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Mario Juárez-Ortega,1 Oscar Rojas-Espinosa,1 Raquel Muñiz-Salazar,2 Enrique Becerril-Villanueva,3 Alejandro Hernández-Solís,4 Patricia Arce-Paredes,1 Sergio Islas-Trujillo,1 Raúl Cicero-Sabido4 1Department of Immunology, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City, Mexico; 2School of Health Sciences, Unidad Ensenada, Universidad Autónoma de Baja California, Ensenada, BC, Mexico; 3Laboratory of Psychoimmunology, Dirección de Investigaciones en Neurociencias, Instituto Nacional de Psiquiatría Ramón de la Fuente, Mexico City, Mexico; 4Pneumology Unit, Hospital General de México “Eduardo Liceaga”, UNAM, Mexico City, Mexico Background: Resident alveolar macrophages, dendritic cells, and immigrating neutrophils (NEU) are the first cells to contact Mycobacterium tuberculosis in the lung. These cells, and additional lymphoid cells in the developing granuloma, release a series of components that may concentrate in the serum and affect disease progression. Purpose: The aim of this study was to investigate the effect of the serum from tuberculosis (TB) patients and their household contacts (HHC) on the nuclear morphology of NEU. Materials and methods: NEU from healthy (HLT) people were incubated with sera from patients with active pulmonary TB, their HHC, and unrelated people. Changes in the nuclear morphology of NEU were analyzed by light and electron microscopy. Results: Sera from patients with TB induced changes in the nuclear morphology of NEU that included pyknosis, swelling, apoptosis, and netosis in some cases. Sera from some HHC induced similar changes, while sera from HLT people had no significant effects. Bacteria did not appear to participate in this phenomenon because bacteremia is not a recognized feature of nonmiliary TB, and because sera from patients that induced nuclear changes maintained their effect after filtration through 0.22 µm membranes. Neither anti-mycobacterial antibodies, TNFα, IL-6, IFNγ, or IL-8 participated in the phenomenon. In contrast, soluble mycobacterial antigens were likely candidates, as small quantities of soluble M. tuberculosis antigens added to the sera of HLT people led to the induction of nuclear changes in NEU in a dose-dependent manner. Conclusion: These results might help to detect subclinical TB within HHC, thus leading to a recommendation of prophylactic treatment. Keywords: tuberculosis, serum, neutrophils, pyknosis, apoptosis, netosis

A small but relatively constant proportion (3–5%) of mice chronically infected withMycobacterium lepraemurium(MLM) develops bilateral paralysis of the rear limbs. The aim of the study was to investigate whether or not the bilateral leg palsy results from nerve involvement. Direct bacterial nerve infection or acute/delayed inflammation might possibly affect the nerves. Therefore, palsied animals were investigated for the presence of: (a) histopathological changes in the leg tissues including nerves, bones and annexes, and (b) serum antibodies toM. lepraemuriumandM. lepraelipids, including phenolic glycolipid I fromM. leprae. Histopathological study of the palsied legs revealed that the paralysis was not the result of direct involvement of the limb nerves, as neither bacilli nor inflammatory cells were observed in the nerve branches studied. Antibodies to brain lipids and cardiolipin were not detected in the serum of the palsied animals, thus ruling out an immune response to self-lipids as the basis for the paralysis. Although high levels of antibodies to MLM lipids were detected in the serum of palsied animals they were not related to limb paralysis, as the nerves of the palsied legs showed no evidence of inflammatory damage. In fact, nerves showed no evidence of damage. Paralysis resulted from severe damage of the leg bones. Within the bones the bone marrow became replaced by extended bacilli-laden granulomas that frequently eroded the bone wall, altering the normal architecture of the bone and its annexes, namely muscle, tendons and connective tissue. Although this study rules out definitively the infectious or inflammatory damage of nerves in murine leprosy, it opens a new avenue of research into the factors that participate in the involvement or the sparing of nerves in human and murine leprosy, respectively. [ABSTRACT FROM AUTHOR]

Copyright of Revista Biociências is the property of Revista Biociencias and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Revista Biociências is the property of Revista Biociencias and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Revista Biociências is the property of Revista Biociencias and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Revista Biociências is the property of Revista Biociencias and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis that induces chronic inflammation. During the development of chronic inflammation there is neuronal activation and changes in the synthesis and production of neurotransmitters and cytokines, that affect functions such as learning, memory and mood. Patients with TB develop diverse mental disturbances like depression and anxiety. Thus, we investigated the effect of lung infection with M. tuberculosis on the immune response in the central nervous system (CNS) and its relationship with behavioural changes in absence of culturable mycobacteria in the brain in a murine model of pulmonary TB. The results showed an increase in TNFa, IFNg, IL-12, IL-4 and TGF- β, as well as the enzymes IDO and iNOS in the hypothalamus, hippocampus and cerebellum. There were significant changes in the production of the neurotransmitters noradrenaline, adrenaline, dopamine and serotonin. Neuronal damage occurred in the hippocampus and cortex at an early stage of the disease, and it led to neuronal death in the progressive phase of the disease, with an increase of p38 and JNK. BDNF levels decreased and an increase of blood-brain barrier permeability was seen. All these changes coexisted with depressive-like behaviour, sickness behaviour, anxiety-like behaviour, neurological damage and impairment of short and long-term memory.These results show for first time that chronic inflammation during pulmonary tuberculosis causes neuroinflammation and behavioral abnormalities in absence of brain infection. [ABSTRACT FROM AUTHOR]

Multiple Sclerosis (MS) is a chronic disease of the Central Nervous System (CNS) in which autoimmune processes against the myelin sheaths lead to neurodegeneration. MS patients show sexual dimorphism in prevalence, prognosis, progression, and age at disease onset. Glatiramer Acetate (GA) is one of the first-line Disease-Modifying Therapies (DMT) used to delay neurodegeneration. It has been reported that GA induces the production of anti-drug antibodies (ADA) with consequences not yet established. The objective was to determine if there is a differential pattern of correlations between anti-GA antibodies and cytokine levels in MS patients grouped by sex. Immunoglobulin IgG levels were measured in 43 MS patients treated with GA: total nonspecific IgG by affinity chromatography, total IgG anti-GA, and IgG anti-GA subclasses (IgG1-4) by ELISA. A correlation analysis between 14 cytokine levels and anti-GA IgG antibodies was determined by Spearman's method. We observed a correlation triangle that connects IL-31, IFN-γ, and IL-25 only in men, while there is a strong positive correlation between IL-31 and sCD40L exclusively in women. About immunoglobulins, we found a correlation in women patients: sCD40L vs. IgG anti-GA (r= 0.41 p<0.05) and IL-31 vs. IgG3 anti-GA (r= 0.498 p<0.01). Men group showed no correlation of sCD40L and IL-31 with immunoglobulins. The evidence presented here suggests that there is a sexual dimorphism in the production of antibodies against GA that might be modulated by a different pattern of cytokines. Therefore, another different mechanism of action could be involved in MS pathophysiology in a sexdependent manner. [ABSTRACT FROM AUTHOR]

The neurobiological mechanisms underlying major depressive disorder (MDD) remain largely unexplored due to the limited availability of study models in humans. Induced pluripotent stem cells (iPSCs) have overcome multiple limitations of retrospective clinical studies, contributing to a more detailed understanding of the molecular pathways that presumably contribute to the manifestation of depression. Despite the significant progress made by these study models, there are still more formidable challenges that will eventually be addressed by these platforms, as further studies may eventually emerge. This review will examine the most recent advances in the comprehension of depression by using human neurons and non-neuronal cells derived from induced pluripotent stem cells of patients with depression. This study highlights the importance of using these platforms to increase our knowledge of depression and address this psychiatric disorder more efficiently., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Villafranco, Martínez-Ramírez, Magaña-Maldonado, González-Ruvalcaba, López-Ornelas, Velasco, Becerril-Villanueva, Pavón, Estudillo and Pérez-Sánchez.)

