RESUMEN
Healthy females and males differ in their immune cell composition and function and females generally mount stronger immune response than males and are much more susceptible to autoimmune rheumatic diseases. Females differ from males in sex hormones, and X-chromosome genes. Sex hormones affect immune cells and responses, and may induce epigenetic DNA changes. The importance of X-chromosome genes is exemplified in men with the Klinefelter syndrome (47,XXY) who have an additional X-chromosome and develop systemic lupus erythematosus(SLE) as frequently as women. X-chromosome contains genes critical for the immune response, such as FOXP3, toll-like receptor(TLR)7, TLR8, CD40 Ligand, IL2RG, IL9R, BTK, and others. Whereas one X-chromosome in females is randomly inactivated early in embryonic development, around 25% of X-linked genes escape inactivation and result in more X-linked gene dosage in females. We use two key female-biased autoimmune rheumatic diseases, SLE and systemic sclerosis, to review differences in immune response, and clinical manifestations between females and males. The inclusion of sex variable in research will facilitate precision medicine and optimal patient outcome.
Asunto(s)
Enfermedades Autoinmunes , Lupus Eritematoso Sistémico , Enfermedades Reumáticas , Masculino , Humanos , Femenino , Sexismo , Enfermedades Autoinmunes/genética , Lupus Eritematoso Sistémico/genética , Enfermedades Reumáticas/genética , Hormonas Esteroides GonadalesAsunto(s)
Síndrome de Churg-Strauss , Granulomatosis con Poliangitis , Miocarditis , Síndrome de Churg-Strauss/diagnóstico , Síndrome de Churg-Strauss/diagnóstico por imagen , Granulomatosis con Poliangitis/diagnóstico , Granulomatosis con Poliangitis/diagnóstico por imagen , Humanos , Inmunosupresores , Miocarditis/diagnóstico por imagen , Miocarditis/etiología , MiocardioAsunto(s)
Inmunosupresores/uso terapéutico , Enfermedades Pulmonares Intersticiales/etiología , Enfermedades Pulmonares Intersticiales/terapia , Miositis/diagnóstico , Miositis/tratamiento farmacológico , Insuficiencia Respiratoria/terapia , Antibacterianos/uso terapéutico , Anticuerpos Antinucleares , Autoantígenos/inmunología , Ciclofosfamida/uso terapéutico , Oxigenación por Membrana Extracorpórea , Femenino , Humanos , Persona de Mediana Edad , Miositis/sangre , Miositis/complicaciones , Terapia por Inhalación de Oxígeno , Insuficiencia Respiratoria/etiología , Ribonucleoproteínas/inmunología , Rituximab/uso terapéutico , Tacrolimus/uso terapéutico , Antígeno SS-BRESUMEN
An association between a number of chronic inflammatory rheumatic diseases and Monoclonal Gammopathy of Undetermined Significance (MGUS) has been reported. To date no cases of Behcet's disease (BD) and MGUS have been documented. BD sits at the interphase of auto-inflammatory and chronic auto-immune disease spectrums. Alterations in the cellular and cytokine microenvironments can promote a pro-inflammatory state in which persistent antigenic stimulation and cellular proliferation can progressively induce cytogenetic abnormalities which could perturbate plasma cell functions such as seen in MGUS. Herein, we present a rare case of a woman presenting with BD who subsequently developed MGUS. Pathogenetic mechanisms that could potentially contribute to development of both conditions, are reviewed and demonstrate that this disease association is not coincidental but is an evolutionary association driven by shared common disease pathogenetic mechanisms.
RESUMEN
Systemic sclerosis (SSc) is characterized by microvasculopathy (Raynaud's phenomenon and fibrointimal proliferation), presence of autoantibodies and collagen deposition in skin (scleroderma) and internal organs. Microvasculopathy, detected by nailfold capillaroscopy, and disease-specific autoantibodies (anti-topoisomerase I, anti-centromere, anti-RNA polymerase III antibodies) usually appear earlier, even years before scleroderma. At that stage of the disease, immune activation with T cells and B cells promote fibrosis. Diagnosis of SSc has been relied on scleroderma, and by this time, internal organs may have developed fibrosis, a lethal feature with no available treatment. The new EULAR/ACR 2013 criteria for the classification of SSc will help identify SSc patients before fibrosis of internal organs. The early diagnosis of SSc, before the development of fibrosis in internal organs, will allow the introduction of immunosuppressive medications in these patients in a controlled setting (randomized trials). It is anticipated that this approach will change the hitherto grim prognosis of SSc for the better.
