RESUMEN
We have used the four core genotypes (FCG) mouse model, which allows a distinction between effects of gonadal secretions and chromosomal complement, to determine when sex differences in the immune system first appear and what influences their development. Using splenic T cell number as a measure that could be applied to neonates with as yet immature immune responses, we found no differences among the four genotypes at postnatal day 1, but by day 7, clear sex differences were observed. These sex differences were unexpectedly independent of chromosomal complement and similar in degree to gonadectomized FCG adults: both neonatal and gonadectomized adult females (XX and XY) showed 2-fold the number of CD4+ and 7-fold the number of CD8+ T cells versus their male (XX and XY) counterparts. Appearance of this long-lived sex difference between days 1 and 7 suggested a role for the male-specific perinatal surge of testicular testosterone. Interference with the testosterone surge significantly de-masculinized the male CD4+, but not CD8+ splenic profile. Treatment of neonates demonstrated elevated testosterone limited mature cell egress from the thymus, whereas estradiol reduced splenic T cell seeding in females. Neonatal male splenic epithelium/stroma expressed aromatase mRNA, suggesting capacity for splenic conversion of perinatal testosterone into estradiol in males, which, similar to administration of estradiol in females, would result in reduced splenic T cell seeding. These sex steroid effects affected both CD4+ and CD8+ cells and yet interference with the testosterone surge only significantly de-masculinized the splenic content of CD4+ cells. For CD8+ cells, male cells in the thymus were also found to express one third the density of sphingosine-1-phosphate thymic egress receptors per cell compared to female, a male characteristic most likely an indirect result of Sry expression. Interestingly, the data also support a previously unrecognized role for non-gonadal estradiol in the promotion of intra-thymic cell proliferation in neonates of both sexes. Microarray analysis suggested the thymic epithelium/stroma as the source of this hormone. We conclude that some immune sex differences appear long before puberty and more than one mechanism contributes to differential numbers and distribution of T cells.
Asunto(s)
Trastornos del Desarrollo Sexual/inmunología , Fenómenos del Sistema Inmunológico/genética , Sistema Inmunológico/fisiología , Animales , Animales Recién Nacidos , Linfocitos T CD4-Positivos/fisiología , Linfocitos T CD8-positivos/fisiología , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Modelos Animales de Enfermedad , Trastornos del Desarrollo Sexual/genética , Trastornos del Desarrollo Sexual/patología , Femenino , Estudios de Asociación Genética , Genotipo , Masculino , Ratones , Ratones Endogámicos C57BL , Embarazo , Caracteres Sexuales , Proteína de la Región Y Determinante del Sexo/genética , Maduración Sexual/genética , Maduración Sexual/inmunologíaRESUMEN
γδT cells represent the majority of lymphocytes in several mucosal tissues where they contribute to tissue homoeostasis, microbial defence and wound repair. Here we characterise a population of interleukin (IL) 17-producing γδ (γδ17) T cells that seed the testis of naive C57BL/6 mice, expand at puberty and persist throughout adulthood. We show that this population is foetal-derived and displays a T-cell receptor (TCR) repertoire highly biased towards Vγ6-containing rearrangements. These γδ17 cells were the major source of IL-17 in the testis, whereas αß T cells mostly provided interferon (IFN)-γ in situ. Importantly, testicular γδ17 cell homoeostasis was strongly dependent on the microbiota and Toll-like receptor (TLR4)/IL-1α/IL-23 signalling. We further found that γδ17 cells contributed to tissue surveillance in a model of experimental orchitis induced by intra-testicular inoculation of Listeria monocytogenes, as Tcrδ-/- and Il17-/- infected mice displayed higher bacterial loads than wild-type (WT) controls and died 3 days after infection. Altogether, this study identified a previously unappreciated foetal-derived γδ17 cell subset that infiltrates the testis at steady state, expands upon puberty and plays a crucial role in local tissue immune surveillance.
Asunto(s)
Microbiota/inmunología , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismo , Maduración Sexual/inmunología , Testículo/inmunología , Testículo/metabolismo , Células Th17/inmunología , Células Th17/metabolismo , Animales , Biomarcadores , Citocinas , Inmunohistoquímica , Vigilancia Inmunológica , Inmunofenotipificación , Interleucina-17/biosíntesis , Interleucina-23/metabolismo , Masculino , Ratones , Ratones Transgénicos , Espermatogénesis , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismoRESUMEN
Puberty is a critical period of neural development, and exposure to stress and inflammation during this period is thought to increase vulnerability to mental illness. The gut microbiome influences brain functioning and behavior and impacts mental health. Yet, the role of the gut microbiome during puberty, a period during which mental health conditions tend to onset, remains largely uninvestigated. We first examined age and sex differences in gut microbial changes among CD-1 mice exposed to an immune challenge (lipopolysaccharide; LPS) at 6 weeks of age (during the pubertal stress-sensitive period) or at 10 weeks of age (in adulthood) (Experiment 1). Compared to their adult counterparts, pubertal males and females showed more significant changes in gut microbial composition following LPS treatment, including the depletion of numerous bacterial genera such as Lactobacillus. Given the beneficial effects of Lactobacillus strains on stress and behaviour, we next investigated whether replenishment of the gut with the probiotic Lactobacillus reuteri (L. reuteri) throughout pubertal development would modulate LPS-induced sickness and enduring effects on memory dysfunction, anxiety-like behaviour and stress reactivity in adulthood (Experiment 2). LPS treatment at 6 weeks of age created enduring changes in anxiety-like behaviors among males only. Similarly, only males showed the protective effects of L. reuteri supplementation during puberty in preventing longstanding LPS-induced changes in anxiety-like behavior and stress-induced brain activation. These findings demonstrate that colonizing the gut with L. reuteri during puberty modulates sickness responses and enduring behavioural and neurochemical outcomes in a sex-specific manner. Therefore, colonizing the gut with beneficial microbes may protect against the development of mental illnesses in adulthood.
