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1.
Pharmacol Res ; 197: 106956, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37820857

RESUMEN

Several immunopharmacological agents are effective in the treatment of cancer and immune-mediated conditions, with a favorable impact on life expectancy and clinical outcomes for a large number of patients. Nevertheless, response variation and undesirable effects of these drugs represent major issues, and overall efficacy remains unpredictable. Males and females show a distinct difference in immune system responses, with females generally mounting stronger responses to a variety of stimuli. Therefore, exploring sex differences in the efficacy and safety of immunopharmacological agents would strengthen the practice of precision medicine. As a pharmacological target highlight, programmed cell death 1 ligand 1 (PD-L1) is the first functionally characterized ligand of the coinhibitory programmed death receptor 1 (PD-1). The PD-L1/PD-1 crosstalk plays an important role in the immune response and is relevant in cancer, infectious and autoimmune disease. Sex differences in the response to immune checkpoint inhibitors are well documented, with male patients responding better than female patients. Similarly, higher efficacy of and adherence to tumor necrosis factor inhibitors in chronic inflammatory conditions including rheumatoid arthritis and Crohn's disease have been reported in male patients. The pharmacological basis of sex-specific responses to immune system modulating drugs is actively investigated in other settings such as stroke and type 1 diabetes. Advances in therapeutics targeting the endothelium could soon be wielded against autoimmunity and metabolic disorders. Based on the established sexual dimorphism in immune-related pathophysiology and disease presentation, sex-specific immunopharmacological protocols should be integrated into clinical guidelines.


Asunto(s)
Antígeno B7-H1 , Neoplasias , Humanos , Masculino , Femenino , Receptor de Muerte Celular Programada 1 , Neoplasias/tratamiento farmacológico , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Autoinmunidad
2.
Int J Mol Sci ; 23(18)2022 Sep 08.
Artículo en Inglés | MEDLINE | ID: mdl-36142329

RESUMEN

Silibinin, a natural polyphenolic flavonoid, is known to possess anti-inflammatory, anticancer, antioxidant, and immunomodulatory properties. However, the effects of Silibinin on the maturation and immunostimulatory functions of human dendritic cells (DC) remain to be elucidated. In this study, we have attempted to ascertain whether Silibinin influences the maturation, cytokine production, and antigen-presenting capacity of human monocyte-derived DC. We show that Silibinin significantly suppresses the upregulation of costimulatory and MHC molecules in LPS-stimulated mature DC and inhibits lipopolysaccharide (LPS)-induced interleukin (IL)-12, IL-23, and TNF-α production. Furthermore, Silibinin impairs the proliferation response of the allogenic memory CD4 T lymphocytes elicited by LPS-matured DC and their Th1/Th17 profile. These findings demonstrate that Silibinin displays immunosuppressive activity by inhibiting the maturation and activation of human DC and support its potential application of adjuvant therapy in the treatment of autoimmune diseases.


Asunto(s)
Lipopolisacáridos , Monocitos , Antiinflamatorios/farmacología , Antioxidantes/farmacología , Diferenciación Celular , Células Cultivadas , Citocinas/farmacología , Células Dendríticas , Flavonoides/farmacología , Humanos , Inmunosupresores/farmacología , Interleucina-12 , Interleucina-23 , Lipopolisacáridos/farmacología , Silibina/farmacología , Factor de Necrosis Tumoral alfa/farmacología
3.
Int J Mol Sci ; 23(16)2022 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-36012424

