, immature monocytes, metamyelocytes, monocyte-macrophages, monocytoid precursors, and promyelocytes-myelocytes, together with mature monocytes and segmented neutrophils. May be the result of a physiological response known as emergency myelopoiesis. These cellular subsets and bronchoalveolar cells express HIF1α and their transcriptional targets related to inflammation (CXCL8, CXCR1, CXCR2, and CXCR4); virus sensing, (TLR2 and TLR4); and metabolism (SLC2A3, PFKFB3, PGK1, GAPDH and SOD2). CONCLUSIONS: The up-regulation and participation of HIF1α in events such as inflammation, immunometabolism, and TLR make it a potential molecular marker for COVID-19 severity and, interestingly, could represent a potential target for molecular therapy. Key messages Critically ill COVID-19 patients show emergency myelopoiesis. HIF1α and its transcriptionally regulated genes are expressed in immature myeloid cells which could serve as molecular targets. HIF1α and its transcriptionally regulated genes is also expressed in lung cells from critically ill COVID-19 patients which may partially explain the hypoxia related events.

A Shift Towards an Immature Myeloid Profile in Peripheral Blood of Critically Ill COVID-19 Patients.

BACKGROUND: SARS-CoV-2, the etiological agent causing COVID-19, has infected more than 27 million people with over 894000 deaths worldwide since its emergence in December 2019. Factors for severe diseases, such as diabetes, hypertension, and obesity have been identified however, the precise pathogenesis is poorly understood. To understand its pathophysiology and to develop effective therapeutic strategies, it is essential to define the prevailing immune cellular subsets. METHODS: We performed whole circulating immune cells scRNAseq from five critically ill COVID-19 patients, trajectory and gene ontology analysis. RESULTS: Immature myeloid populations, such as promyelocytes-myelocytes, metamyelocytes, band neutrophils, monocytoid precursors, and activated monocytes predominated. The trajectory with pseudotime analysis supported the finding of immature cell states. While the gene ontology showed myeloid cell activation in immune response, DNA and RNA processing, defense response to the virus, and response to type 1 interferon. Lymphoid lineage was scarce. Expression of genes such as C/EBPß, IRF1and FOSL2 potentially suggests the induction of trained immunity. CONCLUSIONS: Our results uncover transcriptomic profiles related to immature myeloid lineages and suggest the potential induction of trained immunity.

Effect of Interleukin-17 in the Activation of Monocyte Subsets in Patients with ST-Segment Elevation Myocardial Infarction.

Interleukin- (IL-) 17 is increased in acute myocardial infarction (AMI) and plays a key role in inflammatory diseases through its involvement in the activation of leukocytes. Here, we describe for the first time the effect of IL-17 in the migration and activation of monocyte subsets in patients during ST-segment elevation myocardial infarction (STEMI) and post-STEMI. We analyzed the circulating levels of IL-17 in patient plasma. A gradual increase in IL-17 was found in STEMI and post-STEMI patients. Additionally, IL-17 had a powerful effect on the recruitment of CD14++CD16+/CD14+CD16++ monocytes derived from patients post-STEMI compared with the monocytes from patients with STEMI, suggesting that IL-17 recruits monocytes with inflammatory activity post-STEMI. Furthermore, IL-17 increased the expression of TLR4 on CD14 + CD16 - and CD14++CD16+/CD14+CD16++ monocytes post-STEMI and might enhance the response to danger-associated molecular patterns post-STEMI. Moreover, IL-17 induced secretion of IL-6 from CD14++CD16- and CD14++CD16+/CD14+CD16++ monocytes both in STEMI and in post-STEMI, which indicates that IL-17 has an effect on the secretion of proinflammatory cytokines from monocytes during STEMI and post-STEMI. Overall, we demonstrate that in STEMI and post-STEMI, IL-17 is increased and induces the migration and activation of monocyte subsets, possibly contributing to the inflammatory response through TLR4 and IL-6 secretion.