Major depressive disorder (MDD) is a mood disorder that has become a global health emergency according to the World Health Organization (WHO). It affects 280 million people worldwide and is a leading cause of disability and financial loss. Patients with MDD present immunoendocrine alterations like cortisol resistance and inflammation, which are associated with alterations in neurotransmitter metabolism. There are currently numerous therapeutic options for patients with MDD; however, some studies suggest a high rate of therapeutic failure. There are multiple hypotheses explaining the pathophysiological mechanisms of MDD, in which several systems are involved, including the neuroendocrine and immune systems. In recent years, inflammation has become an important target for the development of new therapeutic options. Extracellular monomeric ubiquitin (emUb) is a molecule that has been shown to have immunomodulatory properties through several mechanisms including cholinergic modulation and the generation of regulatory T cells. In this perspective article, we highlight the influence of the inflammatory response in MDD. In addition, we review and discuss the evidence for the use of emUb contained in Transferon as a concomitant treatment with selective serotonin reuptake inhibitors (SSRIs).

Fibromyalgia (FM) is a chronic condition that causes widespread pain, fatigue, and other symptoms that significantly affect quality of life. The underlying mechanisms of fibromyalgia involve both the immune system and the central nervous system. It has been proposed that changes in multiple ascending and descending pathways in the central nervous system may contribute to increased pain sensitivity in individuals with this condition. Recent research has identified S100 proteins as a new area of interest in fibromyalgia studies. These proteins are a group of small molecular weight proteins involved in inflammation and various functions inside and outside of cells, and they may play a critical role in the development and progression of FM. Although S100B has been the most studied in FM patients, other studies have reported that S100A7, S100A8, S100A9, and S100A12 may also be useful as potential biomarkers or for a deeper understanding of FM pathophysiology. The potential role of S100 proteins in the pathophysiology of fibromyalgia could be mediated by RAGE and TLR4, which signal through JNK, ERK, and p38 to activate AP-1 and NF-κB and induce the release of proinflammatory cytokines, thereby producing the inflammation, fatigue, and chronic pain characteristic of fibromyalgia. To gain new perspectives on targeted therapeutic approaches, it is crucial to understand how S100 proteins could impact the pathophysiology of fibromyalgia. This review examines the potential role of S100 proteins in fibromyalgia and their impact on improving our comprehension of the condition, as well as facilitating further research on this interesting topic., (© 2024. The Author(s).)

Brucellosis is an infection widely distributed around the world, and in some countries it is considered a public health problem. Brucellosis causes insidious symptoms that make it difficult to diagnose. Infection can also trigger chronic pain and neuropsychiatric complications. Antibiotics are not always effective to eradicate infection, contributing to chronicity. We aimed to investigate the effects of antibiotic treatment on proinflammatory cytokines, neurotransmitters, corticosterone, and behavior in a murine model of infecrion of B. abortus strain 2308. Four study groups were created: (a) control; (b) antibiotic control; (c) infected with B. abortus 2308; and (d) infected and treated with rifampicin and doxycycline. We determined B. abortus 2308 colony-forming units (CFUs), the count of dendritic cells, and macrophages in the spleen; serum levels of cytokines and corticosterone; levels of serotonin, dopamine, epinephrine, and norepinephrine in the brain; and equilibrium, physical strength, anxiety, and hopelessness tests. The infected and treated mice group was compared with the control and infected mice to assess whether treatment is sufficient to recover neuroimmunoendocrine parameters. Our results showed that despite the treatment of brucellosis with rifampicin and doxycycline, antibiotic-treated mice showed a persistence of B. abortus 2308 CFUs, an increased count in macrophage number, and higher circulating levels of corticosterone. Furthermore, the levels of IL-12, IL-6, and TNF-α remained higher. We found a decrease in muscular strength and equilibrium concomitant to changes in neurotransmitters in the hippocampus, cerebellum, and frontal cortex. Our data suggest that the remaining bacterial load after antibiotic administration favors inflammatory, neurochemical, and behavioral alterations, partly explaining the widespread and paradoxical symptomatology experienced by patients with chronic brucellosis.

Dopamine and serotonin receptors and transporters play an essential role in the pathophysiology of schizophrenia; changes in their expression have been reported in neurons and leukocytes. Each antipsychotic induces a unique pattern in leukocyte function and phenotype. However, the use of polytherapy to treat schizophrenia makes it challenging to determine the specific effects of risperidone on peripheral blood mononuclear cells (PBMCs). The aim of this study was to evaluate the changes in the expression of D 3 , D 5 , DAT, 5-HT 2A , and SERT in PBMCs from healthy volunteers (HV), drug-naive patients with schizophrenia (PWS), drug-free PWS, and PWS treated with risperidone for up to 40 weeks using quantitative PCR. Our study revealed elevated mRNA levels of D 3 , DAT, 5-HT 2A , and SERT in unmedicated PWS. Treatment with risperidone led to a reduction only in the expression of 5-HT 2A and SERT. Furthermore, we observed a moderate correlation between 5-HT 2A expression and the positive and negative syndrome scale (PANSS), as well as SERT expression and PANSS scale. We also found a moderate correlation between 5-HT 2A and SERT expression and the positive subscale. The duration of risperidone consumption had a significant negative correlation with the expression of 5-HT 2A and SERT. Our study introduces the measurement of 5-HT 2A and SERT expression in PBMCs as a useful parameter for assessing the response to risperidone in PWS.

The menopause transition is a vulnerable period for developing both psychiatric and metabolic disorders, and both can be enhanced by stressful events worsening their effects. The present study aimed to evaluate whether a cafeteria diet (CAF) combined with chronic variable stress (CVS) exacerbates anxious- or depressive-like behavior and neuronal activation, cell proliferation and survival, and microglia activation in middle-aged ovariectomized (OVX) rats. In addition, body weight, lipid profile, insulin resistance, and corticosterone as an index of metabolic changes or hypothalamus-pituitary-adrenal (HPA) axis activation, and the serum pro-inflammatory cytokines IL-6, IL-β, and TNFα were measured. A CAF diet increased body weight, lipid profile, and insulin resistance. CVS increased corticosterone and reduced HDL. A CAF produced anxiety-like behaviors, whereas CVS induced depressive-like behaviors. CVS increased serum TNFα independently of diet. A CAF and CVS separately enhanced the percentage of Iba-positive cells in the hippocampus; the combination of factors further increased Iba-positive cells in the ventral hippocampus. A CAF and CVS increased the c-fos -positive cells in the hippocampus; the combination of factors increased the number of positive cells expressing c-fos in the ventral hippocampus even more. The combination of a CAF and CVS generates a slight neuroinflammation process and neuronal activation in a hippocampal region-specific manner and differentially affects the behavior.