Asunto(s)
Inmunosupresores/uso terapéutico , Enfermedad de Raynaud/diagnóstico , Esclerodermia Sistémica/diagnóstico , Autoanticuerpos , Diagnóstico Precoz , Humanos , Angioscopía Microscópica , Pronóstico , Esclerodermia Sistémica/tratamiento farmacológico , Esclerodermia Sistémica/inmunologíaRESUMEN
The aim of this study was to examine the serum levels of MIF and leptin in patients infected with Trichinella britovi. Thirtysix patients with acute trichinellosis and 20 healthy control subjects were included in the study. Serum high sensitive C-reactive protein (hs-CRP), MIF and leptin levels were studied. Assessments were performed in the patients group during acute infection and after the treatment periods and we also compared these values with healthy controls. In the patients, hs-CRP, leukocyte and eosinophil counts, and the levels of muscle enzymes in the acute infectious period were found to be significantly higher than those in the post treatment period (p < 0.05). Both leptin and MIF were higher in acute trichinellosis patients when compared to controls. However, this was only significant for leptin. This study indicates that leptin and MIF levels are increased in the sera of patients with acute trichinellosis.
Asunto(s)
Brotes de Enfermedades , Leptina/sangre , Factores Inhibidores de la Migración de Macrófagos/sangre , Triquinelosis/sangre , Enfermedad Aguda , Adulto , Aspartato Aminotransferasas/sangre , Proteína C-Reactiva/análisis , Estudios de Casos y Controles , Creatina Quinasa/sangre , Eosinófilos/citología , Femenino , Humanos , L-Lactato Deshidrogenasa/sangre , Recuento de Leucocitos , Masculino , Albúmina Sérica/análisis , Triquinelosis/epidemiología , Turquía/epidemiologíaRESUMEN
INTRODUCTION: Systemic lupus erythematosus (SLE) and rheumatoid arthritis have complex genetic traits, but in both autoimmune diseases, dysfunctional apoptosis appears to play a part in disease pathology. This study examined the levels of in vitro apoptosis in lymphocytes from healthy, rheumatoid arthritis (RA) and SLE individuals and related observed differences to their lymphocyte apoptosis gene profiles. MATERIALS AND METHODS: Lymphocytes were assessed for cell death by nuclear pyknosis and DNA fragmentation. Control, SLE and RA apoptosis gene profiles were obtained by quantitative real-time polymerase chain reaction (QRT-PCR) analysis. RESULTS AND DISCUSSION: The mean levels of pyknosis in RA and SLE freshly isolated lymphocytes were significantly higher than in control lymphocytes. Ninety-three apoptosis genes were analysed by QRT-PCR of mRNA from RA, SLE and healthy lymphocytes. We identified significant differences (p < 0.05) in the expression of the same 11 of 93 and two of 93 apoptotic genes in individual SLE and RA patients tested as compared with controls. CONCLUSION: We propose that similarly altered expression of specific apoptotic regulatory genes (e.g., the death effector domain-containing DNA-binding protein and apoptosis-associated speck-like protein containing a CARD) occurs in the lymphocytes of individual patients with SLE or RA that may influence the extent and rate of spontaneous apoptosis in these autoimmune conditions.
Asunto(s)
Apoptosis , Artritis Reumatoide/genética , Lupus Eritematoso Sistémico/genética , Linfocitos/metabolismo , Adulto , Anciano , Apoptosis/genética , Apoptosis/inmunología , Artritis Reumatoide/inmunología , Artritis Reumatoide/metabolismo , Proteínas Adaptadoras de Señalización CARD/biosíntesis , Proteínas Adaptadoras de Señalización CARD/genética , Proteínas Adaptadoras de Señalización CARD/inmunología , Células Cultivadas , Proteínas Adaptadoras de Señalización del Receptor del Dominio de Muerte/biosíntesis , Proteínas Adaptadoras de Señalización del Receptor del Dominio de Muerte/genética , Proteínas Adaptadoras de Señalización del Receptor del Dominio de Muerte/inmunología , Femenino , Perfilación de la Expresión Génica , Regulación de la Expresión Génica/inmunología , Humanos , Lupus Eritematoso Sistémico/inmunología , Lupus Eritematoso Sistémico/metabolismo , Linfocitos/inmunología , Linfocitos/patología , Masculino , Persona de Mediana EdadRESUMEN
Systemic sclerosis is characterized by extensive fibrosis, microvascular stenosis and autoantibody production. All three characteristics can be accounted for by activation of cells of the immune system. Activation of T cells is antigen-driven and occurs early in the course of the disease, before microscopic evidence of fibrosis. Activated T cells are predominantly of the type 2 T-helper lineage, and produce interleukin-4 and interleukin-13, which induce fibrosis. B cells are also activated early in the course of the disease and, through the production of autoantibodies, cause fibroblasts to adopt a profibrotic phenotype. Macrophages in perivascular infiltrates are activated and produce CC-chemokine ligand 2, transforming growth factor beta and platelet derived growth factor, all of which promote fibrosis and fibroproliferation. These new insights have direct impact on the treatment of patients with systemic sclerosis; therapies that target T cells, B cells and their harmful mediators are a logical approach, and preliminary data are promising.