Role of interleukin-17 in acute myocardial infarction.

Acute myocardial infarction (AMI) is a leading cause of death worldwide. Myocardial necrosis generates damage signals and triggers an intense inflammatory response. Many cytokines that contribute to repair tissue can also cause adverse left ventricular remodeling and heart failure. Several studies have revealed that interleukin-17 (IL-17) is a cytokine with a potential role in AMI. IL-17 plays an important role in the immune response and affects the production of different inflammatory mediators in several types of cells, involved in the damage or scar process in myocardial tissue. In this review, we will discuss the current knowledge of the role of IL-17 in AMI and the effect of IL-17 in different cells, such as cardiomyocytes, smooth muscle cells and immune system cells, in AMI pathogenesis.

Effect of Native and Minimally Modified Low-density Lipoprotein on the Activation of Monocyte Subsets.

BACKGROUND: In atherosclerosis, monocytes are essential and secrete pro-inflammatory cytokines in response to modified low-density lipoprotein (LDL). Human CD14++CD16-, CD14++CD16+ and CD14+CD16++ monocytes produce different cytokines. The objective of this research was to determine the number of monocyte subsets positives to cytokines in response to native (nLDL) and minimally modified LDL (mmLDL). METHODS: Human monocytes from healthy individuals were purified by negative selection and were stimulated with nLDL, mmLDL or LPS. Subsequently, human total monocytes were incubated with monoclonal antibodies specific for CD14 or both CD14 and CD16 to characterize total monocytes and monocyte subsets and with antibodies specific to anti-tumor necrosis factor (TNF)-α, anti-interleukin (IL)-6 and anti-IL-10. The number of cells positive for cytokines was determined and cells cultured with nLDL, mmLDL and LPS were compared with cells cultured only with culture medium. RESULTS: We found that nLDL does not induce in the total monocyte population or in the three monocyte subsets positives to cytokines. MmLDL induced in total monocytes positives to TNF-α and IL-6 as well as in both CD14++CD16+ and CD14+CD16++ and in CD14++CD16+ monocytes, respectively. Moreover, total monocytes and the three monocyte subsets expressed few amounts of cells positives to IL-10 in response to mmLDL. CONCLUSION: Our study demonstrated that nLDL did not induce cells positives to cytokines and that the CD14++CD16+ and CD14+CD16++ monocyte subsets could be the main sources of TNF-α and IL-6, respectively, in response to mmLDL, which promotes the development and progression of atherosclerotic plaque.

IL-17-differentiated macrophages secrete pro-inflammatory cytokines in response to oxidized low-density lipoprotein.

BACKGROUND: Cytokines and macrophages play a central role in the development of atherosclerosis. Interleukin (IL)-17 is a pro-inflammatory cytokine with differential effects on innate immune cells. We investigated the effects of IL-17 on macrophage differentiation and foam cell formation and activation in response to oxidized low-density lipoprotein (oxLDL). METHODS: Human monocytes were treated with IL-17 to induce macrophage differentiation. As controls, human monocytes were differentiated into M1 macrophages (M1) or M2 macrophages (M2). Subsequently, we analyzed the expression levels of markers such as CD80, CD36 and Toll-like receptors (TLRs) as well as foam cell formation and cytokines in M1, M2 and macrophages differentiated with IL-17 with or without oxLDL. RESULTS: The expression of M1 or M2 markers or cytokines was not induced in macrophages differentiated with IL-17. Macrophages differentiated with IL-17 formed few foam cells, with an average proportion of 20%, and expressed 3 times as much TLR2 and 3.8 times as much TLR4 as M0 macrophages. Additionally, macrophages differentiated with IL-17 acquired inflammatory capacity in response to oxLDL through the expression of specific markers, such as CD80, which increased 18-times compared with macrophages differentiated with IL-17 alone, and secreted 1.3 times less tumor necrosis factor (TNF)-α than M1. Additionally, oxLDL increased the levels of CD80, CD86 and IL-6 by 5.7, 2.8 and 1.4 times in M1 compared with M1 in the absence of oxLDL. In M2, oxLDL induced increases in the secretion of IL-6 and TNF-α that were 1.9 times and 1.2 times smaller, respectively, than those observed in M1. CONCLUSION: Our study demonstrates that differentiation of macrophages with IL-17 does not induce the expression of markers or cytokines characteristic of M1 or M2 and these macrophages form few foam cells; however, the expression of TLR is increased. Moreover, these macrophages acquire the inflammatory capacity as evidenced by the expression of costimulatory molecules and secretion of pro-inflammatory cytokines in response to oxLDL. These findings suggest that the activation of macrophages differentiated with IL-17 by oxLDL contributes to the inflammatory process of atherosclerosis.