Background: Major depressive disorder (MDD) affects more than 350 million people worldwide, and there is currently no laboratory test to diagnose it. This pilot study aimed to identify potential biomarkers in peripheral blood mononuclear cells (PBMCs) from MDD patients., Methods: We used tandem mass tagging coupled to synchronous precursor selection (mass spectrometry) to obtain the differential proteomic profile from a pool of PBMCs from MDD patients and healthy subjects, and quantitative PCR to assess gene expression of differentially expressed proteins (DEPs) of our interest., Results: We identified 247 proteins, of which 133 had a fold change ≥ 2.0 compared to healthy volunteers. Using pathway enrichment analysis, we found that some processes, such as platelet degranulation, coagulation, and the inflammatory response, are perturbed in MDD patients. The gene-disease association analysis showed that molecular alterations in PBMCs from MDD patients are associated with cerebral ischemia, vascular disease, thrombosis, acute coronary syndrome, and myocardial ischemia, in addition to other conditions such as inflammation and diabetic retinopathy., Conclusions: We confirmed by qRT-PCR that S100A8 is upregulated in PBMCs from MDD patients and thus could be an emerging biomarker of this disorder. This report lays the groundwork for future studies in a broader and more diverse population and contributes to a deeper characterization of MDD., (© 2023. The Author(s).)

Maternal Immune Activation (MIA) has been linked to the pathogenesis of pre-eclampsia and adverse neurodevelopmental outcomes in the offspring, such as cognitive deficits, behavioral abnormalities, and mental disorders. Pre-eclampsia is associated with an activation of the immune system characterized by persistently elevated levels of proinflammatory cytokines, as well as a decrease in immunoregulatory factors. The Cholinergic Anti-inflammatory Pathway (CAP) may play a relevant role in regulating the maternal inflammatory response during pre-eclampsia and protecting the developing fetus from inflammation-induced damage. Dysregulation in the CAP has been associated with the clinical evolution of pre-eclampsia. Some studies suggest that therapeutic stimulation of this pathway may improve maternal and fetal outcomes in preclinical models of pre-eclampsia. Modulation of vagal activity influences the CAP, improving maternal hemodynamics, limiting the inflammatory response, and promoting the growth of new neurons, which enhances synaptic plasticity and improves fetal neurodevelopment. Therefore, we postulate that modulation of vagal activity may improve maternal and fetal outcomes in pre-eclampsia by targeting underlying immune dysregulation and promoting better fetal neurodevelopment. In this perspective, we explore the clinical and experimental evidence of electrical, pharmacological, physical, and biological stimulation mechanisms capable of inducing therapeutical CAP, which may be applied in pre-eclampsia to improve the mother's and offspring's quality of life., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Abarca-Castro, Talavera-Peña, Reyes-Lagos, Becerril-Villanueva, Pérez-Sanchez, de la Peña, Maldonado-García and Pavón.)

Brucellosis infection causes non-specific symptoms such as fever, chills, sweating, headaches, myalgia, arthralgia, anorexia, fatigue, and mood disorders. In mouse models, it has been associated with increased levels of IL-6, TNF-α, and IFN-γ, a decrease in serotonin and dopamine levels within the hippocampus, induced loss of muscle strength and equilibrium, and increased anxiety and hopelessness. Imipramine (ImiP), a tricyclic antidepressant, is used to alleviate neuropathic pain. This study evaluated the effects of ImiP on Balb/c mice infected with Brucella abortus 2308 (Ba) at 14- and 28-days post-infection. Serum levels of six cytokines (IFN-γ, IL-6, TNF-α, IL-12, MCP-1. and IL-10) were assessed by FACS, while the number of bacteria in the spleen was measured via CFU. Serotonin levels in the hippocampus were analyzed via HPLC, and behavioral tests were conducted to assess strength, equilibrium, and mood. Our results showed that mice infected with Brucella abortus 2308 and treated with ImiP for six days (Im6Ba14) had significantly different outcomes compared to infected mice (Ba14) at day 14 post-infection. The mood was enhanced in the forced swimming test (FST) ( p < 0.01), tail suspension test (TST) ( p < 0.0001), and open-field test ( p < 0.0001). Additionally, there was an increase in serotonin levels in the hippocampus ( p < 0.001). Furthermore, there was an improvement in equilibrium ( p < 0.0001) and muscle strength ( p < 0.01). Lastly, there was a decrease in IL-6 levels ( p < 0.05) and CFU count in the spleen ( p < 0.0001). At 28 days, infected mice that received ImiP for 20 days (Im20Ba28) showed preservation of positive effects compared to infected mice (Ba28). These effects include the following: (1) improved FST ( p < 0.0001) and TST ( p < 0.0001); (2) better equilibrium ( p < 0.0001) and muscle strength ( p < 0.0001); (3) decreased IL-6 levels ( p < 0.05); and (4) reduced CFU count in the spleen ( p < 0.0001). These findings suggest the potential for ImiP to be used as an adjuvant treatment for the symptoms of brucellosis, which requires future studies.

Endotoxic shock (ExSh) and cecal ligature and puncture (CLP) are models that induce sepsis. In this work, we investigated early immunologic and histopathologic changes induced by ExSh or CLP models in female and male mice. Remarkable results showed that females supported twice the LD100 of LPS for males, CLP survival and CFU counts were similar between genders, high circulating LPS levels in ExSh mice and low levels of IgM anti-LPS in males. In the serum of ExSh males, TNF and IL-6 increased in the first 6 h, in CLP males at 12 h. In the liver of ExSh mice, TNF increased at 1.5 and 12 h, IL-1 at 6 h. TGFβ1 increased in females throughout the study and at 12 h in males. In CLP mice, IL-6 decreased at 12 h, TGFβ1 increased at 6-12 h in males and at 12 h in females. In the lungs of ExSh males, IL-1β increased at 1.5-6 h and TGFβ1 at 12 h; in females, TNF decrease at 6 h and TGFβ1 increased from 6 h; in CLP females, TNF and IL-1β decreased at 12 h and 1.5 h, respectively, and TGFβ1 increased from 6 h; in males, TGFβ1 increased at 12 h. In the livers of ExSh mice, signs of inflammation were more common in males; in the CLP groups, inflammation was similar but less pronounced. ExSh females had leucocytes with TGFβ1. The lungs of ExSh males showed patches of hyaline membranes and some areas of inflammatory cells, similar but fewer and smaller lesions were seen in male mice with CLP. In ExSh females, injuries were less extent than in males, similar pulmonary lesions were seen in female mice with CLP. ExSh males had lower levels of TGFβ1 than females, and even lower levels were seen in CLP males. We conclude that the ExSh was the most lethal model in males, associated with high levels of free LPS, low IgM anti-LPS, exacerbated inflammation and target organ injury, while females showed early TGFβ1 production in the lungs and less tissue damage. We didn't see any differences between CLP mice., (© 2023. Sociedad de Biologia de Chile.)