Asunto(s)
Ansiedad , Conducta Animal , Disfunción Cognitiva , Microbioma Gastrointestinal , Limosilactobacillus reuteri , Probióticos/farmacología , Caracteres Sexuales , Maduración Sexual , Estrés Psicológico , Factores de Edad , Animales , Ansiedad/inducido químicamente , Ansiedad/dietoterapia , Ansiedad/inmunología , Ansiedad/prevención & control , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Disfunción Cognitiva/inducido químicamente , Disfunción Cognitiva/dietoterapia , Disfunción Cognitiva/inmunología , Disfunción Cognitiva/prevención & control , Modelos Animales de Enfermedad , Femenino , Microbioma Gastrointestinal/efectos de los fármacos , Microbioma Gastrointestinal/inmunología , Lipopolisacáridos/inmunología , Lipopolisacáridos/farmacología , Masculino , Ratones , Maduración Sexual/inmunología , Estrés Psicológico/inducido químicamente , Estrés Psicológico/dietoterapia , Estrés Psicológico/inmunología , Estrés Psicológico/prevención & controlRESUMEN
Puberty is a critical period of development marked by sexual, immune, and neural maturation. Exposure to stress during this period can lead to enduring changes in brain functioning and in behavior; however, the underlying mechanisms and the programming effects of stress during puberty remain unknown. Therefore, the objective of this study was to investigate the programming effects of pubertal immune challenge in response to a homotypic stressor later in life in CD-1 mice. Age and sex differences in the peripheral and central cytokine levels, along with sickness behavior and telemetry data, were analyzed following the secondary treatment. The results showed that pretreatment with LPS attenuated the immune response to a second homotypic challenge. Males pretreated with LPS during puberty and in early adulthood displayed an attenuated hypothermic response following the second LPS treatment compared with saline-pretreated controls, which is consistent with the attenuated peripheral IL-6 and IFN-γ concentrations. Females pretreated with LPS during puberty displayed lower IL-1ß, TNF-α, and IL-6 mRNA expression in the prefrontal cortex following the secondary immune challenge compared with saline controls. The results of this study show that exposure to LPS during puberty programs the peripheral and central immune responses, resulting in an attenuated immune response following a subsequent homotypic stressor. Thus, exposure to an immune challenge during puberty affects immune function later in life, which could permanently affect brain function and have implications on mental health.
Asunto(s)
Fenómenos del Sistema Inmunológico/efectos de los fármacos , Lipopolisacáridos/toxicidad , Maduración Sexual/inmunología , Estrés Fisiológico/inmunología , Animales , Femenino , Masculino , RatonesRESUMEN
Commensal gut microbiota-host immune responses are experimentally delineated via gnotobiotic animal models or alternatively by antibiotic perturbation of gut microbiota. Osteoimmunology investigations in germ-free mice, revealing that gut microbiota immunomodulatory actions critically regulate physiologic skeletal development, highlight that antibiotic perturbation of gut microbiota may dysregulate normal osteoimmunological processes. We investigated the impact of antibiotic disruption of gut microbiota on osteoimmune response effects in postpubertal skeletal development. Sex-matched C57BL/6T mice were administered broad-spectrum antibiotics or vehicle-control from the age of 6 to 12 weeks. Antibiotic alterations in gut bacterial composition and skeletal morphology were sex dependent. Antibiotics did not influence osteoblastogenesis or endochondral bone formation, but notably enhanced osteoclastogenesis. Unchanged Tnf or Ccl3 expression in marrow and elevated tumor necrosis factor-α and chemokine (C-C motif) ligand 3 in serum indicated that the pro-osteoclastic effects of the antibiotics are driven by increased systemic inflammation. Antibiotic-induced broad changes in adaptive and innate immune cells in mesenteric lymph nodes and spleen demonstrated that the perturbation of gut microbiota drives a state of dysbiotic hyperimmune response at secondary lymphoid tissues draining local gut and systemic circulation. Antibiotics up-regulated the myeloid-derived suppressor cells, immature myeloid progenitor cells known for immunosuppressive properties in pathophysiologic inflammatory conditions. Myeloid-derived suppressor cell-mediated immunosuppression can be antigen specific. Therefore, antibiotic-induced broad suppression of major histocompatibility complex class II antigen presentation genes in bone marrow discerns that antibiotic perturbation of gut microbiota dysregulates critical osteoimmune cross talk.