RESUMEN

Hypovitaminosis D is involved in various inflammatory, infectious and autoimmune diseases such as rheumatoid arthritis and multiple sclerosis. Moreover, the active form of vitamin D, calcitriol, has been shown to modulate the immune response, playing an anti-inflammatory effect. However little is known about the mechanisms underlying this anti-inflammatory effect and the potential sex differences of calcitriol immune regulation. Hence, the aim of this study was to investigate whether calcitriol could act differently in modulating T cell immunity of age-matched male and female healthy donors. We analyzed the effects of calcitriol in T lymphocytes from healthy women and men on the expression levels of the vitamin D receptor (VDR) and pro- and anti-inflammatory cytokine production. We showed that a treatment with calcitriol induced a significant increase in the VDR expression levels of activated T lymphocytes from male and female healthy subjects. Moreover, we found that calcitriol significantly reduced the expression level of pro-inflammatory cytokines IL-17, INF-γ and TNF-α in the T lymphocytes of both sexes. Notably, we observed that calcitriol induced a significant increase in the expression level of anti-inflammatory cytokine IL-10 only in the T lymphocytes from female healthy donors. In conclusion, our study provides new insights regarding the sex-specific anti-inflammatory role of calcitriol in T cell immunity.


Asunto(s)
Calcitriol , Factores Sexuales , Linfocitos T , Calcitriol/farmacología , Citocinas/metabolismo , Femenino , Humanos , Masculino , Receptores de Calcitriol/metabolismo , Linfocitos T/metabolismo , Vitamina D/metabolismo , Vitaminas/metabolismo
4.
Pharmacol Res ; 173: 105848, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34454035

RESUMEN

Making gender bias visible allows to fill the gaps in knowledge and understand health records and risks of women and men. The coronavirus disease 2019 (COVID-19) pandemic has shown a clear gender difference in health outcomes. The more severe symptoms and higher mortality in men as compared to women are likely due to sex and age differences in immune responses. Age-associated decline in sex steroid hormone levels may mediate proinflammatory reactions in older adults, thereby increasing their risk of adverse outcomes, whereas sex hormones and/or sex hormone receptor modulators may attenuate the inflammatory response and provide benefit to COVID-19 patients. While multiple pharmacological options including anticoagulants, glucocorticoids, antivirals, anti-inflammatory agents and traditional Chinese medicine preparations have been tested to treat COVID-19 patients with varied levels of evidence in terms of efficacy and safety, information on sex-targeted treatment strategies is currently limited. Women may have more benefit from COVID-19 vaccines than men, despite the occurrence of more frequent adverse effects, and long-term safety data with newly developed vectors are eagerly awaited. The prevalent inclusion of men in randomized clinical trials (RCTs) with subsequent extrapolation of results to women needs to be addressed, as reinforcing sex-neutral claims into COVID-19 research may insidiously lead to increased inequities in health care. The huge worldwide effort with over 3000 ongoing RCTs of pharmacological agents should focus on improving knowledge on sex, gender and age as pillars of individual variation in drug responses and enforce appropriateness.


Asunto(s)
Vacunas contra la COVID-19/uso terapéutico , COVID-19/prevención & control , Equidad en Salud/tendencias , Farmacología Clínica/tendencias , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Caracteres Sexuales , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , COVID-19/sangre , COVID-19/inmunología , Hormonas Esteroides Gonadales/antagonistas & inhibidores , Hormonas Esteroides Gonadales/sangre , Humanos , Farmacología Clínica/métodos , Medicina de Precisión/métodos , Medicina de Precisión/tendencias , Tratamiento Farmacológico de COVID-19
5.
Int J Mol Sci ; 22(9)2021 Apr 23.
Artículo en Inglés | MEDLINE | ID: mdl-33922607

RESUMEN

Sex is a significant variable in the prevalence and incidence of neurological disorders. Sex differences exist in neurodegenerative disorders (NDs), where sex dimorphisms play important roles in the development and progression of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. In the last few years, some sex specific biomarkers for the identification of NDs have been described and recent studies have suggested that microRNA (miRNA) could be included among these, as influenced by the hormonal and genetic background. Failing to consider the possible differences between males and females in miRNA evaluation could introduce a sex bias in studies by not considering some of these sex-related biomarkers. In this review, we recapitulate what is known about the sex-specific differences in peripheral miRNA levels in neurodegenerative diseases. Several studies have reported sex-linked disparities, and from the literature analysis miR-206 particularly has been shown to have a sex-specific involvement. Hopefully, in the near future, patient stratification will provide important additional clues in diagnosis, prognosis, and tailoring of the best therapeutic approaches for each patient. Sex-specific biomarkers, such as miRNAs, could represent a useful tool for characterizing subgroups of patients.