Objective: Rhupus is a rare disease that shares characteristics of systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). While several studies have explored the clinical and immunological profiles of patients with rhupus, the underlying cause of the disease remains unknown due to its complex pathogenesis. The objective of this study was to investigate the role of tumour necrosis factor (TNF) in the production of inflammatory molecules by peripheral blood mononuclear cells (PBMCs) from patients with rhupus., Methods: The study involved five healthy controls, seven patients with rhupus and seven patients with SLE. PBMCs were obtained from each participant and stimulated with recombinant human TNF for 24 hours. The levels of various molecules secreted by the cells, such as cytokines and chemokines, were measured using immunobead-based assays on xMAP technology., Results: The production levels of some molecules were higher in TNF-stimulated PBMCs from patients with rhupus and SLE than in unstimulated cells. In addition, the levels of certain molecules, including gp130/sIL-6Rb, a proliferation-inducing ligand (APRIL), interferon-β, matrix metalloproteinase-3 and interleukin (IL)-12, were higher in PBMCs from patients with rhupus even without TNF stimulation. Similarly, the levels of gp130/sIL-6Rb and APRIL were higher in TNF-stimulated PBMCs from patients with rhupus than in healthy controls. These results were further validated against patients with RA using enzyme-linked immunosorbent assay., Conclusions: These findings suggest that the spontaneous production of molecules by cells from patients with rhupus may contribute to the development of the disease, and that TNF may play a role in this process by regulating the secretion of gp130/sIL-6Rb and APRIL., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Defective lymphatic drainage and translocation of B-cells in inflamed (Bin) joint-draining lymph node sinuses are pathogenic phenomena in patients with severe rheumatoid arthritis (RA). However, the molecular mechanisms underlying this lymphatic dysfunction remain poorly understood. Herein, we utilized multi-omic spatial and single-cell transcriptomics to evaluate altered cellular composition (including lymphatic endothelial cells, macrophages, B-cells, and T-cells) in the joint-draining lymph node sinuses and their associated phenotypic changes and cell-cell interactions during RA development using the tumor necrosis factor transgenic (TNF-Tg) mouse model., Methods: Popliteal lymph nodes (PLNs) from wild-type (n=10) and TNF-Tg male mice with "Early" (5 to 6-months of age; n=6) and "Advanced" (>8-months of age; n=12) arthritis were harvested and processed for spatial transcriptomics. Single-cell RNA sequencing (scRNAseq) was performed in PLNs from the TNF-Tg cohorts (n=6 PLNs pooled/cohort). PLN histopathology and ELISPOT along with ankle histology and micro-CT were evaluated. Histopathology of human lymph nodes and synovia was performed for clinical correlation., Results: Advanced PLN sinuses exhibited an increased Ighg2b/Ighm expression ratio (Early 0.5 ± 0.1 vs Advanced 1.4 ± 0.5 counts/counts; p<0.001 ) that significantly correlated with reduced talus bone volumes in the afferent ankle (R 2 = 0.54, p<0.001 ). Integration of single-cell and spatial transcriptomics revealed the increased IgG2b + plasma cells localized in MARCO + peri-follicular medullary sinuses. A concomitant decreased Fth1 expression (Early 2.5 ± 0.74 vs Advanced 1.0 ± 0.50 counts, p<0.001 ) within Advanced PLN sinuses was associated with accumulation of iron-laden Prussian blue positive macrophages in lymph nodes and synovium of Advanced TNF-Tg mice, and further validated in RA clinical samples. T-cells were increased 8-fold in Advanced PLNs, and bioinformatic pathway assessment identified the interaction between ALCAM + macrophages and CD6 + T-cells as a plausible co-stimulatory mechanism to promote IgG2b class-switching., Discussion: Collectively, these data support a model of flare in chronic TNF-induced arthritis in which loss of lymphatic flow through affected joint-draining lymph nodes facilitates the interaction between effluxing macrophages and T-cells via ALCAM-CD6 co-stimulation, initiating IgG2b class-switching and plasma cell differentiation of the expanded Bin population. Future work is warranted to investigate immunoglobulin clonality and potential autoimmune consequences, as well as the efficacy of anti-CD6 therapy to prevent these pathogenic events., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Kenney, Rangel-Moreno, Peng, Chen, Bruno, Embong, Pritchett, Fox, Becerril-Villanueva, Gamboa-Domínguez, Quataert, Muthukrishnan, Wood, Korman, Anolik, Xing, Ritchlin, Schwarz and Wu.)

Tuberculosis (TB) is the deadliest disease caused by a bacterial agent. Glucocorticoids (GCs) have a typical anti-inflammatory effect, but recently it has been shown that they can present proinflammatory activity, mainly by increasing molecules from innate immunity. In the current study, we evaluated the effect of low doses of dexamethasone on Mycobacterium tuberculosis in vivo and in vitro. We used an established mice model of progressing tuberculosis (TB) in the in vivo studies. Intratracheal or intranasal dexamethasone therapy administered with conventional antibiotics in the late stage of the disease decreased the lung bacilli load and lung pneumonia, and increased the survival of the animals. Finally, the treatment decreased the inflammatory response in the SNC and, therefore, sickness behavior and neurological abnormalities in the infected animals. In the in vitro experiments, we used a cell line of murine alveolar macrophages infected with Mtb . Low-dose dexamethasone treatment increased the clearance capacity of Mtb by MHS macrophages, MIP-1α, and TLR2 expression, decreased proinflammatory and anti-inflammatory cytokines, and induced apoptosis, a molecular process that contributes to the control of the mycobacteria. In conclusion, the administration of low doses of dexamethasone represents a promising adjuvant treatment for pulmonary TB.

Objective: To investigate the hypothesis that selective inhibitors of nuclear export (SINE compounds), recently approved for treatment of refractory plasma cell (PC) malignancy, may have potential in the treatment of lupus., Methods: Female NZB/NZW mice were treated with the SINE compound KPT-350 or vehicle control. Tissue specimens were harvested and analyzed by flow cytometry, using standard markers. Nephritis was monitored by determining the proteinuria score and by histologic analysis of kidney specimens. Serum anti-double-stranded DNA (anti-dsDNA) levels were measured by enzyme-linked immunosorbent assay, and total numbers of IgG-secreting and dsDNA-specific antibody-secreting cells were assessed by enzyme-linked immunospot assay., Results: KPT-350 abrogated murine lupus nephritis at both early and late stages of the disease and rapidly impaired generation of autoreactive PCs in germinal centers (GCs). SINE compounds inhibited the production of NF-κB-driven homeostatic chemokines by stromal cells, altering splenic B and T cell strategic positioning and significantly reducing follicular helper T cell, GC B cell, and autoreactive PC counts. KPT-350 also decreased levels of cytokines and chemokines involved in PC survival and recruitment in the kidney of lupus-prone mice. Exportin 1, the target of SINE compounds, was detected in GCs of human tonsils, splenic B cells of lupus patients, and multiple B cell subsets in the kidneys of patients with lupus nephritis., Conclusion: Collectively, our results provide support for the therapeutic potential of SINE compounds, via their targeting of several molecular and cellular pathways critical in lupus pathogenesis, including autoantibody production by plasma cells., (© 2022 American College of Rheumatology.)