Asunto(s)
Antibacterianos/efectos adversos , Microbioma Gastrointestinal , Osteogénesis , Maduración Sexual , Animales , Antibacterianos/farmacología , Quimiocina CCL3/inmunología , Femenino , Microbioma Gastrointestinal/efectos de los fármacos , Microbioma Gastrointestinal/inmunología , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/patología , Masculino , Mesenterio/inmunología , Mesenterio/patología , Ratones , Células Supresoras de Origen Mieloide/inmunología , Células Supresoras de Origen Mieloide/patología , Osteoclastos/inmunología , Osteoclastos/patología , Osteogénesis/efectos de los fármacos , Osteogénesis/inmunología , Maduración Sexual/efectos de los fármacos , Maduración Sexual/inmunología , Bazo/inmunología , Bazo/patología , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
Pubertal immune challenge can permanently alter hippocampus-dependent memory processes in a sex-specific manner. Although gonadal hormones can influence various cognitive processes, their role in regulating the cognitive sequelae to pubertal immune challenge has not been thoroughly assessed. We examined whether a pubertal immune challenge could affect hippocampus-dependent memory functions in adulthood and whether these effects are regulated by gonadal steroid hormones. We hypothesized that exposure to an immune challenge during puberty would induce sex-specific deficits in the behavioral and cellular correlates of hippocampus-dependent memory during adulthood. At six weeks of age, during the stress-vulnerable pubertal period, male and female CD-1 mice were injected with either saline or the bacterial endotoxin lipopolysaccharide (LPS). Three weeks later, mice underwent either gonadectomy or sham-surgery. At ten weeks of age (i.e., in adulthood), mice began behavioral testing in an open field, Barnes maze, and Morris water maze. Brain tissue was collected at 17 weeks of age and stained for doublecortin and Ki67 to examine migrating neuronal progenitor cells and cellular proliferation in the neurogenic subgranular zone (SGZ) and the cornus ammonis (CA)1 and CA3 regions of the hippocampus. Pubertal LPS treatment impaired learning during adulthood in both sexes and increased cellular proliferation in the CA1 region in castrated males only. Although adult sex hormones did not reliably modulate these changes, gonadectomy impaired learning during the Morris water maze in both sexes. Learning deficits were more prominent during the Barnes maze, which suggests a stress-dependent expression of LPS-induced cognitive deficits. Neurogenesis in the SGZ and cellular proliferation in the CA3 were not affected by pubertal LPS treatment or gonadectomy. These novel findings emphasize the sensitivity of developing cognitive processes during puberty to immune challenges and suggest a possible mechanism for learning-based difficulties in adulthood.
Asunto(s)
Cognición/fisiología , Maduración Sexual/fisiología , Memoria Espacial/fisiología , Factores de Edad , Animales , Encéfalo/fisiología , Castración , Trastornos del Conocimiento/metabolismo , Femenino , Hormonas Esteroides Gonadales/metabolismo , Hipocampo/fisiología , Lipopolisacáridos/farmacología , Masculino , Aprendizaje por Laberinto/fisiología , Ratones , Neurogénesis/fisiología , Neuronas/metabolismo , Maduración Sexual/inmunología , Estrés Fisiológico/inmunologíaRESUMEN
OBJECTIVE: To summarize the current literature on the sex disparity in asthma and the role of sex hormone signaling in allergic and neutrophilic airway inflammation. DATA SOURCES: PubMed and Centers for Disease Control and Prevention health surveys were searched. STUDY SELECTIONS: Clinical and epidemiologic studies in children and adults as well as animal models of asthma were included in this review. RESULTS: Compared with males, females have an increase in asthma prevalence starting around puberty, and fluctuations in hormones during menstruation, pregnancy, and menopause are associated with changes in asthma symptoms. Animal studies using genetic deletions of estrogen receptors or androgen receptors have shown that estrogen signaling promotes and androgen signaling attenuates allergen-mediated type 2 airway inflammation. Furthermore, animal studies have found that ovarian hormones are important for interleukin 17A-mediated airway inflammation. CONCLUSION: Sex hormones are important in regulating asthma pathogenesis. However, additional studies need to be conducted to further elucidate how sex hormones are initiating and driving the inflammatory response(s) in asthma. Determining these pathways will provide the foundation necessary for the development of treatment strategies and potentially new therapeutics for patients, in particular females, with asthma.