[ANCA-associated vasculitides at Mexico City's metropolitan Eastern area]. / Vasculitis asociadas a ANCA en la zona metropolitana oriente de la Ciudad de México.

BACKGROUND: The anti-neutrophil cytoplasmic antibody-associated (ANCA) vasculitides includes granulomatosis with polyangiitis (Wegener's) (GPW), Chrug-Strauss syndrome (CSS) and microscopic polyangiitis (MPA). Since it has low incidence in our field, there are a few published papers. The aim of this study was to report the clinical characteristics, activity and damage of these vasculitides in Mexico City's metropolitan eastern area. METHODS: We studied 28 cases with ANCA-associated vasculitis in the aforementioned area. The classification was made according to the ACR 1990 criteria, the Chapel Hill 2012 consensus, and the EULAR 2007 recommendations. We collected demographic data, as well as data of clinical manifestations, laboratory, management and outcomes. The activity was established using the Birmingham Vasculitis Activity Score (BVAS) and the damage using the Vasculitis Damage Index (VDI). We used paired t test and 95% confidence intervals (95% CI). RESULTS: 15 females and 13 males were included, 20 with GPW and 8 with CCS. The mean age was 50.1 ± 12.7 years, and the evolution time was 69 ± 49.6 months. We didn't find cases of MAP. 23 patients (82.1%) had general symptoms. The initial and final BVAS means were 10.5 and 1.5 (p < 0.001) and the global VDI was 2.4. CONCLUSIONS: The presence of ANCA-associated vasculitides is rare in the eastern Metropolitan area of Mexico City. GPW was predominant over CCS, and MPA was absent. They are multi-system vasculitides with high scores of initial activity and moderate damage.

Introducción: las vasculitis asociadas a anticuerpos anticitoplasma de neutrófilo (ANCA) incluyen la granulomatosis con poliangeítis (GPW), el síndrome de Churg-Strauss (SChS) y la poliangeítis microscópica (PAM). Como son de baja incidencia, los informes son escasos. El objetivo fue reportar las características clínicas, la actividad y el daño de casos con estas vasculitis en la zona oriente de la Ciudad de México. Métodos: Se incluyeron 28 casos. La clasificación de las vasculitis se hizo según los criterios ACR 1990, Chapel Hill 2012 y EULAR 2007. Se recabaron datos demográficos, manifestaciones clínicas, de laboratorio, tratamientos y evolución clínica. Se determinó el puntaje de actividad de Birmingham (BVAS) y el daño de la vasculitis (VDI). Se utilizó la prueba t pareada e intervalos de confianza al 95% (IC 95%). Resultados: 15 mujeres y 13 hombres fueron incluidos, 20 con GPW y 8 con SChS, con edad de 50.1 ± 12.7 años y evolución de 69 ± 49.6 meses. No hubo casos con PAM. Presentaron ataque al estado general 23 (82.1%). Los promedios BVAS inicial y final fueron: 10.5 y 1.5 (p < 0.001) y el VDI global fue de 2.4. Conclusiones: las vasculitis asociadas a ANCA son raras en esta zona de la Ciudad de México. Predominaron los casos de GPW sobre SChS y fueron nulos para PAM. Tienen presentación multisistémica, altos puntajes de actividad inicial y daño moderado.