Asunto(s)
Linfocitos B/inmunología , Sistema Inmunológico/inmunología , Esclerodermia Sistémica/inmunología , Linfocitos T/inmunología , Animales , Linfocitos B/patología , Modelos Animales de Enfermedad , Fibrosis/inmunología , Fibrosis/patología , Humanos , Sistema Inmunológico/patología , Sistema Inmunológico/fisiopatología , Activación de Linfocitos , Esclerodermia Sistémica/patología , Esclerodermia Sistémica/fisiopatología , Esclerodermia Sistémica/terapia , Linfocitos T/patologíaRESUMEN
Neutrophils are the major cellular immune components in response to bacterial infections. Neutrophil enzymes are important in invasion, inflammation, and infection processes. In order to understand the basic effects of protein malnutrition on neutrophils we studied matrix metalloproteinases 8 and 9 (MMP-8 and MMP-9) production in severe quantitative and qualitative protein malnutrition in rats. Wistar rats (2 months old) were divided into four groups each with three subgroups and fed various protein-containing diets (24% protein, 20% gelatin-containing and N-free) for 7, 14, 21, and/or 28 days. Neutrophil enzyme expression was determined by Western blotting. Leukocytes decreased significantly due to malnutrition (p = 0.001 ) whilst the percentage of neutrophils increased (p = 0.02) in protein-deprived groups. Neutrophils of malnourished rats produced lower levels of MMP-8 at early stages of protein deprivation with an increase in the following weeks. MMP-9 production by neutrophils from N-free diet fed animals was highest after one week. Serum MMP-9 levels decreased in the qualitative but not in the quantitative protein malnutrition groups. Results suggest that neutrophils might be important in reuse of body cell proteins during fasting or malnutrition conditions and dietary manipulation might have profound effects on MMP-8 and -9 production in rats.
Asunto(s)
Regulación Enzimológica de la Expresión Génica , Metaloproteinasa 8 de la Matriz/biosíntesis , Metaloproteinasa 9 de la Matriz/biosíntesis , Neutrófilos/enzimología , Deficiencia de Proteína/enzimología , Animales , Masculino , Ratas , Ratas WistarRESUMEN
In this study, the possible role of MIF as an immunologic marker in cutaneous leishmaniasis was evaluated. Twenty patients with acute cutaneous leishmaniasis (CL) and 20 healthy subjects were included in the study. MIF serum levels were measured using a sandwich ELISA method. The MIF levels were 3.50 +/- 7.07 ng/ml in the control group and 69.05 +/- 149.48 ng/ml in the CL group (p < 0,001). The increase in MIF levels in CL patients may be due to the stimulation of a T cell-mediated cellular immune response by Leishmania.
RESUMEN
High field 1H NMR spectroscopy demonstrated that addition of Co(II) ions to osteoarthritic knee-joint synovial fluid (SF) resulted in its complexation by a range of biomolecules, the relative efficacies of these complexants/chelators being citrate >> histidine - threonine >> glycine - glutamate - glutamine - phenylalanine tyrosine > formate > lactate >> alanine > valine > acetate > pyruvate > creatinine, this order reflecting the ability of these ligands to compete for the available Co(II) in terms of (1) thermodynamic equilibrium constants for the formation of their complexes and (2) their SF concentrations. Since many of these SF Co(II) complexants (e.g. histidinate) serve as powerful *OH scavengers, the results acquired indicate that any of this radical generated from the Co(II) source in such complexes via Fenton or pseudo-Fenton reaction systems will be "site-specifically" scavenged. The significance of these observations with regard to cobalt toxicity and the in vivo corrosion of cobalt-containing metal alloy joint prostheses (e.g. CoCr alloys) is discussed.