Although no precise moment or unique event marks its birth, neuroimmunoendocrinology arguably shares a great deal of history with other medical and biologic disciplines. It originated from empirical observations and suppositions that failed to prevail upon the existing axioms. Despite the widespread resistance to embracing novel ideas, the seeming defeats inspired visionary researchers. Those pioneers managed to systematize the emerging knowledge and were able to contribute to science with real foundations. In consequence, new concepts and ideas arose in physiology, anatomy, endocrinology and early immunology. Together, they gave rise to a budding approach on the integration between the nervous, immune and endocrine systems. Then, neuroimmunoendocrinology emerged as a discipline integrating an intricate system with multidirectional functions and interactions that allow for responding to internal and external threats. Such response is mediated by cytokines, hormones and neurotransmitters, involved in different physiologic mechanisms of the organism homeostasis. Neuroimmunoendocrinology is no longer an area of scientific skepticism; on the contrary, it has cemented its position as a biomedical discipline worldwide for the past 70 years. Now, it offers a better understanding of pathologic processes., (©2022 Society for Leukocyte Biology.)

Murine leprosy is a systemic infectious disease of mice caused by Mycobacterium lepraemurium (MLM) in which the central nervous system (CNS) is not infected; nevertheless, diseased animals show measurable cognitive alterations. For this reason, in this study, we explored the neurobehavioral changes in mice chronically infected with MLM. BALB/c mice were infected with MLM, and 120 days later, the alterations in mice were evaluated based on immunologic, histologic, endocrine, neurochemical, and behavioral traits. We found increases in the levels of IL-4 and IL-10 associated with high bacillary loads. We also found increase in the serum levels of corticosterone, epinephrine, and norepinephrine in the adrenal gland, suggesting neuroendocrine deregulation. Mice exhibited depression-like behavior in the tail suspension and forced swimming tests and anxiolytic behavior in the open field and elevated plus maze tests. The neurobehavioral alterations of mice were correlated with the histologic damage in the prefrontal cortex, ventral hippocampus, and amygdala, as well as with a blood-brain barrier disruption in the hippocampus. These results reveal an interrelated response of the neuroimmune--endocrinological axis in unresolved chronic infections that result in neurocognitive deterioration., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 IBRO. Published by Elsevier Ltd. All rights reserved.)

Airline pilots are frequently exposed to numerous flights per week, changes in their circadian rhythms, and extended periods away from home. All these stressors make pilots susceptible to developing psychiatric disorders. Recently, emphasis has been placed on the need for molecular tests that help in the diagnosis of depression. The genes SLC6A4 and S100A10 encode serotonin transporter (SERT) and p11 protein, respectively. Their expression has been frequently associated with stress and depression. In this work, we quantified, by quantitative PCR, the expression of SERT and p11 in peripheral mononuclear cells of airline pilots compared to patients with depression and healthy volunteers. Moreover, by mass spectrometry, we quantified the serum serotonin levels in the same three groups. We found that SERT and p11 were overexpressed in the mononuclear cells of airline pilots and depressed patients compared to healthy volunteers. Although serum serotonin was not different between healthy volunteers and airline pilots, a decreasing trend was observed in the latter. As expected, serum serotonin in the patients was significantly lower. Alterations in SERT and p11 in airline pilots could be related to professional stress, a condition that could potentially affect their long-term mental health., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Becerril-Villanueva, Olvera-Alvarez, Alvarez-Herrera, Maldonado-García, López-Torres, Ramírez-Marroquín, González-Ruiz, Nogueira-Fernández, Mendoza-Contreras, Sánchez-García, José-Alfallo, Valencia Baños, Torres-Serrano, Jiménez-Genchi, Mendieta-Cabrera, Pérez-Sánchez and Pavón.)

Introduction: Fibromyalgia (FM) is a non-degenerative syndrome characterized by generalized, chronic musculoskeletal pain, as well as mood, memory and sleep disorders., Objective: To search for serum anti-neural antibodies (ANeuA) in patients with FM (FMP) in order to rule out autoimmune etiology., Methods: The Fibromyalgia Impact Questionnaire (FIQ) and Beck's depression inventory (BDI) were applied. Immunoreactivity and the target recognized on the sera from FMPs and healthy subjects were analyzed by indirect immunofluorescence and Western blot., Results: Both FIQ and BDI values were significantly altered in FMPs in comparison with those of controls (FIQ, 70 ± 25 vs. 12 ± 12, p < 0.0001; BDI, 17 ± 11 vs. 4 ± 3, p < 0.0002). Only five out of 15 FMP sera had ANeuA specifically directed against neurons from the medial vestibular nucleus of the brainstem. This immunoreactivity was not detected in the sera from the 14 controls. ANeuA recognized a 45 kDa protein., Conclusions: 30% of FMPs have ANeuA that have not been described before. In future studies, it will be necessary for anti-neural immunoreactivity to be determined in a larger sample and for the role of ANeuAs in the pathophysiology of FM to be established., (Copyright: © 2022 Permanyer.)

Laboratory parameters display limited accuracy in predicting mortality in coronavirus disease 2019 (COVID-19) patients, as with serum albumin. Emerging evidence suggests that cytokine serum values may enhance the predictive capacity of albumin, especially interleukin (IL)-15. We thus investigated whether the use of the IL-15-to-albumin ratio enables improving mortality prediction at hospital admission in a large group of COVID-19 patients. In this prospective cross-sectional study, we enrolled and followed up three hundred and seventy-eight patients with a COVID-19 diagnosis until hospital discharge or death. Two hundred and fifty-five patients survived, whereas one hundred and twenty-three died. Student's T -test revealed that non-survivors had a significant two-fold increase in the IL-15-to-albumin ratio compared to survivors (167.3 ± 63.8 versus 74.2 ± 28.5), a difference that was more evident than that found for IL-15 or albumin separately. Likewise, mortality prediction considerably improved when using the IL-15-to-albumin ratio with a cut-off point > 105.4, exhibiting an area under the receiver operating characteristic curve of 0.841 (95% Confidence Interval, 0.725-0.922, p < 0.001). As we outlined here, this is the first study showing that combining IL-15 serum values with albumin improves mortality prediction in COVID-19 patients.

Brucellosis is a zoonosis affecting 50,000,000 people annually. Most patients progress to a chronic phase of the disease in which neuropsychiatric symptoms upsurge. The biological processes underlying the progression of these symptoms are yet unclear. Peripheral inflammation mounted against Brucella may condition neurochemical shifts and hence unchained neuropsychiatric disorders. Our work aimed at establishing whether neurological, behavioral, and neurochemical disarrays are circumstantially linked to peripheral inflammation uprise secondary to Brucella abortus 2308 infections. We then evaluated, in control and Brucella -infected mice, skeletal muscle strength, movement coordination, and balance and motivation, as well as dopamine, epinephrine, norepinephrine, and serotonin availability in the cerebellum, frontal cortex, and hippocampus. Serum levels of proinflammatory cytokines and corticosterone in vehicle-injected and -infected mice were also estimated. All estimates were gathered at the infection acute and chronic phases. Our results showed that infected mice displayed motor disabilities, muscular weakness, and reduced motivation correlated with neurochemical and peripheral immunological disturbances that tended to decrease after 21 days of infection. The present observations support that disturbed peripheral inflammation and the related neurochemical disruption might lead to mood disorders in infected mice. Future experiments must be aimed at establishing causal links and to explore whether similar concepts might explain neurological and mood disorders in humans affected by brucellosis.

