RESUMEN
INTRODUCTION: Malnutrition in children is epidemic in developing countries. Several health issues and consequences are believed to develop due to this phenomenon. Children's oral health is also affected by malnutrition. The main aspects of oral health status are caries experience, the existence of cariogenic bacteria, and salivary immunoglobulin A.
Asunto(s)
Caries Dental , Salud Bucal , Saliva , Humanos , Caries Dental/epidemiología , Niño , Saliva/inmunología , Masculino , Femenino , Desnutrición/epidemiología , Inmunoglobulina A Secretora/metabolismo , Inmunoglobulina A/metabolismoRESUMEN
IgA antibodies play an important role in mucosal immunity. However, there is still no effective way to consistently boost mucosal IgA responses, and the factors influencing these responses are not fully understood. We observed that colonization with the murine intestinal symbiotic protozoan Tritrichomonas musculis (T.mu) boosted antigen-specific mucosal IgA responses in wild-type C57BL/6 mice. This enhancement was attributed to the accumulation of free arachidonic acid (ARA) in the intestinal lumen, which served as a signal to stimulate the production of antigen-specific mucosal IgA. When ARA was prevented from undergoing its downstream metabolic transformation using the 5-lipoxygenase inhibitor zileuton or by blocking its downstream biological signaling through genetic deletion of the Leukotriene B4 receptor 1 (Blt1), the T.mu-mediated enhancement of antigen-specific mucosal IgA production was suppressed. Moreover, both T.mu transfer and dietary supplementation of ARA augmented the efficacy of an oral vaccine against Salmonella infection, with this effect being dependent on Blt1. Our findings elucidate a tripartite circuit linking nutrients from the diet or intestinal microbiota, host lipid metabolism, and the mucosal humoral immune response.
Asunto(s)
Inmunidad Mucosa , Inmunoglobulina A , Metabolismo de los Lípidos , Ratones Endogámicos C57BL , Receptores de Leucotrieno B4 , Transducción de Señal , Animales , Metabolismo de los Lípidos/inmunología , Inmunoglobulina A/inmunología , Inmunoglobulina A/metabolismo , Transducción de Señal/inmunología , Ratones , Receptores de Leucotrieno B4/metabolismo , Receptores de Leucotrieno B4/inmunología , Ácido Araquidónico/metabolismo , Mucosa Intestinal/inmunología , Mucosa Intestinal/metabolismo , Femenino , Microbioma Gastrointestinal/inmunología , Ratones NoqueadosRESUMEN
BACKGROUND: Sunitinib, a multi-targeted tyrosine kinase inhibitor, is used as a second-line therapy for gastrointestinal stromal tumors (GIST) resistant to imatinib. However, its impact on the vascular endothelial growth factor (VEGF) pathway can lead to significant toxicities, including hypertension and thrombotic microangiopathy (TMA). CASE PRESENTATION: This case report describes a unique instance of a patient with metastatic GIST who developed endocapillary proliferative glomerulonephritis (EPGN) with IgA2 deposits and TMA following sunitinib treatment. The patient presented with severe hypertension, nephrotic syndrome, and acute kidney injury. Renal biopsy confirmed the diagnosis, revealing IgA2 deposits, which are not commonly associated with TMA. Discontinuation of sunitinib led to a rapid improvement in renal function and proteinuria. The potential mechanisms underlying sunitinib-induced glomerular injury may involve the blockade of VEGFR-1, affecting immune cell recruitment and function, and the disruption of the nitric oxide and endothelin systems, leading to endothelial damage and immune dysregulation. Management of these toxicities requires a personalized approach, with options ranging from symptomatic relief to drug discontinuation. The use of endothelin receptor antagonists and other therapeutic alternatives for GIST management is discussed. CONCLUSIONS: This case highlights the complex interplay between the therapeutic effects of sunitinib and its potential renal and cardiovascular toxicities, emphasizing the need for close monitoring and effective management strategies to optimize patient outcomes.