Asunto(s)
Biomarcadores/análisis , MicroARNs/genética , Enfermedades Neurodegenerativas/diagnóstico , Humanos , MicroARNs/análisis , Enfermedades Neurodegenerativas/genética , Factores Sexuales
6.
Monaldi Arch Chest Dis ; 90(2)2020 May 25.
Artículo en Inglés | MEDLINE | ID: mdl-32449614

RESUMEN

In December 2019 a novel coronavirus emerged in Wuhan, China causing many cases of severe pneumonia. World Health Organization (WHO) named this disease Coronavirus Disease 2019 (COVID-19). The infection has rapidly spread across China to many other countries, and on March 12, 2020 the WHO declared pandemic outbreak of COVID-19. As of May 16, 2020, COVID-19 has been diagnosed in more than 4,490,000 patients, associated to 305,976 deaths worldwide; in Italy 224,760 COVID-19 cases have been reported with 31,763 deaths. The main routes of transmission are respiratory droplets and direct contact with infected people, so numerous prevention strategies are employed to mitigate the spread of disease, including social distancing and isolation. The aim of this narrative review is to underline gender differences in epidemiology, etiopathogenesis, risk factors, clinical presentation, diagnosis, prognosis and mortality of patients infected with SARS-CoV-2. Currently data on the sex indicators for admitted or deceased patients are only available, but there is no analysis about other gender indicators. The data considered in our study are the only currently available in the literature, but it is appropriate to implement a specific analysis with all gender indicators to identify appropriate strategies. Moreover, the evaluation of a health service efficiency is a key element to define gender outcomes. Knowing the gender differences in COVID-19 outbreak would be a fundamental tool to understand the effects of a health emergency on individuals and communities as well as to carry out effective and equitable policies, public health measures and targeted solutions.


Asunto(s)
Betacoronavirus/fisiología , Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/fisiopatología , Neumonía Viral/epidemiología , Neumonía Viral/fisiopatología , Enzima Convertidora de Angiotensina 2 , Animales , Betacoronavirus/genética , COVID-19 , Comorbilidad , Infecciones por Coronavirus/diagnóstico , Infecciones por Coronavirus/mortalidad , Humanos , Inmunidad Innata , Pandemias , Peptidil-Dipeptidasa A/metabolismo , Neumonía Viral/diagnóstico , Neumonía Viral/mortalidad , Prevalencia , Pronóstico , Factores de Riesgo , SARS-CoV-2 , Serina Endopeptidasas/metabolismo , Factores Sexuales , Acoplamiento Viral
7.
Cell Physiol Biochem ; 53(1): 186-199, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31278696

RESUMEN

BACKGROUND/AIMS: Estrogen could play a key role in the mechanisms underlying sex-related disparity in the incidence of thrombotic events. We investigated whether estrogen receptors (ERs) were expressed in human red blood cells (RBCs), and if they affected cell signaling of erythrocyte constitutive isoform of endothelial NO-synthase (eNOS) and nitric oxide (NO) release. METHODS: RBCs from 29 non-smoker volunteers (15 males and 14 females) aged between 20 and 40 years were analyzed by cytometry and western blot. In particular, content and distribution of ER-α and ER-ß, tyrosine kinases and eNOS phosphorylation and NO release were analyzed. RESULTS: We demonstrated that: i) both ER-α and ER-ß were expressed by RBCs; ii) they were both functionally active; and iii) ERs distribution and function were different in males and females. In particular, ERs modulated eNOS phosphorylation and NO release in RBCs from both sexes, but they induced the phosphorylation of specific tyrosine residues of kinases linked to eNOS activation and NO release in the RBCs from females only. CONCLUSION: Collectively, these data suggest that ERs could play a critical role in RBC intracellular signaling. The possible implication of this signaling in sex-linked risk disparity in human cardiovascular diseases, e.g. in thrombotic events, may not be ruled out.


