RESUMEN
Inflammation is known to alter nervous system function, but its effect on muscle spindle afferent mechanosensation and sensory integration in the spinal cord has not been well studied. We tested the hypothesis that systemic inflammation induced by an intraperitoneal injection of the endotoxin lipopolysaccharide (LPS; 7.5 × 105 endotoxin units/kg 18 h before experiment) would alter muscle spindle afferent mechanosensation and spinal cord excitability to Group Ia input in male and female adult C57Bl/6 mice. LPS injection caused a systemic immune response, evidenced by decreased white blood cell, monocyte, and lymphocyte concentrations in the blood, increased blood granulocyte concentration, and body weight loss. The immune response in both sexes was qualitatively similar. We used an in vitro muscle-nerve preparation to assay muscle spindle afferent response to stretch and vibration. LPS injection did not significantly change the response to stretch or vibration, with the exception of small decreases in the ability to entrain to high-frequency vibration in male mice. Similarly, LPS injection did not alter spinal cord excitability to Group Ia muscle spindle afferent input as measured by the Hoffman's reflex test in anesthetized mice (100 mg/kg ketamine, 10 mg/kg xylazine). Specifically, there were no changes in M or H wave latencies nor in the percentage of motor neurons excited by electrical afferent stimulation (Hmax /Mmax ). Overall, we found no major alterations in muscle proprioceptor function or sensory integration following exposure to LPS at a dose and time course that causes changes in nociceptor function and central processing.
Asunto(s)
Mecanotransducción Celular , Husos Musculares/fisiología , Neuronas Aferentes/fisiología , Médula Espinal/fisiología , Animales , Femenino , Reflejo H , Inflamación , Lipopolisacáridos/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Neuronas Motoras/inmunología , Neuronas Motoras/fisiología , Husos Musculares/inmunología , Neuronas Aferentes/inmunología , Propiocepción , Médula Espinal/inmunología , VibraciónRESUMEN
Antibody-secreting cells are generated in regional lymphoid tissues and traffic as plasmablasts (PBs) via lymph and blood to target sites for local immunity. We used multiparameter flow cytometry to define PB trafficking programs (TPs, combinations of adhesion molecules and chemoattractant receptors) and their imprinting in patients in response to localized infection or immune insults. TPs enriched after infection or autoimmune inflammation of mucosae correlate with sites of immune response or symptoms, with different TPs imprinted during small intestinal, colon, throat, and upper respiratory immune challenge. PBs induced after intramuscular or intradermal influenza vaccination, including flu-specific antibody-secreting cells, display TPs characterized by the lack of mucosal homing receptors. PBs of healthy donors display diverse mucosa-associated TPs, consistent with homeostatic immune activity. Identification of TP signatures of PBs may facilitate noninvasive monitoring of organ-specific immune responses.
Asunto(s)
Células Productoras de Anticuerpos/inmunología , Tejido Linfoide/inmunología , Formación de Anticuerpos , Transporte Biológico , Enfermedad Celíaca/inmunología , Colitis Ulcerosa/inmunología , Humanos , Inmunidad Mucosa , Tejido Linfoide/citología , Infecciones del Sistema Respiratorio/inmunología , Infecciones Estreptocócicas/inmunologíaRESUMEN
Bordetella pertussis (B. pertussis) is the causative agent of whooping cough, a respiratory disease that is reemerging worldwide. Mechanisms of selective lymphocyte trafficking to the airways are likely to be critical in the immune response to this pathogen. We compared murine infection by B. pertussis, B. parapertussis, and a pertussis toxin-deleted B. pertussis mutant (BpΔPTX) to test the hypothesis that effector memory T-helper cells (emTh) display an altered pattern of trafficking receptor expression in B. pertussis infection due to a defect in imprinting. Increased cell recruitment to the lungs at 5 days post infection (p.i.) with B. parapertussis, and to a lesser extent with BpΔPTX, coincided with an increased frequency of circulating emTh cells expressing the mucosal-associated trafficking receptors α4ß7 and α4ß1 while a reduced population of these cells was observed in B. pertussis infection. These cells were highly evident in the blood and lungs in B. pertussis infection only at 25 days p.i. when B. parapertussis and BpΔPTX infections were resolved. Although at 5 days p.i., an equally high percentage of lung dendritic cells (DCs) from all infections expressed maturation markers, this expression persisted only in B. pertussis infection at 25 days p.i. Furthermore, at 5 days p.i with B. pertussis, lung DCs migration to draining lymph nodes may be compromised as evidenced by decreased frequency of CCR7(+) DCs, inhibited CCR7-mediated in vitro migration, and fewer DCs in lung draining lymph nodes. Lastly, a reduced frequency of allogeneic CD4(+) cells expressing α4ß1 was detected following co-culture with lung DCs from B. pertussis-infected mice, suggesting a defect in DC imprinting in comparison to the other infection groups. The findings in this study suggest that B. pertussis may interfere with imprinting of lung-associated trafficking receptors on T lymphocytes leading to extended survival in the host and a prolonged course of disease.