Enteral Docosahexaenoic Acid Reduces Analgesic Administration in Neonates Undergoing Cardiovascular Surgery.

BACKGROUND: Neonates undergoing surgery require analgesic medication to ameliorate acute pain. These medications produce negative side effects. Docosahexaenoic acid (DHA) has an antinociceptive effect in animals, but this has not been evaluated in human neonates. We evaluated the DHA effect on cumulative dose and duration of analgesics administered to neonates undergoing cardiovascular surgery. METHODS: A secondary analysis was performed with data from a clinical trial, in which enteral DHA was administered perioperatively compared with sunflower oil (SO). Present study assessed the antinociceptive effect of DHA by measuring the cumulative dose and duration of analgesics administered during postoperative stay in a neonatal intensive care unit. Multivariate linear regression models were performed. RESULTS: Seventeen neonates received DHA and 18 received SO in the control group. Compared with the control group, the DHA group received lower cumulative dose (14.6 ± 2.2 vs. 25.2 ± 4.8 µg/kg, p = 0.029) and shorter duration of buprenorphine (2 days (1-8) vs. 4.5 days (1-12); p = 0.053). After adjusting for confounders, the DHA group received significantly lesser buprenorphine (ß = -27 µg/kg, p = 0.028; R2 model = 0.90) for shorter duration (ß = -9 days, p = 0.003; R2 model = 0.94). No differences in fentanyl or ketorolac were detected. CONCLUSIONS: Buprenorphine administration was reduced in neonates who received DHA, suggesting that DHA likely has analgesic effects.

Differential Expression of O-Glycans in CD4(+) T Lymphocytes from Patients with Systemic Lupus Erythematosus.

T cells from patients with systemic lupus erythematosus (SLE) show a decreased activation threshold and increased apoptosis. These processes seem to be regulated by glycosylated molecules on the T cell surface. Here, we determined through flow cytometry the expression of mucin-type O-glycans on T helper cells in peripheral blood mononuclear cells (PBMC) from 23 SLE patients and its relation with disease activity. We used lectins specific for the disaccharide Gal-GalNAc, such as Amaranthus leucocarpus lectin (ALL), Artocarpus integrifolia lectin (jacalin) and Arachis hypogaea lectin (peanut agglutinin, PNA), as well as lectins for sialic acid such as Sambucus nigra agglutinin (SNA) and Maakia amurensis agglutinin (MAA). The results showed that ALL, but not jacalin or PNA, identified significant differences in O-glycan expression on T helper cells from active SLE patients (n = 10). Moreover, an inverse correlation was found between the frequency of T helper cells recognized by ALL and SLE Disease Activity Index (SLEDAI) score in SLE patients. In contrast, SNA and MAA lectins did not identify any differences between CD4(+) T cells from SLE patients. There was no difference in the recognition by ALL on activated T helper cells and T regulatory (Treg) cells. Our findings point out that activation of SLE disease diminishes the expression of O-glycans in T helper cells; ALL could be considered as a marker to determine activity of the disease.

Beneficial Effects of Enteral Docosahexaenoic Acid on the Markers of Inflammation and Clinical Outcomes of Neonates Undergoing Cardiovascular Surgery: An Intervention Study.