Asunto(s)
Andrógenos/inmunología , Asma/inmunología , Estrógenos/inmunología , Regulación del Desarrollo de la Expresión Génica/inmunología , Hormonas Esteroides Gonadales/inmunología , Interleucina-17/inmunología , Maduración Sexual/inmunología , Adulto , Andrógenos/genética , Animales , Asma/genética , Asma/fisiopatología , Niño , Estrógenos/genética , Femenino , Hormonas Esteroides Gonadales/genética , Humanos , Interleucina-17/genética , Masculino , Menopausia/genética , Menopausia/inmunología , Ciclo Menstrual/genética , Ciclo Menstrual/inmunología , Ratones , Embarazo , Factores Sexuales , Maduración Sexual/genética , Transducción de Señal/genética , Transducción de Señal/inmunologíaRESUMEN
In high burden settings, the risk of infection with Mycobacterium tuberculosis increases throughout childhood due to cumulative exposure. However, the risk of progressing from tuberculosis (TB) infection to disease varies by age. Young children (<5 years) have high risk of disease progression following infection. The risk falls in primary school children (5 to <10 years), but rises again during puberty. TB disease phenotype also varies by age: generally, young children have intrathoracic lymph node disease or disseminated disease, while adolescents (10 to <20 years) have adult-type pulmonary disease. TB risk also exhibits a gender difference: compared to adolescent boys, adolescent girls have an earlier rise in disease progression risk and higher TB incidence until early adulthood. Understanding why primary school children, during what we term the "Wonder Years," have low TB risk has implications for vaccine development, therapeutic interventions, and diagnostics. To understand why this group is at low risk, we need a better comprehension of why younger children and adolescents have higher risks, and why risk varies by gender. Immunological response to M. tuberculosis is central to these issues. Host response at key stages in the immunopathological interaction with M. tuberculosis influences risk and disease phenotype. Cell numbers and function change dramatically with age and sexual maturation. Young children have poorly functioning innate cells and a Th2 skew. During the "Wonder Years," there is a lymphocyte predominance and a Th1 skew. During puberty, neutrophils become more central to host response, and CD4+ T cells increase in number. Sex hormones (dehydroepiandrosterone, adiponectin, leptin, oestradiol, progesterone, and testosterone) profoundly affect immunity. Compared to girls, boys have a stronger Th1 profile and increased numbers of CD8+ T cells and NK cells. Girls are more Th2-skewed and elicit more enhanced inflammatory responses. Non-immunological factors (including exposure intensity, behavior, and co-infections) may impact disease. However, given the consistent patterns seen across time and geography, these factors likely are less central. Strategies to protect children and adolescents from TB may need to differ by age and sex. Further work is required to better understand the contribution of age and sex to M. tuberculosis immunity.
Asunto(s)
Interacciones Huésped-Patógeno/inmunología , Inmunidad Innata/fisiología , Mycobacterium tuberculosis/inmunología , Vacunas contra la Tuberculosis/inmunología , Tuberculosis/inmunología , Adolescente , Adulto , Factores de Edad , Niño , Progresión de la Enfermedad , Humanos , Incidencia , Mycobacterium tuberculosis/patogenicidad , Factores Sexuales , Maduración Sexual/inmunología , Tuberculosis/diagnóstico , Tuberculosis/epidemiología , Tuberculosis/prevención & control , Vacunas contra la Tuberculosis/administración & dosificación , Adulto JovenRESUMEN
BACKGROUND: Cross-sectional studies suggested that allergy prevalence in childhood is higher in boys compared to girls, but it remains unclear whether this inequality changes after puberty. We examined the sex-specific prevalence of asthma and rhinitis as single and as multimorbid diseases before and after puberty onset in longitudinal cohort data. METHODS: In six European population-based birth cohorts of MeDALL, we assessed the outcomes: current rhinitis, current asthma, current allergic multimorbidity (ie, concurrent asthma and rhinitis), puberty status and allergic sensitization by specific serum antibodies (immunoglobulin E) against aero-allergens. With generalized estimating equations, we analysed the effects of sex, age, puberty (yes/no) and possible confounders on the prevalence of asthma and rhinitis, and allergic multimorbidity in each cohort separately and performed individual participant data meta-analysis. FINDINGS: We included data from 19 013 participants from birth to age 14-20 years. Current rhinitis only affected girls less often than boys before and after puberty onset: adjusted odds ratio for females vs males 0.79 (95%-confidence interval 0.73-0.86) and 0.86 (0.79-0.94), respectively (sex-puberty interaction P = .089). Similarly, for current asthma only, females were less often affected than boys both before and after puberty onset: 0.71, 0.63-0.81 and 0.81, 0.64-1.02, respectively (sex-puberty interaction P = .327). The prevalence of allergic multimorbidity showed the strongest sex effect before puberty onset (female-male-OR 0.55, 0.46-0.64) and a considerable shift towards a sex-balanced prevalence after puberty onset (0.89, 0.74-1.04); sex-puberty interaction: P < .001. INTERPRETATION: The male predominance in prevalence before puberty and the "sex-shift" towards females after puberty onset were strongest in multimorbid patients who had asthma and rhinitis concurrently.