Asunto(s)
Receptores de Estrógenos/metabolismo , Transducción de Señal , Adulto , Dronabinol/farmacología , Eritrocitos/citología , Eritrocitos/efectos de los fármacos , Eritrocitos/metabolismo , Receptor alfa de Estrógeno/antagonistas & inhibidores , Receptor alfa de Estrógeno/metabolismo , Receptor beta de Estrógeno/antagonistas & inhibidores , Receptor beta de Estrógeno/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Fosforilación/efectos de los fármacos , Piperidinas/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Pirazoles/farmacología , Transducción de Señal/efectos de los fármacos , Adulto Joven
10.
Apoptosis ; 20(5): 671-8, 2015 May.
Artículo en Inglés | MEDLINE | ID: mdl-25637184

RESUMEN

It has become widely accepted that along with their ability to directly regulate gene expression, estrogens also influence cell signalling and cell function via rapid membrane-initiated events. Many of these signalling processes are dependent on estrogen receptors (ER) localized to the plasma membrane. However, the mechanisms by which ER are able to trigger cell signalling when targeted to the membrane surface have to be determined yet. Lipid rafts seem to be essential for the plasma membrane localization of ER and play a critical role in their membrane-initiated effects. In this review, we briefly recapitulate the localization and function of ER in different cell types and mostly discuss the possible role of lipid rafts in this context. Further studies in this field may disclose new promising therapeutic avenues by the disruption of lipid rafts in those diseases in which membrane ER activation has been demonstrated to play a pathogenetic role.


Asunto(s)
Estrógenos/fisiología , Homeostasis , Microdominios de Membrana/fisiología , Animales , Plaquetas/fisiología , Células Endoteliales/fisiología , Humanos , Linfocitos/fisiología , Músculo Liso Vascular/citología , Miocitos Cardíacos/fisiología , Miocitos del Músculo Liso/fisiología , Neuronas/fisiología , Transducción de Señal
11.
J Autoimmun ; 58: 78-89, 2015 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-25623267

RESUMEN

T lymphocytes from patients with Systemic Lupus Erythematosus (SLE) display multiple abnormalities, including increased cell activation, abnormal cell death by apoptosis and impairment of autophagy pathway. In the present study we report the presence of specific antibodies to D4GDI, a small GTPase family inhibitor, in a significant percentage (46%) of SLE patient sera. We also found a significant association between the presence of these autoantibodies and hematologic manifestations occurring in these patients. Investigating the possible implication of anti-D4GDI autoantibodies in SLE pathogenesis or progression, we found that these antibodies were capable of binding D4GDI expressed at the lymphocyte surface and triggering a series of subcellular events, including Rho GTPase activation. These antibodies were also able to induce autophagy in T cells from both healthy donors and SLE patients, but only those negative to these antibodies. We can conclude that anti-D4GDI autoantibodies could be capable of triggering important responses in T cells such as cytoskeleton remodeling and autophagy pathway and that, in SLE patients, the chronic exposure to these specific autoantibodies could lead to the selection of autophagy-resistant T cell clones contributing to the pathogenesis of the disease.


Asunto(s)
Autoanticuerpos/sangre , Lupus Eritematoso Sistémico/inmunología , Linfocitos T/metabolismo , Proteínas de Unión al GTP rho/metabolismo , Inhibidor beta de Disociación del Nucleótido Guanina rho/inmunología , Adulto , Anciano , Autofagia/genética , Citoesqueleto/metabolismo , Progresión de la Enfermedad , Femenino , Humanos , Células Jurkat , Masculino , Persona de Mediana Edad , Unión Proteica/genética , ARN Interferente Pequeño/genética , Linfocitos T/inmunología , Adulto Joven , Inhibidor beta de Disociación del Nucleótido Guanina rho/genética
12.
FASEB J ; 28(2): 524-35, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24196588