Melatonin is a hormone that produces behavioral, pharmacological, and physiological effects through the activation of MT1 and MT2 melatonin receptors. Melatonin receptors participate in the modulation of the reinforcing effects of cocaine. Some studies report that dosing of melatonin decreases cocaine-induced locomotor activity and cocaine self-administration and that luzindole, an MT1, and MT2 melatonin receptor antagonist, blocks the melatonin-dependent decrease in cocaine-induced locomotor activity. The objective of this study was to evaluate the effect of acute or chronic dosing of melatonin on the induction and expression of cocaine-induced locomotor sensitization and cocaine-CPP in rats. Male Wistar rats received cocaine during the induction and expression of locomotor sensitization. Melatonin was administered 30 min before cocaine. After each treatment, locomotor activity was recorded for 30 min. Additionally, dopamine levels were determined in the ventral striatum, the prefrontal cortex (PFc), and the ventral tegmental area (VTA) by HPLC in animals treated with melatonin and cocaine. Melatonin decreased cocaine-induced locomotor sensitization and intracellular dopamine levels, as well as cocaine-CPP. Luzindole blocked the melatonin-induced decrease in the expression of locomotor sensitization in rats. These data suggest that melatonin may be a useful therapeutic agent to reduce cocaine abuse; additionally, they suggest that MT1 and MT2 receptors could be therapeutic targets, useful for the treatment of drug abuse disorder., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Tuberculosis (TB) is a chronic infectious disease in which prolonged, non-resolutive inflammation of the lung may lead to metabolic and neuroendocrine dysfunction. Previous studies have reported that individuals coursing pulmonary TB experience cognitive or behavioural changes; however, the pathogenic substrate of such manifestations have remained unknown. Here, using a mouse model of progressive pulmonary TB, we report that, even in the absence of brain infection, TB is associated with marked increased synthesis of both inflammatory and anti-inflammatory cytokines in discrete brain areas such as the hypothalamus, the hippocampal formation and cerebellum accompanied by substantial changes in the synthesis of neurotransmitters. Moreover, histopathological findings of neurodegeneration and neuronal death were found as infection progressed with activation of p38, JNK and reduction in the BDNF levels. Finally, we perform behavioural analysis in infected mice throughout the infection, and our data show that the cytokine and neurochemical changes were associated with a marked onset of cognitive impairment as well as depressive- and anxiety-like behaviour. Altogether, our results suggest that besides pulmonary damage, TB is accompanied by an extensive neuroinflammatory and neurodegenerative state which explains some of the behavioural abnormalities found in TB patients., Competing Interests: The authors of this manuscript declare that there are no actual or potential conflicts of interest. The authors affirm that there are no financial, personal or other relationships with other people or organisations that have inappropriately influenced or biased their research.

Background: Major depressive disorder (MDD) is a global health issue that affects 350 million people of all ages. Although between 2% and 5.6% of affected individuals are adolescents, research on young patients is limited. The inflammatory response contributes to the onset of depression, and in adult MDD patients, symptom severity has been linked to chemokine levels., Aim: To determine the differences in circulatory levels of chemokines in healthy volunteers (HVs) and adolescents with MDD, and assess the changes induced by fluoxetine consume., Methods: The 22 adolescents with MDD were monitored during the first 8 wk of clinical follow-up and clinical psychiatric evaluation was done using the Hamilton depresión rating scale (HDRS). The serum levels of monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein (MIP)-1α, MIP-1β, interleukin (IL)-8, interferon gamma-induced protein (IP)-10, and eotaxin were measured in patients and HVs., Results: In all cases, significant differences were detected in circulating chemokine levels between patients before treatment and HVs ( P < 0.0001). All chemokines decreased at 4 wk, but only MCP-1 and IL-8 significantly differed ( P < 0.05) between 0 wk and 4 wk. In the patients, all chemokines rose to their initial concentrations by 8 wk vs 0 wk, but only IP-10 did so significantly ( P < 0.05). All patients experienced a significant decrease in HDRS scores at 4 wk ( P < 0.0001) and 8 wk ( P < 0.0001) compared with 0 wk., Conclusion: Despite the consumption of fluoxetine, patients had significantly higher chemokine levels, even after considering the improvement in HDRS score. The high levels of eotaxin, IP-10, and IL-8 partially explain certain aspects that are affected in MDD such as cognition, memory, and learning., Competing Interests: Conflict-of-interest statement: The authors report no conflicts of interest in relation to the topic of this study., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Murine leprosy is a chronic granulomatous disease caused by Mycobacterium lepraemurium (MLM) in mice and rats. The disease evolves with the development of cellular anergy that impedes the production of interferon gamma (IFNγ), tumor necrosis factor-alpha (TNFα), and nitric oxide (NO) required to kill the microorganism. In this study we investigated whether histone deacetylase inhibitors (HDACi) (valproic acid and sodium butyrate [NaB]) and the immunomodulator transfer factor in dialyzable leukocyte extracts (DLE) can prevent anergy in murine leprosy., Methods: Five groups of six Balb/c mice were intraperitoneally inoculated with 2 × 107 MLM. Thirty-days post inoculation, treatment was started; one group received no treatment, one was treated with rifampicin-clofazimine (R-C), one with sodium valproate (VPA), one with NaB, and one with DLE. The animals were monitored for the evidence of disease for 96 days. After euthanasia, their spleens were removed and processed for histologic, bacteriologic, and cytokine studies., Results: R-C completely controlled the ongoing disease. DLE and NaB significantly reduced the development of lesions, including granuloma size and the number of bacilli; VPA was less effective. DLE, NaB, and VPA reverted the anergic condition in diverse grades and allowed the expression of IFNγ, TNFα, and inducible NO synthase, also in diverse grades., Conclusion: Anergy in leprosy and murine leprosy allows disease progression. In this study, anergy was prevented, in significant degree, by DLE (an immunomodulator) and NaB (HDACi). VPA was less effective. These results suggest potential beneficial effects of DLE and NaB in the ancillary treatment of leprosy., Competing Interests: None

Atypical antipsychotics (AAP) or second-generation antipsychotics are the clinical option for schizophrenia treatment during acute psychoses, but they are also indicated for maintenance during lifetime, even though they are being used for other psychiatric conditions in clinical practice such as affective disorders and autism spectrum disorder, among others. These drugs are differentiated from typical antipsychotics based on their clinical profile and are a better choice because they cause fewer side effects regarding extrapyramidal symptoms (EPS). Even though they provide clear therapeutic benefits, AAP induce peripheral effects that trigger phenotypic, functional, and systemic changes outside the Central Nervous System (CNS). Metabolic disease is frequently associated with AAP and significantly impacts the patient's quality of life. However, other peripheral changes of clinical relevance are present during AAP treatment, such as alterations in the immune and endocrine systems as well as the intestinal microbiome. These less studied alterations also have a significant impact in the patient's health status. This manuscript aims to revise the peripheral immunological, endocrine, and intestinal microbiome changes induced by AAP consumption recommended in the clinical guidelines for schizophrenia and other psychiatric disorders., (Copyright © 2020 Alvarez-Herrera, Escamilla, Medina-Contreras, Saracco, Flores, Hurtado-Alvarado, Maldonado-García, Becerril-Villanueva, Pérez-Sánchez and Pavón.)