Asunto(s)
Antineoplásicos , Tumores del Estroma Gastrointestinal , Sunitinib , Microangiopatías Trombóticas , Humanos , Sunitinib/uso terapéutico , Sunitinib/efectos adversos , Microangiopatías Trombóticas/inducido químicamente , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Masculino , Inmunoglobulina A/metabolismo , Glomerulonefritis por IGA/patología , Glomerulonefritis Membranoproliferativa/inducido químicamente , Glomerulonefritis Membranoproliferativa/patología , Glomerulonefritis Membranoproliferativa/tratamiento farmacológico , Persona de Mediana Edad , Neoplasias Gastrointestinales/tratamiento farmacológico , Neoplasias Gastrointestinales/patologíaRESUMEN
A T-cell-independent (TI) pathway activated by microbiota results in the generation of low-affinity homeostatic IgA with a critical role in intestinal homeostasis. Moderate aerobic exercise (MAE) provides a beneficial impact on intestinal immunity, but the action of MAE on TI-IgA generation under senescence conditions is unknown. This study aimed to determine the effects of long-term MAE on TI-IgA production in young (3 month old) BALB/c mice exercised until adulthood (6 months) or aging (24 months). Lamina propria (LP) from the small intestine was obtained to determine B cell and plasma cell sub-populations by flow cytometry and molecular factors related to class switch recombination [Thymic Stromal Lymphopoietin (TSLP), A Proliferation-Inducing Ligand (APRIL), B Cell Activating Factor (BAFF), inducible nitric oxide synthase (iNOS), and retinal dehydrogenase (RDH)] and the synthesis of IgA [α-chain, interleukin (IL)-6, IL-21, and Growth Factor-ß (TGF-ß)]; and epithelial cells evaluated IgA transitosis [polymeric immunoglobulin receptor (pIgR), tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), IL-4] by the RT-qPCR technique. The results were compared with data obtained from sedentary age-matched mice. Statistical analysis was computed with ANOVA, and p < 0.05 was considered to be a statistically significant difference. Under senescence conditions, MAE promoted the B cell and IgA+ B cells and APRIL, which may improve the intestinal response and ameliorate the inflammatory environment associated presumably with the downmodulation of pro-inflammatory mediators involved in the upmodulation of pIgR expression. Data suggested that MAE improved IgA and downmodulate the cytokine pro-inflammatory expression favoring homeostatic conditions in aging.
Asunto(s)
Envejecimiento , Homeostasis , Inmunoglobulina A , Ratones Endogámicos BALB C , Condicionamiento Físico Animal , Animales , Inmunoglobulina A/metabolismo , Inmunoglobulina A/inmunología , Ratones , Envejecimiento/inmunología , Citocinas/metabolismo , Linfocitos B/inmunología , Linfocitos B/metabolismo , Factor Activador de Células B/metabolismo , Factor Activador de Células B/genética , Mucosa Intestinal/metabolismo , Mucosa Intestinal/inmunología , Intestino Delgado/inmunología , Intestino Delgado/metabolismo , Masculino , Células Plasmáticas/inmunología , Células Plasmáticas/metabolismo , Miembro 13 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/metabolismo , Miembro 13 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/genéticaRESUMEN
OBJECTIVES: This study aimed to assess the intricate relationship between salivary IgA antibody levels to PAc (361-386) (PPA), mutans streptococci colonization, and root caries development in older adults. MATERIALS AND METHODS: This study included 307 participants aged 76 years residing in Niigata city, Japan. Clinical oral examinations were performed at baseline in 2004 and 1 year later, during which the total number of untreated and treated root caries was assessed using the root decayed, filled tooth (DFT) index. The stimulated saliva samples were collected using the spitting method during the baseline survey. Salivary IgA antibody levels to amino acid residues 361-386 of Streptococcus mutans PAc were quantified using an enzyme-linked immunosorbent assay. Statistical analyses, including the χ2 test, Mann-Whitney U test, and logistic regressions, were performed to examine the association of increased root DFT with the independent variables. RESULTS: Among the 307 participants (53.1% men), the mean root DFT at baseline was 3.77 ± 3.66, and 36.5% of the study sample exhibited increased root DFT after 1 year with a mean increment of 0.36 ± 0.48. Participants with increase in root DFT after 1 year had significantly higher rates of low PPA levels (≤ 25th percentile) than those without increased root DFT (p = 0.020). Low PPA levels (≤ 25th percentile) were significantly more likely to have an increased risk of root caries development compared with PPA levels > 25th percentile (adjusted OR: 1.88, 95% CI: 1.09-3.25). CONCLUSION: Low PPA levels and root caries incidence correlated significantly, suggesting that low levels of salivary IgA antibody to PAc (361-386) may serve as a risk factor for increased root caries in older adults.