RESUMEN

Autophagy represents a key mechanism of cytoprotection that can be activated by a variety of extracellular and intracellular stresses and allows the cell to sequester cytoplasmic components and damaged organelles, delivering them to lysosomes for degradation and recycling. However, the autophagy process has also been associated with the death of the cell. It has been demonstrated to be constitutive in some instances and inducible in others, and the idea that it could represent a pathogenetic determinant as well as a possible prognostic tool and a therapeutic target in a plethora of human diseases has recently been considered. Among these, cancer represents a major one. In this review, we recapitulate the critical implications of autophagy in the pathogenesis, progression, and treatment of lymphoproliferative disorders. Leukemias and lymphomas, in fact, represent paradigmatic human diseases in which advances have recently been made in this respect.


Asunto(s)
Autofagia/fisiología , Trastornos Linfoproliferativos/fisiopatología , Animales , Enfermedad de Hodgkin/fisiopatología , Humanos , Linfocitos/fisiología , Linfoma no Hodgkin/fisiopatología
13.
Blood ; 120(16): 3360-70, 2012 Oct 18.
Artículo en Inglés | MEDLINE | ID: mdl-22932793

RESUMEN

ß(2)-glycoprotein I (ß(2)GPI) is the major antigenic target for antiphospholipid Abs. Anti-ß(2)GPI Abs are a heterogeneous population of Igs targeting all domains of the molecule. Abs specific to ß(2)GPI domain I are strongly associated with thrombosis and obstetric complications. In the present study, we sought to understand the possible pathogenic mechanism for this subset of anti-ß(2)GPI Abs, investigating their potential cross-reactivity with other self-proteins involved in inflammatory or coagulant events. We compared the amino acid sequence of the ß(2)GPI domain I with human proteins in a protein databank and identified a peptide sharing 88% identity with an epitope of human TLR4. A high percentage of patients with antiphospholipid syndrome (41%) and systemic lupus erythematosus (50%) presented serum IgG specific to this peptide. Anti-ß(2)GPI peptide Abs binding the TLR4 were able to induce NF-κB activation in HEK293 cells that were stably transfected with the TLR4 gene. Anti-ß(2)GPI peptide Abs induced activation of TLR4 and triggered interleukin-1 receptor-associated kinase phosphorylation and NF-κB translocation, promoting VCAM expression on endothelial cells and TNF-α release by monocytes. In conclusion, our observations suggest a novel pathogenic mechanism in the TLR4 stimulation by anti-ß(2)GPI peptide Abs that links adaptive immune responses with innate immunity in antiphospholipid syndrome and systemic lupus erythematosus.


Asunto(s)
Autoanticuerpos/sangre , Células Endoteliales de la Vena Umbilical Humana/inmunología , Mediadores de Inflamación/metabolismo , Monocitos/inmunología , Fragmentos de Péptidos/inmunología , Receptor Toll-Like 4/inmunología , beta 2 Glicoproteína I/inmunología , Adolescente , Adulto , Anciano , Síndrome Antifosfolípido/inmunología , Síndrome Antifosfolípido/metabolismo , Síndrome Antifosfolípido/patología , Estudios de Casos y Controles , Periodontitis Crónica/inmunología , Periodontitis Crónica/metabolismo , Periodontitis Crónica/patología , Reacciones Cruzadas , Ensayo de Inmunoadsorción Enzimática , Femenino , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Células Endoteliales de la Vena Umbilical Humana/patología , Humanos , Lupus Eritematoso Sistémico/inmunología , Lupus Eritematoso Sistémico/metabolismo , Lupus Eritematoso Sistémico/patología , Masculino , Persona de Mediana Edad , Monocitos/metabolismo , Monocitos/patología , FN-kappa B/metabolismo , Transporte de Proteínas , ARN Interferente Pequeño/genética , Receptor Toll-Like 4/antagonistas & inhibidores , Receptor Toll-Like 4/genética , Factor de Necrosis Tumoral alfa/metabolismo , Adulto Joven
14.
Part Fibre Toxicol ; 11: 74, 2014 Dec 14.
Artículo en Inglés | MEDLINE | ID: mdl-25498254