Asunto(s)
Asma/epidemiología , Pubertad/inmunología , Rinitis Alérgica/epidemiología , Caracteres Sexuales , Adolescente , Estudios de Cohortes , Comorbilidad , Femenino , Humanos , Masculino , Prevalencia , Maduración Sexual/inmunología , Adulto JovenRESUMEN
The study examined the influence of age, sex and peripubertal gonadectomy on a set of T-cell phenotypic parameters. Rats of both sexes were gonadectomised at the age of 1 month and peripheral blood and spleen T lymphocytes from non-gonadectomised and gonadectomised 3- and 11-month-old rats were examined for the expression of differentiation/activation (CD90/CD45RC) and immunoregulatory markers. Peripheral blood T lymphocytes from non-gonadectomised rats showed age-dependent sexual dimorphisms in (1) total count (lower in female than male 11-month-old rats); (2) CD4+:CD8 + cell ratio (higher in female than male rats of both ages); (3) the proportion of recent thymic emigrants in CD8 + T cells (lower in female than male 3-month-old rats) and (4) the proportions of mature naïve and memory/activated cells (irrespective of age, the proportion of naïve cells was higher, whereas that of memory/activated cells was lower in females). Gonadectomy influenced magnitudes or direction of these sex differences. Additionally, sex differences in peripheral blood T-lymphocyte parameters did not fully correspond to those observed in T-splenocyte parameters, suggesting the compartment-specific regulation of the major T-cell subpopulations' and their subsets' composition. Furthermore, there was no sexual dimorphism in the proportion of either CD25 + Foxp3 + cells among CD4 + or CD161+ (NKT) cells within CD8 + T lymphocytes. However, there was gonadal hormone-independent age-associated sexual dimorphism in the proportion of CD161 + cells (NKT cells) in CD8 + T splenocytes. Overall, the study revealed age-dependent variations in sexual dimorphisms in T-cell parameters relevant for immune response efficacy and showed that they are T-cell compartment-specific and partly gonadal hormone-related.
Asunto(s)
Envejecimiento/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Caracteres Sexuales , Maduración Sexual/inmunología , Envejecimiento/sangre , Animales , Antígenos CD/inmunología , Antígenos CD/metabolismo , Relación CD4-CD8 , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/metabolismo , Castración , Femenino , Masculino , RatasRESUMEN
Puberty is a critical period of development during which the brain undergoes reorganizing and remodeling. Exposure to stress during this period is thought to interfere with normal brain development and increase susceptibility to mental illnesses. In female mice, pubertal exposure to lipopolysaccharide (LPS), a bacterial endotoxin, has been shown to alter sexual, anxiety-like, and depression-like behaviors and cognition in an enduring manner. However, the mechanisms underlying these effects remain unknown. The present study examined age and sex difference in tyrosine hydroxylase (TH) expression and dopamine-dependent and Parkinson-like behaviors following LPS treatment. The results show that LPS treatment during adulthood causes an enduring increase in TH expression in many of the brain regions examined. In contrast, there is no change in TH expression following LPS treatment during puberty. However, pubertal LPS treatment induces enduring behavioral deficits in tests of Parkinson-like behaviors, more so in male than in female mice. These results suggest that the low levels of TH following exposure to pubertal immune challenge may predispose mice to Parkinson-like behavior. These findings add to our understanding of stress and immune responses during puberty and their impact on mental health later in life.
Asunto(s)
Conducta Animal/efectos de los fármacos , Lipopolisacáridos/farmacología , Enfermedad de Parkinson , Maduración Sexual/efectos de los fármacos , Tirosina 3-Monooxigenasa/metabolismo , Factores de Edad , Animales , Modelos Animales de Enfermedad , Femenino , Masculino , Ratones , Enfermedad de Parkinson/inmunología , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/fisiopatología , Factores Sexuales , Maduración Sexual/inmunología , Tirosina 3-Monooxigenasa/efectos de los fármacosRESUMEN
Puberty is an important developmental event that is marked by the reorganizing and remodeling of the brain. Exposure to stress during this critical period of development can have enduring effects on both reproductive and non-reproductive behaviors. The purpose of this study was to investigate age and sex differences in immune response by examining sickness behavior, body temperature changes, and serum cytokine levels following an immune challenge. The effects of circulating gonadal hormones on age and sex differences in immune response were also examined. Results showed that male mice display more sickness behavior and greater fluctuations in body temperature following LPS treatment than female mice. Moreover, adult male mice display more sickness behavior and a greater drop in body temperature following LPS treatment compared to pubertal male mice. Following gonadectomy, pubertal and adult males displayed steeper and prolonged drops in body temperature compared to sham-operated counterparts. Gonadectomy did not eliminate sex differences in LPS-induced body temperature changes, suggesting that additional factors contribute to the observed differences. LPS treatment increased cytokine levels in all mice. However, the increase in pro-inflammatory cytokines was higher in adult compared to pubertal mice, while the increase in anti-inflammatory cytokines was greater in pubertal than in adult mice. Our findings contribute to a better understanding of age and sex differences in acute immune response following LPS treatment and possible mechanisms involved in the enduring alterations in behavior and brain function following pubertal exposure to LPS.