Asunto(s)
Caries Radicular , Saliva , Streptococcus mutans , Humanos , Caries Radicular/inmunología , Caries Radicular/epidemiología , Anciano , Femenino , Masculino , Saliva/inmunología , Saliva/microbiología , Saliva/química , Streptococcus mutans/inmunología , Streptococcus mutans/aislamiento & purificación , Factores de Riesgo , Japón/epidemiología , Inmunoglobulina A Secretora/análisis , Inmunoglobulina A Secretora/inmunología , Ensayo de Inmunoadsorción Enzimática , Inmunoglobulina A/análisis , Inmunoglobulina A/inmunología , Inmunoglobulina A/metabolismo , Anticuerpos Antibacterianos/análisis , Anticuerpos Antibacterianos/inmunología , Índice CPORESUMEN
Thermal comfort in an office impacts physical health, stress, and productivity. Humidity affects thermal comfort; however, the underlying mechanism remains unclear. This study assessed the influence of humidity on body temperature, thermal comfort, stress, and their relationship in working individuals. Thirteen participants performed three sets of 20-min calculation tasks followed by a 10-min rest in 26 °C or 33 °C with relative humidity (RH) of 30 % or 60 %. Core body temperature (Tcore), mean skin surface temperature (Tskin), and electrocardiogram were continuously recorded. Subjective thermal sensations and comfort were assessed with visual analog scales. Stress level was estimated based on α-amylase activity and immunoglobulin A level in saliva and heart rate variability. Mean Tskin and Tcore elevated at 33 °C with 60 % RH, where warm sensation and thermal discomfort also increased. Heart rate variability reflecting parasympathetic nerve activity decreased. There was a negative linear relationship between weighted body temperature and thermal comfort. However, thermal discomfort was augmented at a given weighted body temperature at 60 % RH. Thus, under indoor working conditions, high humidity may augment thermal discomfort and become a stress factor. Increases in Tskin and Tcore are involved in the mechanism, alongside other factors.
Asunto(s)
Temperatura Corporal , Frecuencia Cardíaca , Humedad , Saliva , Humanos , Masculino , Frecuencia Cardíaca/fisiología , Temperatura Corporal/fisiología , Adulto Joven , Adulto , Saliva/metabolismo , Saliva/química , Femenino , Sensación Térmica/fisiología , Electrocardiografía , alfa-Amilasas/metabolismo , Temperatura Cutánea/fisiología , Estrés Psicológico/fisiopatología , Inmunoglobulina A/metabolismo , Estrés Fisiológico/fisiología , Condiciones de TrabajoRESUMEN
Post-injury dysfunction of humoral immunity accounts for infections and poor outcomes in cardiovascular diseases. Among immunoglobulins (Ig), IgA, the most abundant mucosal antibody, is produced by plasma B cells in intestinal Peyer's patches (PP) and lamina propria. Here we show that patients with stroke and myocardial ischemia (MI) had strongly reduced IgA blood levels. This was phenocopied in experimental mouse models where decreased plasma and fecal IgA were accompanied by rapid loss of IgA-producing plasma cells in PP and lamina propria. Reduced plasma IgG was detectable in patients and experimental mice 3-10 d after injury. Stroke/MI triggered the release of neutrophil extracellular traps (NETs). Depletion of neutrophils, NET degradation or blockade of NET release inhibited the loss of IgA+ cells and circulating IgA in experimental stroke and MI and in patients with stroke. Our results unveil how tissue-injury-triggered systemic NET release disrupts physiological Ig secretion and how this can be inhibited in patients.
Asunto(s)
Trampas Extracelulares , Infarto del Miocardio , Neutrófilos , Trampas Extracelulares/metabolismo , Trampas Extracelulares/inmunología , Humanos , Animales , Infarto del Miocardio/inmunología , Infarto del Miocardio/patología , Infarto del Miocardio/metabolismo , Masculino , Neutrófilos/inmunología , Neutrófilos/metabolismo , Femenino , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Accidente Cerebrovascular/inmunología , Accidente Cerebrovascular/patología , Accidente Cerebrovascular/metabolismo , Ganglios Linfáticos Agregados/inmunología , Ganglios Linfáticos Agregados/patología , Ganglios Linfáticos Agregados/metabolismo , Inmunoglobulina A/metabolismo , Inmunoglobulina A/inmunología , Inmunoglobulina A/sangre , Anciano , Persona de Mediana Edad , Inmunoglobulina G/inmunología , Inmunoglobulina G/metabolismo , Inmunidad Humoral , Estudios de Casos y Controles , Ratones , Células Plasmáticas/inmunología , Células Plasmáticas/metabolismoRESUMEN
Autoantibodies to nuclear antigens are hallmarks of systemic lupus erythematosus (SLE) where they contribute to pathogenesis. However, there remains a gap in our knowledge regarding how different isotypes of autoantibodies contribute to this autoimmune disease, including the production of the critical type I interferon (IFN) cytokines by plasmacytoid dendritic cells (pDCs) in response to immune complexes (ICs). We focused on IgA, which is the second-most prevalent isotype in serum and, along with IgG, is deposited in glomeruli in individuals with lupus nephritis. We show that individuals with SLE have serum IgA autoantibodies against most nuclear antigens, correlating with IgG against the same antigen. We investigated whether IgA autoantibodies against a major SLE autoantigen, Smith ribonucleoprotein (Sm/RNP), played a role in IC activation of pDCs. We found that pDCs expressed the IgA-specific Fc receptor, FcαR, and IgA1 autoantibodies synergized with IgG in RNA-containing ICs to generate robust primary blood pDC IFN-α responses in vitro. pDC responses to these ICs required both FcαR and FcγRIIa, showing synergy between these Fc receptors. Sm/RNP IC binding to and internalization by pDCs were greater when ICs contained both IgA1 and IgG. Circulating pDCs from individuals with SLE had higher binding of IgA1-containing ICs and higher expression of FcαR than pDCs from healthy control individuals. Although pDC FcαR expression correlated with the blood IFN-stimulated gene signature in SLE, Toll-like receptor 7 agonists, but not IFN-α, up-regulated pDC FcαR expression in vitro. Together, we show a mechanism by which IgA1 autoantibodies contribute to SLE pathogenesis.