RESUMEN

BACKGROUND: Diesel exhaust particles (DEP) are major constituents of ambient air pollution and their adverse health effect is an area of intensive investigations. With respect to the immune system, DEP have attracted significant research attention as a factor that could influence allergic diseases interfering with cytokine production and chemokine expression. With this exception, scant data are available on the impact of DEP on lymphocyte homeostasis. Here, the effects of nanoparticles from Euro 4 (E4) and Euro 5 (E5) light duty diesel engines on the phenotype and function of T lymphocytes from healthy donors were evaluated. METHODS: T lymphocytes were isolated from peripheral blood obtained from healthy volunteers and subsequently stimulated with different concentration (from 0.15 to 60 µg/ml) and at different time points (from 24 h to 9 days) of either E4 or E5 particles. Immunological parameters, including apoptosis, autophagy, proliferation levels, mitochondrial function, expression of activation markers and cytokine production were evaluated by cellular and molecular analyses. RESULTS: DEP exposure caused a pronounced autophagic-lysosomal blockade, thus interfering with a key mechanism involved in the maintaining of T cell homeostasis. Moreover, DEP decreased mitochondrial membrane potential but, unexpectedly, this effect did not result in changes of the apoptosis and/or necrosis levels, as well as of intracellular content of adenosine triphosphate (ATP). Finally, a down-regulation of the expression of the alpha chain of the interleukin (IL)-2 receptor (i.e., the CD25 molecule) as well as an abnormal Th1 cytokine expression profile (i.e., a decrease of IL-2 and interferon (IFN)-γ production) were observed after DEP exposure. No differences between the two compounds were detected in all studied parameters. CONCLUSIONS: Overall, our data identify functional and phenotypic T lymphocyte parameters as relevant targets for DEP cytotoxicity, whose impairment could be detrimental, at least in the long run, for human health, favouring the development or the progression of diseases such as autoimmunity and cancer.


Asunto(s)
Contaminantes Atmosféricos/toxicidad , Regulación hacia Abajo/efectos de los fármacos , Subunidad alfa del Receptor de Interleucina-2/antagonistas & inhibidores , Activación de Linfocitos/efectos de los fármacos , Hollín/toxicidad , Linfocitos T/efectos de los fármacos , Emisiones de Vehículos/toxicidad , Adulto , Contaminantes Atmosféricos/química , Contaminantes Atmosféricos/metabolismo , Autofagia/efectos de los fármacos , Transporte Biológico , Biomarcadores/metabolismo , Células Cultivadas , Femenino , Humanos , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Cinética , Masculino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Persona de Mediana Edad , Tamaño de la Partícula , Hollín/química , Hollín/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismo , Linfocitos T/ultraestructura , Emisiones de Vehículos/análisis , Adulto Joven
15.
J Pers Med ; 14(9)2024 Aug 27.
Artículo en Inglés | MEDLINE | ID: mdl-39338162

RESUMEN

Gender medicine studies how health status and diseases differ between men and women in terms of prevention, therapeutic approach, prognosis, and psychological and social impact. Sex and gender analyses have been demonstrated to improve science, contributing to achieving real appropriateness and equity in the cure for each person. Therefore, it is fundamental to consider, both in preclinical and clinical research, the different clinical and biological features associated with sex and/or gender, where sex differences are mainly influenced by biological determinants and gender ones by socio-cultural and economic matters. This article was developed to provide knowledge and methodological tools for the development of studies/research protocols in which sex and gender should be taken into account.