Asunto(s)
Envejecimiento/inmunología , Inmunidad , Caracteres Sexuales , Maduración Sexual/inmunología , Animales , Temperatura Corporal , Citocinas/sangre , Femenino , Conducta de Enfermedad , Inflamación/inmunología , Mediadores de Inflamación/inmunología , Lipopolisacáridos/administración & dosificación , Masculino , RatonesRESUMEN
The immune system is known to affect reproductive function, and maternal-fetal immune tolerance is essential for a successful pregnancy. To investigate the relationship between autoimmune disease and female reproductive function, we performed a comparative analysis of the ovarian phenotypes for C57BL/6 mice, autoimmune disease-prone MRL/MpJ (MRL/+) mice and congenic MRL/MpJ-Fas(lpr) (MRL/lpr) mice harboring a mutation in the Fas gene that speeds disease onset. Both MRL-background strains showed earlier vaginal opening than C57BL/6 mice. The estrous cycle became irregular by 6 and 12 months of age in MRL/lpr mice and mice of the other two strains, respectively. Histological analysis at 3 months revealed that the number of primordial follicles was smaller in MRL-background mice than in C57BL/6 mice after 3 months. In addition, MRL/lpr and MRL/+ mice displayed lower numbers of ovarian follicles and corpora lutea at 3 and 6 months, and 6 and 12 months, respectively, than that in age-matched C57BL/6 mice. MRL/lpr and MRL/+ mice developed ovarian interstitial glands after 3 and 6 months, respectively. In particular, MRL/lpr mice showed numerous infiltrating lymphocytes within the ovarian interstitia, and partially stratified ovarian surface epithelia with more developed microvilli than that observed in C57BL/6 mice at 6 months. No significant differences in serum hormone levels were observed between the strains. In conclusion, MRL/lpr mice display altered ovarian development, morphology and function consistent with the progression of severe autoimmune disease, as these findings are less severe in MRL/+ counterparts.
Asunto(s)
Enfermedades Autoinmunes/etiología , Enfermedades Autoinmunes/patología , Ovario/patología , Ovario/fisiopatología , Factores de Edad , Animales , Enfermedades Autoinmunes/diagnóstico , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Ciclo Estral/genética , Ciclo Estral/inmunología , Femenino , Hormona Folículo Estimulante/sangre , Leucocitos/inmunología , Leucocitos/patología , Ratones , Ratones Endogámicos MRL lpr , Mutación , Ovario/ultraestructura , Maduración Sexual/genética , Maduración Sexual/inmunología , Testosterona/sangre , Receptor fas/genéticaRESUMEN
KISS1 gene-encoding kisspeptins are critical for the onset of puberty and control of adult fertility. This study investigated whether KISS1 can be used as a novel target for immunocastration. Human KISS1 was fused with the HBsAg-S gene for constructing an antibiotic-free recombinant plasmid pKS-asd that coded for 31.168 kDa target fusion protein. Six male Hu sheep lambs were divided into two equal groups, treatment and control. The vaccine (1mg/ram lamb) prepared in saline solution was injected into lambs at weeks 0, 3 and 6 of the experiment, respectively. Vaccine efficacy was evaluated in terms of KISS1-specific IgG antibody response, serum testosterone levels, scrotal circumference, testicular weight, length and breadth, extent of testicular tissue damage, and sexual behaviour changes. The specific anti-KISS1 antibody titre in vaccinated animals was significantly higher than that in controls (p<0.05). In addition, vaccinated animals showed lower serum testosterone level, testicular weight and length and smaller scrotal circumference than those in controls (p<0.05). Spermatogenesis of seminiferous tubules in vaccinated animals was suppressed; sexual behaviours in vaccinated animals were significantly lower (p<0.05) than those in controls. In conclusion, the immunization against KISS1 in this DNA vaccine induced a strong antibody response and resulted in the suppression of gonadal function and sexual behaviour in animals, demonstrating that KISS1 can be used as a novel target for developing a DNA immunocastration vaccine.
Asunto(s)
Anticoncepción Inmunológica/veterinaria , Kisspeptinas/inmunología , Maduración Sexual/efectos de los fármacos , Espermatogénesis/efectos de los fármacos , Vacunas Anticonceptivas/inmunología , Vacunas de ADN/inmunología , Animales , Anticoncepción Inmunológica/métodos , Expresión Génica , Antígenos de Superficie de la Hepatitis B/genética , Antígenos de Superficie de la Hepatitis B/inmunología , Humanos , Inmunoglobulina G/biosíntesis , Inmunoglobulina G/sangre , Kisspeptinas/genética , Masculino , Tamaño de los Órganos/efectos de los fármacos , Plásmidos/administración & dosificación , Plásmidos/química , Plásmidos/inmunología , Proteínas Recombinantes de Fusión/administración & dosificación , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/inmunología , Conducta Sexual Animal/efectos de los fármacos , Maduración Sexual/inmunología , Oveja Doméstica , Espermatogénesis/genética , Espermatogénesis/inmunología , Testículo/efectos de los fármacos , Testículo/crecimiento & desarrollo , Testículo/inmunología , Testosterona/sangre , Vacunas Anticonceptivas/administración & dosificación , Vacunas Anticonceptivas/genética , Vacunas de ADN/administración & dosificación , Vacunas de ADN/genéticaRESUMEN
BACKGROUND: For reasons that remain unclear, three times more women develop multiple sclerosis (MS) than men. This preponderance among women is evident only after 12 years of age, implicating pubertal factors in the risk of MS. OBJECTIVE: To investigate the influence of female puberty on central nervous system (CNS) autoimmunity. METHODS: We examined the relationship between age of menarche on MS outcomes in 116 female children (< 16 years old) whom presented with incident 'acquired demyelinating syndromes' (ADS) and were followed prospectively in the national Canadian Pediatric Demyelinating Disease Study, from 2004-2013. Furthermore, we directly investigated the effects of puberty on susceptibility to experimental autoimmune encephalomyelitis (EAE) in two groups of female mice that differed only in their pubertal status. RESULTS: In the ADS children, a later age of menarche was associated with a decreased risk of subsequent MS diagnosis. This relationship persisted, after accounting for patient age at ADS presentation and the presence of ≥1 T2 lesions on brain magnetic resonance imaging (MRI), with a hazard ratio (HR) of 0.64; and additional factors that associate with MS outcomes in ADS children, including low vitamin D levels. Furthermore, we found female mice that had transitioned through puberty were more susceptible to EAE than age-matched, pre-pubertal mice. CONCLUSION: Puberty in females enhances CNS autoimmune mechanisms that lead to MS in humans and EAE in mice.