Asunto(s)
Cobalto/análisis , Articulación de la Rodilla , Osteoartritis/metabolismo , Líquido Sinovial/química , Cobalto/aislamiento & purificación , Depuradores de Radicales Libres/química , Depuradores de Radicales Libres/metabolismo , Humanos , Radical Hidroxilo/química , Espectroscopía de Resonancia Magnética/métodos , Persona de Mediana Edad , Peso MolecularRESUMEN
Corticosteroids (CSs) have potent immunosuppressive effects and are commonly used to treat a range of immunological and inflammatory diseases such as rheumatoid arthritis (RA). These effects are mediated by the ability of CSs to modulate gene expression. CSs act by binding to the CS receptor (CR), which exists as alpha and beta isoforms. Only CRalpha binds CS. CRbeta functions as an endogenous inhibitor of CS and is expressed in several tissues. The CS/CRalpha complex binds to the glucocorticosteroid response element in the nucleus and also interferes with AP-1 and NF-kappaB binding. Thus, CSs inhibit the transcription of AP-1 and NF-kappaB inducible genes, such as interleukin (IL)-2, IL-6, IL-8, IL-1beta, and tumor necrosis factor (TNF) alpha, as well as T-cell proliferation. In clinical practice, a proportion of RA patients do not respond adequately to CS therapy. On this basis, RA patients can be divided on clinical grounds and on the ability of CSs to inhibit concanavalin A (conA)-induced peripheral blood T-cell proliferation in vitro into CS-sensitive (SS) and CS-resistant (SR) subgroups. The in vitro defined SS and SR subgroups correlate with the clinical responses to CS therapy. The mechanisms of the SR in RA patients remain unknown but may include the following: dysregulation of CRalpha function, alterations in the intracellular signaling mechanisms and/or utilization of various other cellular activation pathways, perturbations of the cytokine milieu, and inhibition of lipocortin. In SR subjects, CSs fail to significantly inhibit conA-induced IL-2 and IL-4 secretion and LPS-induced IL-8, IL-1beta secretion in vitro. CS therapy fails to reduce the circulating levels of IL-8, IL-1beta, and TNFalpha in SR RA patients. Peripheral blood mononuclear cells (PBMCs) from SR significantly overexpress activated NF-kappaB and IkappaBalpha. In vitro CSs fail to significantly inhibit conA-induced NF-kappaB activation in PBMCs from SR RA patients. Our preliminary observations show enhanced CRbeta expression by PBMCs from SR RA patients. It is most likely that other molecular mechanisms such as enhanced AP-1 expression are involved, and we currently are investigating such possibilities.
Asunto(s)
Corticoesteroides/farmacología , Antiinflamatorios/farmacología , Artritis Reumatoide/tratamiento farmacológico , Enfermedades Autoinmunes/tratamiento farmacológico , Inmunosupresores/farmacología , Receptores de Glucocorticoides/efectos de los fármacos , Corticoesteroides/uso terapéutico , Antiinflamatorios/uso terapéutico , Artritis Reumatoide/metabolismo , Enfermedades Autoinmunes/metabolismo , Citocinas/metabolismo , Resistencia a Medicamentos , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Inmunosupresores/uso terapéutico , Sustancias Macromoleculares , Neuroinmunomodulación , Prolactina/fisiología , Receptores de Glucocorticoides/fisiología , Transducción de Señal , Esteroides , Factores de Transcripción/metabolismo , Transcripción Genética/efectos de los fármacosRESUMEN
Juvenile rheumatoid arthritis (JRA) is the most common childhood chronic systemic autoimmune inflammatory disease. The therapeutic approach to JRA has, to date, been casual and based on extensions of clinical experiences gained in the management of adult rheumatoid arthritis (RA). The physiology of inflammation has been systemically studied and this has led to the identification of specific therapeutic targets and the development of novel approaches to the management of JRA. The classical treatments of the disease such as methotrexate, sodium aurothiomalate and sulfasalazine, are not always effective in controlling RA and JRA. This has necessitated the development of novel agents for treating RA, most of which are biological in nature and are targeted at specific sites of the inflammatory cascades. These biological therapeutic strategies in RA have proved successful and are being applied in the management of JRA. These developments have been facilitated by the advances in molecular biology which have heralded the advent of biodrugs (recombinant proteins) and gene therapy, in which specific genes can be introduced locally to enhance in vivo gene expression or suppress gene(s) of interest with a view to down-regulating inflammation. Some of these biodrugs, such as anti-tumor necrosis factor alpha (anti-TNFalpha), monoclonal antibodies (infliximab, adalimumab), TNF soluble receptor constructs (etanercept) and interleukin-1 receptor antagonist (IL-1Ra) have been tested and shown to be effective in RA. Etanercept has now been licensed for JRA. Clinical trials of infliximab in JRA are planned. Studies show that the clinical effects are transient, necessitating repeated treatments and the risk of vaccination effects. Anti-inflammatory cytokines such as IL-4, IL-10, transforming growth factor-beta and interferon-beta (IFN-beta) are undergoing clinical trials. Many of these agents have to be administered parenterally and production costs are very high; thus, there is a need, especially for pediatric use, to develop agents that can be taken orally. Long-term studies will be required to assess the tolerability and toxicity of these approaches in JRA, since cytokines and other mediators play important roles in host defenses, and the chronic inhibition, exogenous administration or constitutive over-expression of some cytokines/mediators may have undesirable effects.