16.
FASEB J ; 26(4): 1400-12, 2012 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-22247332

RESUMEN

Autophagy is a lysosome-mediated catabolic process that allows cells to degrade unwanted cytoplasmic constituents and to recycle nutrients. Autophagy is also involved in innate and adaptive immune responses, playing a key role in interactions against microbes, in antigen processing for major histocompatibility complex (MHC) presentation, and in lymphocyte development, survival, and proliferation. Over recent years, perturbations in autophagy have been implicated in a number of diseases, including autoimmunity. Systemic lupus erythematosus (SLE) is a multifactorial disease characterized by autoimmune responses against self-antigens generated by dying cells. Genome-wide association studies have linked several single-nucleotide polymorphisms (SNPs) in the autophagy-related gene Atg5 to SLE susceptibility. Loss of Atg5-dependent effects, including clearance of dying cells and cell antigen presentation, might contribute to the autoimmunity and inflammation associated with SLE. Moreover, activation of the mammalian target of rapamycin (mTOR), a key player in the autophagy regulation, has recently been demonstrated in SLE, confirming an altered autophagy pathway in this disease. In the present review, we summarize the autophagy mechanisms, their molecular regulation, and their relevance in immunity and autoimmunity. The potential of targeting autophagy pathway in SLE, by developing innovative therapeutic approaches, has finally been discussed.


Asunto(s)
Inmunidad Adaptativa , Autoinmunidad/inmunología , Autofagia/inmunología , Inmunidad Innata , Lupus Eritematoso Sistémico/inmunología , Humanos , Lupus Eritematoso Sistémico/fisiopatología , Linfocitos/inmunología , Fagocitos/inmunología
17.
FASEB J ; 26(11): 4722-32, 2012 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-22835828

RESUMEN

Autophagy, the cytoprotection mechanism that takes place under metabolic impairment, has been implicated in the pathogenesis of autoimmunity. Here, we investigated the spontaneous and induced autophagic behavior of T lymphocytes from patients with systemic lupus erythematosus (SLE) compared with that of T lymphocytes from healthy donors by measuring the autophagy marker microtubule-associated protein 1 light chain 3 (LC3)-II. No significant differences in spontaneous autophagy were found between T lymphocytes from patients with SLE and from healthy donors, apart from CD4(+) naive T cells from patients with SLE in which constitutively higher levels of autophagy (P<0.001) were detected. At variance, whereas treatment of T lymphocytes from healthy donors with serum IgG from patients with SLE resulted in a 2-fold increase in LC3-II levels (P<0.001), T lymphocytes from SLE patients were resistant to autophagic induction and also displayed an up-regulation of genes negatively regulating autophagy, e.g., α-synuclein. These findings could open new perspectives in the search for pathogenetic determinants of SLE progression and in the development of therapeutic strategies aimed to recover T-cell compartment homeostasis by restoring autophagic susceptibility.


Asunto(s)
Autofagia/fisiología , Lupus Eritematoso Sistémico/inmunología , Linfocitos T/fisiología , Adulto , Anciano , Autoanticuerpos , Ensayo de Inmunoadsorción Enzimática , Femenino , Técnica del Anticuerpo Fluorescente Indirecta , Regulación de la Expresión Génica , Humanos , Inmunoglobulina G/sangre , Masculino , Persona de Mediana Edad , Reacción en Cadena en Tiempo Real de la Polimerasa , Adulto Joven
18.
Arthritis Rheum ; 64(3): 778-87, 2012 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-21968947

RESUMEN

OBJECTIVE: Estrogens influence many physiologic processes and are also implicated in the development or progression of numerous diseases, including autoimmune disorders. Aberrations of lymphocyte homeostasis that lead to the production of multiple pathogenic autoantibodies, including autoantibodies specific to estrogen receptor (ER), have been detected in the peripheral blood of patients with systemic lupus erythematosus (SLE). This study was undertaken to assess the presence of both anti-ERα and anti-ERß antibodies in sera from patients with SLE, to analyze the effect of these antibodies on peripheral blood T lymphocyte homeostasis, and to evaluate their role as determinants of disease pathogenesis and progression. METHODS: Anti-ER antibody serum immunoreactivity was analyzed by enzyme-linked immunosorbent assay in samples from 86 patients with SLE and 95 healthy donors. Phenotypic and functional analyses were performed by flow cytometry and Western blotting. RESULTS: Anti-ERα antibodies were present in 45% of the patients with SLE, whereas anti-ERß antibodies were undetectable. In healthy donors, anti-ERα antibodies induced cell activation and consequent apoptotic cell death in resting lymphocytes as well as proliferation of anti-CD3-stimulated T lymphocytes. A significant association between anti-ERα antibody values and clinical parameters, i.e., the SLE Disease Activity Index and arthritis, was found. CONCLUSION: Our data suggest that anti-ERα autoantibodies interfere with T lymphocyte homeostasis and are significantly associated with lupus disease activity.