Asunto(s)
Enfermedades Autoinmunes Desmielinizantes SNC/inmunología , Susceptibilidad a Enfermedades/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Menarquia/inmunología , Esclerosis Múltiple/inmunología , Maduración Sexual/inmunología , Adolescente , Factores de Edad , Animales , Niño , Modelos Animales de Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Ratones , Factores de Riesgo , Factores SexualesRESUMEN
Exposure to prenatal infection and traumatizing experiences in peripubertal life are two environmental risk factors for developmental neuropsychiatric disorders. Modeling the cumulative neuronal impact of these factors in a translational animal model has led to the recent identification of pathological interactions between these environmental adversities in the development of adult brain dysfunctions. The present study explored the consequences of combined prenatal immune challenge and peripubertal stress on discrete cellular abnormalities in the γ-aminobutyric acid (GABA) system of the hippocampus. Pregnant mice were treated with the viral mimetic poly(I:C) (=polyriboinosinic-polyribocytidilic acid) or control solution, and offspring born to poly(I:C)-exposed or control mothers were then left undisturbed or subjected to unpredictable sub-chronic stress during peripubertal development. Stereological estimations of parvalbumin-expressing cells revealed a significant reduction of these GABAergic interneurons in the ventral dentate gyrus of adult offspring exposed to combined immune activation and stress. Single exposure to either environmental factor was insufficient to cause similar neuropathology. We further found that peripubertal stress exerted opposite effects on reelin-immunoreactive cells in the dorsal cornu ammonis (CA) region of the hippocampus, with stress increasing and decreasing reelin expression in control offspring and prenatally immune challenged animals, respectively. The present data suggest that the combination of two environmental risk factors, which have each been implicated in the etiology of major neuropsychiatric disease, induces significant but restricted neuropathological effects on hippocampal GABAergic cell populations known to be affected in brain disorders with neurodevelopmental components.
Asunto(s)
Moléculas de Adhesión Celular Neuronal/metabolismo , Proteínas de la Matriz Extracelular/metabolismo , Hipocampo/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Parvalbúminas/metabolismo , Efectos Tardíos de la Exposición Prenatal/inmunología , Serina Endopeptidasas/metabolismo , Maduración Sexual/inmunología , Estrés Psicológico/metabolismo , Animales , Femenino , Neuronas GABAérgicas/metabolismo , Hipocampo/efectos de los fármacos , Masculino , Ratones , Poli I-C/farmacología , Embarazo , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Proteína ReelinaRESUMEN
The epididymis is an organ involved in the maturation, transport, and storage of sperm prior to ejaculation. As epididymis is exposed to a constant risk of inflammatory conditions that may lead to transient or permanent sterility, protection of this organ from pathogens is an essential aspect of reproductive physiology. The families of antimicrobial peptides ß-defensins and the pattern-recognition receptors Toll-like (TLR) mediate innate immunity in various vertebrates including avian species. As rooster infertility is a major concern in the poultry industry, the objectives of this study were to determine the expression profile of the entire family of the avian ß-defensins (AvBD) and TLR genes in the rooster epididymis, to investigate whether sexual maturation affects their epididymidal mRNA abundance and to determine the changes in their expression levels in response to Salmonella enteritidis (SE) infection in the epididymis of sexually mature roosters. RNA was extracted from the epididymis of healthy pubertal, sexually mature and aged birds, and from sexually mature SE infected birds. RT-PCR analysis revealed that 10 members of the AvBD and nine members of the TLR gene families were expressed in the epididymis. Quantitative real-time PCR analysis revealed that the epididymidal mRNA abundance of certain AvBD and TLR genes was developmentally regulated with respect to sexual maturation. SE infection resulted in a significant induction of AvBD 1, 9, 10, 12 and 14, as well as TLR 1-2, 2-1, 2-2, 4, 5 and 7 genes, in the epididymis of sexually mature roosters, compared to healthy birds of the same age. These findings provide strong evidence to suggest that the rooster epididymis is capable of initiating an inflammatory response to Salmonella, through activation of certain members of the AvBD and TLR gene families.