Asunto(s)
Infecciones por Bordetella/metabolismo , Bordetella pertussis , Integrina alfa4/metabolismo , Pulmón/metabolismo , Bazo/metabolismo , Linfocitos T Colaboradores-Inductores/metabolismo , Animales , Infecciones por Bordetella/inmunología , Infecciones por Bordetella/patología , Bordetella parapertussis , Adhesión Celular/inmunología , Movimiento Celular/inmunología , Femenino , Pulmón/inmunología , Pulmón/patología , Ratones , Ratones Endogámicos BALB C , Bazo/inmunología , Bazo/patología , Linfocitos T Colaboradores-Inductores/patologíaRESUMEN
BACKGROUND: The incidence of pediatric ulcerative colitis (UC), a chronic autoinflammatory disease of the colon, is on the rise. Although an increased infiltration of B cells from the peripheral blood into the colon occurs in UC, B-cell trafficking is understudied. We hypothesized that the frequency of circulating plasmablasts (PBs) and their trafficking receptor (TR) expression may be indicative of the location and degree of pathology in pediatric UC. METHODS: We conducted multicolor flow cytometry analyses of circulating IgA(+/-) PBs and IgA(+) memory B cells (MBCs) in pediatric UC patients with remission, mild, moderate, and severe state of disease (n = 12), and healthy pediatric (n = 2) and adult donors (n = 11). RESULTS: Compared to healthy donors the average frequency of PBs among total peripheral blood lymphocytes is increased 30-fold during severe UC activity, and positively correlates with Pediatric Ulcerative Colitis Activity Index score, C-reactive protein level, and erythrocyte sedimentation rate. A greater percent of PBs in severe patients express the gut-homing receptors α4ß7 and CCR10, and the inflammatory homing molecule P-selectin ligand (P-sel lig). The percent of IgA(+) MBCs expressing α4ß7, however, is reduced. Furthermore, expression of the small intestine TR CCR9 is decreased on α4ß7(high) PBs, and on α4ß7(high) /CCR10(high) PBs and MBCs in these patients, consistent with preferential cell targeting to the colon. CONCLUSIONS: Peripheral blood PBs with a colon-homing phenotype (α4ß7/CCR10/P-sel lig) are elevated in children with severe UC. Screening this B-cell subset may provide a complementary approach in monitoring disease activity or therapeutic efficacy in pediatric UC.
Asunto(s)
Colitis Ulcerosa/metabolismo , Células Plasmáticas/fisiología , Receptores Mensajeros de Linfocitos/metabolismo , Adolescente , Adulto , Subgrupos de Linfocitos B/fisiología , Proteína C-Reactiva/análisis , Estudios de Casos y Controles , Niño , Colitis Ulcerosa/inmunología , Femenino , Citometría de Flujo , Humanos , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Receptores Mensajeros de Linfocitos/fisiología , Índice de Severidad de la Enfermedad , Adulto JovenRESUMEN
BACKGROUND: Filamentous hemagglutinin (FHA) is a cell-associated and secreted adhesin produced by Bordetella pertussis with pro-apoptotic and pro-inflammatory activity in host cells. Given the importance of the NF-kappaB transcription factor family in these host cell responses, we examined the effect of FHA on NF-kappaB activation in macrophages and bronchial epithelial cells, both of which are relevant cell types during natural infection. METHODOLOGY/PRINCIPAL FINDINGS: Exposure to FHA of primary human monocytes and transformed U-937 macrophages, but not BEAS-2B epithelial cells, resulted in early activation of the NF-kappaB pathway, as manifested by the degradation of cytosolic IkappaB alpha, by NF-kappaB DNA binding, and by the subsequent secretion of NF-kappaB-regulated inflammatory cytokines. However, exposure of macrophages and human monocytes to FHA for two hours or more resulted in the accumulation of cytosolic IkappaB alpha, and the failure of TNF-alpha to activate NF-kappaB. Proteasome activity was attenuated following exposure of cells to FHA for 2 hours, as was the nuclear translocation of RelA in BEAS-2B cells. CONCLUSIONS: These results reveal a complex temporal dynamic, and suggest that despite short term effects to the contrary, longer exposures of host cells to this secreted adhesin may block NF-kappaB activation, and perhaps lead to a compromised immune response to this bacterial pathogen.