Fetal heart rate variability (fHRV) is an essential source of information to monitor fetal well-being during pregnancy. This study aimed to apply a nonlinear approach, known as symbolic dynamics (SD), for comparing human fHRV in the third trimester of pregnancy during active fetal state (TT) and active labor at term (P). We performed a longitudinal, prospective, descriptive, and comparative study composed of 42 longitudinal recordings of 5-minutes of fetal heartbeat interval series. Recordings were collected from 21 low-risk, healthy, pregnant women attending the Maternal and Child Research Center (CIMIGen), Mexico City. We calculated relevant linear parameters of fHRV between TT and P stages, such as the percentage of differences between adjacent RR intervals >5 ms (PRR5, related to vagal modulations) and other SD parameters such as the percentage of no variations between three successive symbols (%0V, reflects sympathetic modulations) and the probability of low variability with a threshold of 4 ms (POLVAR4, associated with a low variability). We identified statistical differences for PRR5 between TT and P (37.13% [28.47-47.60%] vs. 28.84% [19.36-36.76%], p = 0.03), respectively. Also, for 0V% (65.66% [59.01-71.80%] vs. 71.14% [65.94-75.87%], p = 0.03) and for POLVAR4 values (0.06 [0.04-0.11] vs. 0.15 [0.09-0.24], p = 0.002), respectively. Our results indicate that during parturition, the short-term fetal fHRV is decreased, showing a decreased vagal modulations and higher adrenergic response of the heart. These autonomic modifications may result from the fetal response to the stressful inflammatory challenge of labor. We thus confirmed that the analysis of the SD applied to fHRV time series could be a potential clinical biomarker to differentiate the fetal autonomic cardiac condition at different stages of pregnancy., (© 2020 The Authors.)

During angiogenesis, new vessels emerge from existing endothelial lined vessels to promote the degradation of the vascular basement membrane and remodel the extracellular matrix (ECM), followed by endothelial cell migration, and proliferation and the new generation of matrix components. Matrix metalloproteinases (MMPs) participate in the disruption, tumor neovascularization, and subsequent metastasis while tissue inhibitors of metalloproteinases (TIMPs) downregulate the activity of these MMPs. Then, the angiogenic response can be directly or indirectly mediated by MMPs through the modulation of the balance between pro- and anti-angiogenic factors. This review analyzes recent knowledge on MMPs and their participation in angiogenesis., (Copyright © 2019 Quintero-Fabián, Arreola, Becerril-Villanueva, Torres-Romero, Arana-Argáez, Lara-Riegos, Ramírez-Camacho and Alvarez-Sánchez.)

Major depressive disorder (MDD) has a prevalence of 5% in adolescents. Several studies have described the association between the inflammatory response and MDD, but little is known about the relationship between MDD and growth factors, such as IL-7, IL-9, IL-17A, VEGF, basic FGF, G-CSF, and GM-CSF. It must be appointed that there are scarce reports on growth factors in adolescents with MDD and even fewer with a clinical follow-up. In this work, we evaluated the levels of growth factors (IL-7, IL-9, IL-17A, VEGF, basic FGF, G-CSF, and GM-CSF) in MDD adolescents and the clinical follow-up during eight weeks of treatment with fluoxetine. Methods . All patients were diagnosed according to the DSM-IV-TR, and the severity of the symptoms was evaluated using the Hamilton Depression Rating Scale (HDRS). Growth factors IL-7, IL-9, IL-17A, VEGF, basic FGF, G-CSF, and GM-CSF were quantified by cytometric bead array using serum samples from 22 adolescents with MDD and 18 healthy volunteers. Results . All patients showed clinical improvement since the fourth week of pharmacological treatment according to the HDRS. Considerably higher levels of IL-7, IL-9, IL-17A, VEGF, basic FGF, G-CSF, and GM-CSF were detected in MDD adolescents as compared to healthy volunteers. A significant but temporal decrease was detected in basic FGF, G-CSF, and GM-CSF at week four of fluoxetine administration. Conclusions . To the best of our knowledge, this is the first report to show alterations in the levels of growth factors, such as IL-7, IL-9, IL-17A, VEGF, basic FGF, G-CSF, and GM-CSF in MDD adolescents during eight weeks of clinical follow-up. These disturbances might be involved in the physiopathology of MDD since such growth factors have been proven to participate in the neural development and correct functioning of the CNS; therefore, subtle alterations in it may contribute to MDD., Competing Interests: The authors declare no conflicts of interest associated with the present manuscript., (Copyright © 2019 Enrique Becerril-Villanueva et al.)

Background: Glatiramer acetate (GA) is a drug for Multiple Sclerosis (MS) treatment. However, its administration induces anti-drug antibodies (ADA). This research evaluated the sex differences in humoral response against GA in RR-MS patients METHODS: We analyzed 69 RR-MS patients, 43 treated with GA and 26 treated with IFN-β. In all cases, the serum concentration of IgG antibodies was determined by UPLC, whereas the levels of IgG subclasses (1-4) of anti-GA antibodies and the concentration of IL-6 were detected by Multiplex and IL-10, and IFN-γ were detected by ELISA., Results: The total concentration of IgG antibodies in patients did not differ between treatments, whereas the IgG levels of ADA were higher in male and female patients treated with GA (P ≤ 0.0001). The subclasses of IgG anti-GA antibodies were as follows: IgG4>>IgG3>IgG1>IgG2. Statistical analysis showed differences in the IgG2 (P ≤ 0.01) and IgG4 (P ≤ 0.0001) subclasses by sex in RR-MS patients. Levels of IgG1 subclass in male patients correlated positively with the circulatory levels of IL-6 (r s  = 0.587, P ≤ 0.04) and IFN-γ (r s  = 0.721, P ≤ 0.001), while IgG2 subclass levels in female patients correlated with serum levels of IFN-γ (r s  = 0.628, P ≤ 0.0006). Statistical analysis did not detect correlations between the levels of IgG (1-4) subclasses of anti-GA antibodies and the evaluated clinical parameters., Conclusion: This study showed differences in the levels of IgG2 and IgG4 subclasses of ADA between male and female RR-MS patients. Further studies are necessary to take advantage of the clinical potential of this finding., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Parturition in mammals demands a precise coordination of several neuro-immune-endocrine interactions including: a sterile inflammatory response that involves secretion of inflammation mediators like cytokines/chemokines; changes in the secretion of hormones such as progestogen, estrogens, cortisol, and oxytocin; as well as adjustments of the neuroautonomic function. Specifically, the so-called cholinergic anti-inflammatory pathway seems to play a key role in the homeostasis of the neuro-immune-endocrine axis by adjusting the vagus nerve activity during parturition. Here, we provide insights into the importance of the vagus during parturition from an autonomic, endocrine, and immune interplay perspective, and describe the potential role of heart rate variability analysis to explore these interactions noninvasively, economically, and accessibly., (© 2018 New York Academy of Sciences.)

Changes in cytokine levels in major depression and during treatment have been reported in adults. However, few studies have examined cytokine levels in an adolescent sample despite this being a common age of onset. Methods . We measured proinflammatory (IL-2, IFN- γ , IL-1 β , TNF- α , IL-6, IL-12, and IL-15) and anti-inflammatory (IL-4, IL-5, IL-13, IL-1Ra, and IL-10) cytokine serum levels in 22 adolescents with major depression and 18 healthy volunteers. Cytokines were measured by multiplex bead-based immunoassays at baseline, and 4 and 8 weeks after commencement of fluoxetine administration in the clinical group. Results . Compared to healthy volunteers, adolescents with major depression at baseline showed significant increases in all pro- and anti-inflammatory cytokines, except IL-1Ra and IL-10. Significant changes were observed in fluoxetine treatment compared to baseline: proinflammatory cytokines IFN- γ , IL-1 β , TNF- α , IL-6, IL-12, and IL-15 were decreased only at week 4 whereas IL-2 was increased only at week 8; anti-inflammatory cytokines IL-4 and IL-5 were increased at week 8 while IL-1Ra was reduced only at week 4. There were no significant correlations between cytokine levels and symptomatic improvement in HDRS. Discussion . The results suggest a significant interplay between cytokine levels, the depressive state, and the stage of treatment with an SSRI. To the best of our knowledge, this is the first report in depressed adolescents with elevated IL-12, IL-13, and IL-15 levels. Further studies are necessary to clarify the role and mechanisms of altered cytokine levels in the pathogenesis and physiopathology of major depressive disorder.