BACKGROUND: Neonates undergoing surgery are at risk for uncontrolled inflammatory response and adverse clinical outcomes. Docosahexaenoic acid (DHA) ameliorates inflammation, improving clinical outcomes. However, its effect has not been evaluated in neonates undergoing surgery. We evaluated the effect of DHA on markers of inflammation and clinical outcomes in neonates undergoing surgery. METHODS: A double-blind clinical trial evaluated the effect of enteral DHA (DHA group) versus sunflower oil (SO group) perioperatively administered in neonates scheduled for cardiovascular surgery. Inflammation was evaluated by percentage of cells+ for cytokines and CD69 in mononuclear cells at baseline, 24 h and 7 days post surgery. Clinical outcomes measured were sepsis, organ dysfunctions (ODs), length of stay in intensive care and bleeding. Repeated measures analysis of variance and logistic regression were applied. RESULTS: Sixteen neonates received DHA and 18 received SO. Cells+ from neonates in the DHA group showed an early increase in receptor antagonist of interleukin (IL)-1+ (IL-1ra+) and IL-10+ and a late decrease in IL-6+. IL-1ß+ and IL-10+ changes were different between groups. After adjusting for confounders, less cells from DHA group were IL-1ß+, IL-6+, IL-1ra+ and IL-10+. DHA group presented less sepsis, ODs and shorter stay, but no difference in CD69+CD4+ cells or bleeding between groups. CONCLUSIONS: Administration of enteral DHA ameliorates markers of inflammation and improves clinical outcomes in surgical neonates.

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.

Function of Treg Cells Decreased in Patients With Systemic Lupus Erythematosus Due To the Effect of Prolactin.

Prolactin has different functions, including cytokine secretion and inhibition of the suppressor effect of regulatory T (Treg) cells in healthy individuals. Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by defects in the functions of B, T, and Treg cells. Prolactin plays an important role in the physiopathology of SLE. Our objective was to establish the participation of prolactin in the regulation of the immune response mediated by Treg cells from patients with SLE. CD4CD25CD127 cells were purified using magnetic beads and the relative expression of prolactin receptor was measured. The functional activity was evaluated by proliferation assay and cytokine secretion in activated cells, in the presence and absence of prolactin. We found that both percentage and function of Treg cells decrease in SLE patients compared to healthy individuals with statistical significance. The prolactin receptor is constitutively expressed on Treg and effector T (Teff) cells in SLE patients, and this expression is higher than in healthy individuals. The expression of this receptor differs in inactive and active patients: in the former, the expression is higher in Treg cells than in Teff cells, similar to healthy individuals, whereas there is no difference in the expression between Treg and Teff cells from active patients. In Treg:Teff cell cocultures, addition of prolactin decreases the suppressor effect exerted by Treg cells and increases IFNγ secretion. Our results suggest that prolactin plays an important role in the activation of the disease in inactive patients by decreasing the suppressor function exerted by Treg cells over Teff cells, thereby favoring an inflammatory microenvironment.

Clinical outcome in patients with acute coronary syndrome and outward remodeling is associated with a predominant inflammatory response.

BACKGROUND: Pro-inflammatory molecules and low-density lipoproteins play essential roles in the atherosclerosis. The aim of our study was to establish an association among the cytokines secreted by peripheral blood mononuclear cells and the serum concentration in patients with unstable angina and coronary outward remodeling before and after percutaneous coronary intervention. The clinical and coronary responses were evaluated 6 months after the procedure. FINDINGS: Twenty-two patients with unstable angina were evaluated prior to after percutaneous coronary intervention and 6 months after procedure by coronary intravascular ultrasound. Eleven of the patients had recurrent angina, while 9 presented restenosis and an increase in the percentage of total plaque area. These 11 patients displayed higher levels of C-reactive protein than those without coronary events (1.27 vs. 0.43 mg/dl, respectively; p = 0.029) and a tendency to increase levels of interleukin (IL)-8 and transforming growth factor-ß1, but lower levels of IL-10 (52.09 vs. 141.5 pg/ml, respectively; p = 0.035). Activated peripheral blood mononuclear cells from patients with restenosis presented higher levels of proliferation, CD86 expression and higher IL-1, and increased IL-10 compared to those in patients without restenosis. CONCLUSIONS: Patients with unstable angina and coronary outward remodeling who displayed a pro-inflammatory response experienced recurrent coronary events and an increased percentage of total plaque area. In contrast, better outcomes were observed in patients with anti-inflammatory responses. This response could be secondary to low-density lipoproteins.