Asunto(s)
Autoanticuerpos/inmunología , Receptor alfa de Estrógeno/inmunología , Homeostasis/inmunología , Lupus Eritematoso Sistémico/inmunología , Linfocitos T/inmunología , Adulto , Anciano , Artritis Reumatoide/sangre , Artritis Reumatoide/inmunología , Autoanticuerpos/sangre , Autoantígenos/inmunología , Síndrome de Behçet/sangre , Síndrome de Behçet/inmunología , Western Blotting , Células Cultivadas , Ensayo de Inmunoadsorción Enzimática , Receptor beta de Estrógeno/inmunología , Femenino , Citometría de Flujo , Humanos , Lupus Eritematoso Sistémico/diagnóstico , Lupus Eritematoso Sistémico/fisiopatología , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Adulto Joven
19.
Neural Plast ; 2013: 971817, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23606988

RESUMEN

A growing body of evidence suggests that psychological stress is a major risk factor for psychiatric disorders. The basic mechanisms are still under investigation but involve changes in neuroendocrine-immune interactions, ultimately affecting brain plasticity. In this study we characterized central and peripheral effects of different stressors, applied for different time lengths, in adult male C57BL/6J mice. We compared the effects of repeated (7 versus 21 days) restraint stress (RS) and chronic disruption of social hierarchy (SS) on neuroendocrine (corticosterone) and immune function (cytokines and splenic apoptosis) and on a marker of brain plasticity (brain-derived neurotrophic factor, BDNF ). Neuroendocrine activation did not differ between SS and control subjects; by contrast, the RS group showed a strong neuroendocrine response characterized by a specific time-dependent profile. Immune function and hippocampal BDNF levels were inversely related to hypothalamic-pituitary-adrenal axis activation. These data show a fine modulation of the crosstalk between central and peripheral pathways of adaptation and plasticity and suggest that the length of stress exposure is crucial to determine its final outcome on health or disease.


Asunto(s)
Encéfalo/metabolismo , Sistema Hipotálamo-Hipofisario/metabolismo , Plasticidad Neuronal/fisiología , Sistema Hipófiso-Suprarrenal/metabolismo , Estrés Psicológico/sangre , Animales , Encéfalo/inmunología , Corticosterona/sangre , Sistema Hipotálamo-Hipofisario/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Sistema Hipófiso-Suprarrenal/inmunología , Estrés Psicológico/inmunología , Factores de Tiempo
20.
Biology (Basel) ; 12(7)2023 Jul 12.
Artículo en Inglés | MEDLINE | ID: mdl-37508423

RESUMEN

Fracture healing is a long-term and complex process influenced by a huge variety of factors. Among these, there is a sex/gender disparity. Based on significant differences observed in the outcome of bone healing in males and females, in the present review, we report the main findings, hypotheses and pitfalls that could lead to these differences. In particular, the role of sex hormones and inflammation has been reported to have a role in the observed less efficient bone healing in females in comparison with that observed in males. In addition, estrogen-induced cellular processes such as autophagic cell cycle impairment and molecular signals suppressing cell cycle progression seem also to play a role in female fracture healing delay. In conclusion, it seems conceivable that a complex framework of events could contribute to the female bias in bone healing, and we suggest that a reappraisal of the compelling factors could contribute to the mitigation of sex/gender disparity and improve bone healing outcomes.

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