Asunto(s)
Pollos/inmunología , Epidídimo/inmunología , Enfermedades de las Aves de Corral/microbiología , Salmonelosis Animal/inmunología , Salmonella enteritidis/inmunología , Receptores Toll-Like/inmunología , beta-Defensinas/inmunología , Animales , Epidídimo/microbiología , Masculino , Enfermedades de las Aves de Corral/inmunología , ARN Mensajero/química , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa/veterinaria , Salmonelosis Animal/microbiología , Maduración Sexual/inmunología , Estadísticas no Paramétricas , Receptores Toll-Like/genética , beta-Defensinas/genéticaRESUMEN
The aim of this study was to evaluate endocrinological and immunological effects of early postnatal immunisation against gonadotrophin-releasing hormone (GnRH) in heifer calves, as similar treatment in sheep provokes long-term immunocastration. Heifer calves were injected with either a construct of GnRH - bovine herpes virus 1 glycoprotein D (BHV1 gD; n=9) or saline (n=9) at 2, 6 and 13.5 weeks of age. Antibody (GnRH and carrier) and endocrine responses to immunisation were measured twice monthly (FSH and progesterone) or during intensive sampling regimes (LH). Early postnatal immunisation against GnRH induced a high, but variable, antibody response against both GnRH and carrier. Based on antibody responses, animals were divided into high-titre (HT, n=5) and low-titre (LT, n=4). Occurring mainly in HT, a further peak in anti-GnRH antibodies, stimulated independently of the carrier, was observed at 23 weeks of age, with antibody titres ≥ 10% binding for ≈ 9 weeks post-peak. Conversely immunisation had only temporary, reversible effects on reproductive function, not affecting age at puberty. We hypothesise that the newly generated antibody measured 10 weeks after the final immunisation resulted from antigenic stimulation and immunological memory cell activation to an endogenous GnRH release. This outcome offers an opportunity for further manipulation of reproductive function based on modulation of GnRH secretion and activity where long-term immunological memory may contribute to durable endocrine effects.
Asunto(s)
Anticoncepción Inmunológica/veterinaria , Hormona Liberadora de Gonadotropina/inmunología , Animales , Animales Recién Nacidos , Bovinos , Femenino , Esquemas de Inmunización , Folículo Ovárico , Maduración Sexual/inmunología , Vacunas ConjugadasRESUMEN
Avian ß-defensins (AvßDs) constitute a family of antimicrobial peptides that are critical to innate immunity in chickens, providing protection against microbial pathogens including Salmonella Enteritidis (SE). As apart from the digestive tract another main route of SE colonization in birds is via infection of the oviduct and specifically of the vagina, the aim of this study was to investigate the expression of the complete family of AvßDs, in the chicken vagina in vivo, to determine whether sexual maturation affects their mRNA abundance and to investigate whether SE infection alters the vaginal AvßDs expression. Expression analysis revealed that 11 members of the AvßD family were expressed in the chicken vagina. Quantitative real-time PCR analysis revealed that the mRNA abundance of five AvßDs was up regulated and of one AvßD was down regulated with respect to sexual maturation. In addition SE infection resulted in a significant induction of AvßD5, 7, 10, 11, 12 and 14 in the vagina of sexually mature birds, and in a significant induction of AvßD5 and 11 in the vagina of aged birds. These findings provide strong evidence to suggest that an AvßD-mediated immune response mechanism exists in the chicken vagina providing protection against bacterial pathogens including Salmonella species.
Asunto(s)
Pollos , Enfermedades de las Aves de Corral/microbiología , Salmonelosis Animal/microbiología , Salmonella enteritidis/inmunología , Maduración Sexual/fisiología , beta-Defensinas/biosíntesis , Animales , Femenino , Enfermedades de las Aves de Corral/genética , Enfermedades de las Aves de Corral/inmunología , Enfermedades de las Aves de Corral/metabolismo , ARN Mensajero/química , ARN Mensajero/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/veterinaria , Salmonelosis Animal/genética , Salmonelosis Animal/inmunología , Salmonelosis Animal/metabolismo , Maduración Sexual/genética , Maduración Sexual/inmunología , Estadísticas no Paramétricas , Vagina/inmunología , Vagina/microbiología , beta-Defensinas/genética , beta-Defensinas/inmunologíaRESUMEN
Puberty is a period characterized by brain reorganization that contributes to the development of neural and behavioral responses to gonadal steroids. A single injection of the bacterial endotoxin, lipopolysaccharide (LPS), during the pubertal period decreases sexual receptivity in response to ovarian hormones in adulthood. Because chronic estradiol treatment alleviates depression-like symptoms in ovariectomized adult mice, we investigated the effect of pubertal LPS treatment on estradiol's antidepressant effects. We hypothesized that pubertal LPS treatment would decrease the antidepressant-like effect of estradiol in adult ovariectomized female mice, as it decreases other behavioral responses to ovarian hormones. As expected, chronic estradiol treatment decreased depression-like behavior, as measured by the duration of immobility, in saline-treated mice from two different strains, as well as in mice treated with LPS in adulthood. In contrast, in mice treated pubertally with LPS, estradiol strikingly increased the duration of immobility. No difference in body weight and in locomotion was found among the groups, suggesting that the differences in depression-like behavior were not due to differences in body weight or locomotor activity between LPS-treated and control mice. These results suggest that exposure to an immune challenge during the pubertal period alters the responsiveness of depression-like behavior to estradiol.