The role of TLR2, TLR4 and CD36 in macrophage activation and foam cell formation in response to oxLDL in humans.

UNLABELLED: Toll-like receptor (TLR)2, TLR4 and CD36 are central in inflammation and the development of atherosclerosis. Oxidized low-density lipoprotein (oxLDL) plays a critical role in this disease through its involvement in the formation of foam cells and the activation of leukocytes. The aim of this research was to analyze the role of TLR2, TLR4 and CD36 in foam cell differentiation and macrophage activation. METHODS: Human macrophages were incubated with monoclonal antibodies specific for TLR2, TLR4 and CD36 prior to stimulation with oxLDL. Subsequently, we analyzed foam cell formation, cytokine secretion, histocompatibility complex (MHC) class II molecules and CD86 expression and T cell proliferation. RESULTS: The stimulation of macrophages with oxLDL induced foam cell formation, cytokine secretion, HLA-DR and CD86 expression and T cell proliferation. The blockage of TLR2, TLR4 and CD36 reduced the secretion of IL-1ß, IL-6 and IL-8, the expression of HLA-DR and CD86, T cell proliferation and foam cell formation. However, the blockage of TLR2 did not affect the formation of foam cells. CONCLUSION: Our study demonstrates that TLR2, TLR4 and CD36 participate in the immune response to oxLDL by inducing an increase in pro-inflammatory cytokines, the expression HLA-DR and CD86 and the proliferation of T cells. However, TLR2 does not participate in the formation of foam cells, while TLR4 and CD36 play a relevant role in this process. These findings suggest that the activation of these receptors by oxLDL contributes to the pathogenesis of atherosclerosis.

Innate immune system cells in atherosclerosis.

Atherosclerosis is a chronic inflammatory disease of the arterial wall characterized by innate and adaptive immune system involvement. A key component of atherosclerotic plaque inflammation is the persistence of different innate immune cell types including mast cells, neutrophils, natural killer cells, monocytes, macrophages and dendritic cells. Several endogenous signals such as oxidized low-density lipoproteins, and exogenous signals such as lipopolysaccharides, trigger the activation of these cells. In particular, these signals orchestrate the early and late inflammatory responses through the secretion of pro-inflammatory cytokines and contribute to plaque evolution through the formation of foam cells, among other events. In this review we discuss how innate immune system cells affect atherosclerosis pathogenesis.

Monocyte locomotion inhibitory factor produced by E. histolytica improves motor recovery and develops neuroprotection after traumatic injury to the spinal cord.

Monocyte locomotion inhibitory factor (MLIF) is a pentapeptide produced by Entamoeba histolytica that has a potent anti-inflammatory effect. Either MLIF or phosphate buffered saline (PBS) was administered directly onto the spinal cord (SC) immediately after injury. Motor recovery was evaluated. We also analyzed neuroprotection by quantifying the number of surviving ventral horn motor neurons and the persistence of rubrospinal tract neurons. To evaluate the mechanism through which MLIF improved the outcome of SC injury, we quantified the expression of inducible nitric oxide synthase (iNOS), interleukin-10 (IL-10), and transforming growth factor- ß (TGF- ß ) genes at the site of injury. Finally, the levels of nitric oxide and of lipid peroxidation were also determined in peripheral blood. Results showed that MLIF improved the rate of motor recovery and this correlated with an increased survival of ventral horn and rubrospinal neurons. These beneficial effects were in turn associated with a reduction in iNOS gene products and a significant upregulation of IL-10 and TGF- ß expression. In the same way, MLIF reduced the concentration of nitric oxide and the levels of lipid peroxidation in systemic circulation. The present results demonstrate for the first time the neuroprotective effects endowed by MLIF after SC injury.

Prolactin levels correlate with abnormal B cell maturation in MRL and MRL/lpr mouse models of systemic lupus erythematosus-like disease.