The long-term effect of immune system activation by a low dose of lipopolysaccharide on neuro-immune-endocrine regulation is unclear. Sleep, neurotransmitter concentrations, TNF-α, and corticosterone levels were evaluated in male Wistar rats implanted with conventional sleep recordings. In this work, we found that REM sleep was reduced in the first 4 h post-injection, without affecting the total sleep time, while adrenaline concentration was reduced in the hippocampus at 24 h post-injection of LPS. Our results demonstrated that, although the acute immune response was not evident 24 h after the injection of LPS, it was able to promote the reduction of AD in the hippocampus, which may explain in part the depressive behavior reported in rodents following LPS administration., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Murine leprosy, caused by Mycobacterium lepraemurium (MLM), is a chronic disease that closely resembles human leprosy. Even though this disease does not directly involve the nervous system, we investigated a possible effect on working memory during this chronic infection in Balb/c mice. We evaluated alterations in the dorsal region of the hippocampus and measured peripheral levels of cytokines at 40, 80, and 120 days post-infection. To evaluate working memory, we used the T-maze while a morphometric analysis was conducted in the hippocampus regions CA1, CA2, CA3, and dentate gyrus (DG) to measure morphological changes. In addition, a neurochemical analysis was performed by HPLC. Our results show that, at 40 days post-infection, there was an increase in the bacillary load in the liver and spleen associated to increased levels of IL-4, working memory deterioration, and changes in hippocampal morphology, including degeneration in the four subregions analyzed. Also, we found a decrease in neurotransmitter levels at the same time of infection. Although MLM does not directly infect the nervous system, these findings suggest a possible functional link between the immune system and the central nervous system.

Mycobacterium lepraemurium is the causative agent of murine leprosy, a chronic, granulomatous disease similar to human leprosy. Due to the similar clinical manifestations of human and murine leprosy and the difficulty of growing both bacilli axenically, Mycobacterium leprae and M. lepraemurium were once thought to be closely related, although it was later suggested that M. lepraemurium might be related to Mycobacterium avium In this study, the complete genome of M. lepraemurium was sequenced using a combination of PacBio and Illumina sequencing. Phylogenomic analyses confirmed that M. lepraemurium is a distinct species within the M. avium complex (MAC). The M. lepraemurium genome is 4.05 Mb in length, which is considerably smaller than other MAC genomes, and it comprises 2,682 functional genes and 1,139 pseudogenes, which indicates that M. lepraemurium has undergone genome reduction. An error-prone repair homologue of the DNA polymerase III α-subunit was found to be nonfunctional in M. lepraemurium , which might contribute to pseudogene formation due to the accumulation of mutations in nonessential genes. M. lepraemurium has retained the functionality of several genes thought to influence virulence among members of the MAC. IMPORTANCE Mycobacterium lepraemurium seems to be evolving toward a minimal set of genes required for an obligatory intracellular lifestyle within its host, a niche seldom adopted by most mycobacteria, as they are free-living. M. lepraemurium could be used as a model to elucidate functions of genes shared with other members of the MAC. Its reduced gene set can be exploited for studying the essentiality of genes in related pathogenic species, which might lead to discovery of common virulence factors or clarify host-pathogen interactions. M. lepraemurium can be cultivated in vitro only under specific conditions and even then with difficulty. Elucidating the metabolic (in)capabilities of M. lepraemurium will help develop suitable axenic media and facilitate genetic studies., (Copyright © 2017 Benjak et al.)

Labor is regarded as increased myometrial activity with a regular contractility pattern. At this final stage of pregnancy, myometrial quiescence is lost, accompanied by altered immune homeostasis. It is well known that the interleukin (IL)-10 family of cytokines modulates immunological responses mainly in epithelial cells, including the endometrium. To investigate their inflammatory profile during labor, we performed a longitudinal study in a group of healthy pregnant women (n = 20) with uncomplicated pregnancies in the third trimester of pregnancy and during active labor. Blood was sampled from pregnant women in the third trimester (gestational age 32-38 weeks, mean 36 ± 2 weeks) and during active labor (39-41 weeks of gestation, mean 40 ± 1 weeks). Serum levels of several cytokines were measured using multiplex immunoassays for both stages, indicating that the concentrations of IL-10, IL-20, IL-22, IL-28A, and interferon (IFN)-γ were significantly decreased during active labor in comparison with third-trimester levels (p < 0.05). Our analysis did not find significant correlations between IL-10, IL-20, IL-22, IL-28A, and IFN-γ levels and gestational age. However, our data suggest that the systemic downregulation of several members of the IL-10 family of cytokines plays an important role in the activation of myometrial smooth cells associated with uterine contractions during active labor. Downregulation of this IL-10 family of cytokines seems to coincide with the well-reported functional progesterone withdrawal during labor. Likewise, lower plasma IFN-γ concentrations may indicate a role for IFN-γ in active labor., (© 2017 S. Karger AG, Basel.)

Fibromyalgia (FM) is a chronic disease that has been linked to inflammatory reactions and changes in the systemic levels of proinflammatory cytokines that modulate responses in the sympathetic nervous system and hypothalamic-pituitary-adrenal axis. We found that concentrations of IL-6 and IL-8 were elevated in FM patients. Both cytokines correlated with clinical scores, suggesting that IL-6 and IL-8 have additive or synergistic effects in perpetuating the chronic pain in FM patients. These findings indicate that IL-6 and IL-8 are two of the most constant inflammatory mediators in FM and that their levels correlate significantly with the severity of symptoms., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Dopamine (DA), a neurotransmitter in the central nervous system (CNS), has modulatory functions at the systemic level. The peripheral and central nervous systems have independent dopaminergic system (DAS) that share mechanisms and molecular machinery. In the past century, experimental evidence has accumulated on the proteins knowledge that is involved in the synthesis, reuptake, and transportation of DA in leukocytes and the differential expression of the D1- like (D1R and D5R) and D2- like receptors (D2R, D3R, and D4R). The expression of these components depends on the state of cellular activation and the concentration and time of exposure to DA. Receptors that are expressed in leukocytes are linked to signaling pathways that are mediated by changes in cAMP concentration, which in turn triggers changes in phenotype and cellular function. According to the leukocyte lineage, the effects of DA are associated with such processes as respiratory burst, cytokine and antibody secretion, chemotaxis, apoptosis, and cytotoxicity. In clinical conditions such as schizophrenia, Parkinson disease, Tourette syndrome, and multiple sclerosis (MS), there are evident alterations during immune responses in leukocytes, in which changes in DA receptor density have been observed. Several groups have proposed that these findings are useful in establishing clinical status and clinical markers.