Prolactin (PRL) plays an important role in modulating the immune response. In B cells, PRL enhances antibody production, including antibodies with self-specificity. In this study, our aims were to determine the level of PRL receptor expression during bone-marrow B-cell development and to assess whether the presence of high PRL serum concentrations influences absolute numbers of developing populations and disease outcome in lupus-prone murine models. We observed that the PRL-receptor is expressed in early bone-marrow B-cell; the expression in lupus-prone mice, which had the highest level of expression in pro-B cells and immature cells, differed from that in wild-type mice. These expression levels did not significantly change in response to hyperprolactinemia; however, populations of pro-B and immature cells from lupus-prone strains showed a decrease in the absolute numbers of cells with high PRL-receptor expression in response to PRL. Because immature self-reactive B cells are constantly being eliminated, we assessed the expression of survival factor BIRC5, which is more highly expressed in both pro-B and immature B-cells in response to PRL and correlates with the onset of disease. These results identify an important role of PRL in the early stages of the B-cell maturation process: PRL may promote the survival of self-reactive clones.

Participación de la prolactina en la respuesta inmune / Role of prolactin in the immune response

Existen evidencias de la relación entre el sistema inmune y el endocrino vía múltiples factores de comunicación, como citocinas, neuropéptidos, neurotransmisores y hormonas. Se ha demostrado la participación de la hormona prolactina en la respuesta inmune innata y adaptativa. Además de ser producida por la glándula pituitaria, también es producida y secretada por las células del sistema inmunológico. El objetivo de esta revisión fue puntualizar acerca de la participación de la prolactina secretada por estas células en la respuesta inmune.

Evidence exists about the relationship between the immune and the endocrine systems through communication of multiple factors such as cytokines, neuropeptides, neurotransmitters and hormones. Among the hormones, prolactin (PRL) has been shown to participate in the innate and adaptive immune response. In addition to being produced by the pituitary gland, PRL is also produced and secreted by cells of the immune system. The aim of this review is to update information about the involvement of PRL secreted by immune system cells in the immune response.

Increased levels of prolactin receptor expression correlate with the early onset of lupus symptoms and increased numbers of transitional-1 B cells after prolactin treatment.

BACKGROUND: Prolactin is secreted from the pituitary gland and other organs, as well as by cells such as lymphocytes. Prolactin has an immunostimulatory effect and is associated with autoimmune diseases that are characterised by abnormal B cell activation, such as systemic lupus erythematosus (SLE). Our aim was to determine if different splenic B cell subsets express the prolactin receptor and if the presence of prolactin influences these B cell subsets and correlates with development of lupus. RESULTS: Using real-time PCR and flow cytometry, we found that different subsets of immature (transitional) and mature (follicular, marginal zone) B cells express different levels of the prolactin receptor and are differentially affected by hyperprolactinaemia. We found that transitional B cells express the prolactin receptor at higher levels compared to mature B cells in C57BL/6 mice and the lupus-prone MRL/lpr and MRL mouse strains. Transitional-1 (T1) B cells showed a higher level of prolactin receptor expression in both MRL/lpr and MRL mice compared to C57BL/6 mice. Hyperprolactinaemia was induced using metoclopramide, which resulted in the development of early symptoms of SLE. We found that T1 B cells are the main targets of prolactin and that prolactin augments the absolute number of T1 B cells, which reflects the finding that this B cell subpopulation expresses the highest level of the prolactin receptor. CONCLUSIONS: We found that all B cell subsets express the prolactin receptor but that transitional B cells showed the highest prolactin receptor expression levels. Hyperprolactinaemia in mice susceptible to lupus accelerated the disease and increased the absolute numbers of T1 and T3 B cells but not of mature B cells, suggesting a primary effect of prolactin on the early stages of B cell maturation in the spleen and a role of prolactin in B cell differentiation, contributing to SLE onset.