Asunto(s)
Complejo Antígeno-Anticuerpo , Autoanticuerpos , Células Dendríticas , Inmunoglobulina A , Inmunoglobulina G , Lupus Eritematoso Sistémico , Humanos , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Inmunoglobulina A/inmunología , Inmunoglobulina A/metabolismo , Inmunoglobulina A/sangre , Autoanticuerpos/inmunología , Inmunoglobulina G/inmunología , Inmunoglobulina G/metabolismo , Complejo Antígeno-Anticuerpo/inmunología , Complejo Antígeno-Anticuerpo/metabolismo , Lupus Eritematoso Sistémico/inmunología , Lupus Eritematoso Sistémico/sangre , ARN/metabolismo , Femenino , Interferón-alfa/metabolismo , Adulto , Receptores Fc/metabolismo , Receptores Fc/inmunología , Receptor Toll-Like 7/metabolismo , Masculino , Receptores de IgG/metabolismoRESUMEN
SCOPE: Immunoglobulin A (IgA) selectively coats gut bacteria and contributes to regulatory functions in gastrointestinal inflammation and glucose metabolism. Excess intake of lard leads to decrease in the IgA coating of gut bacteria, although the underlying mechanisms remain unknown. This study validates how unabsorbed fat derived from a high-lard diet in the gut affects the IgA coating of bacteria, as assessed in mouse models using three types of dietary fat (lard, medium-, and long-chain triglycerides [MLCTs], and medium-chain triglycerides [MCTs]) exhibiting different digestibilities. METHODS AND RESULTS: C57BL/6J mice are maintained on diets containing lard, MLCTs, or MCTs at 7% or 30% w/w for 10 weeks (n = 6 per group). The fecal fatty acid concentration is measured to quantify unabsorbed fat content. The ratio of IgA-coated bacteria to total bacteria (IgA coating ratio) in the feces is measured by flow cytometry. Compared to lard-fed mice, MLCT- and MCT-fed mice exhibit lower fecal concentrations of palmitic acid, stearic acid, and oleic acid and higher IgA coating ratios at both 7% and 30% dietary fat, and these parameters exhibit significant negative correlations. CONCLUSION: Unabsorbed fat content in the gut may result in attenuated IgA coating of bacteria in high-lard diet-fed mice.
Asunto(s)
Dieta Alta en Grasa , Heces , Microbioma Gastrointestinal , Inmunoglobulina A , Animales , Masculino , Ratones , Dieta Alta en Grasa/efectos adversos , Grasas de la Dieta , Ácidos Grasos , Heces/microbiología , Heces/química , Microbioma Gastrointestinal/efectos de los fármacos , Microbioma Gastrointestinal/fisiología , Inmunoglobulina A/metabolismo , Ratones Endogámicos C57BL , Triglicéridos/metabolismoRESUMEN
Immunoglobulin A (IgA)-mediated mucosal immunity is important for the host because it contributes to reducing infection risk and to establishing host-microbe symbiosis. BTB and CNC homology 1 (Bach1) is a transcriptional repressor with physiological and pathophysiological functions that are of particular interest for their relation to gastrointestinal diseases. However, Bach1 effects on IgA-mediated mucosal immunity remain unknown. For this study using Bach1-deficient (Bach1-/-) mice, we investigated the function of Bach1 in IgA-mediated mucosal immunity. Intestinal mucosa, feces, and plasma IgA were examined using immunosorbent assay. After cell suspensions were prepared from Peyer's patches and colonic lamina propria, they were examined using flow cytometry. The expression level of polymeric immunoglobulin receptor (pIgR), which plays an important role in the transepithelial transport of IgA, was evaluated using Western blotting, quantitative real-time PCR, and immunohistochemistry. Although no changes in the proportions of IgA-producing cells were observed, the amounts of IgA in the intestinal mucosa were increased in Bach1-/- mice. Furthermore, plasma IgA was increased in Bach1-/- mice, but fecal IgA was decreased, indicating that Bach1-/- mice have abnormal secretion of IgA into the intestinal lumen. In fact, Bach1 deficiency reduced pIgR expression in colonic mucosa at both the protein and mRNA levels. In the human intestinal epithelial cell line LS174T, suppression of Bach1 reduced pIgR mRNA stability. In contrast, the overexpression of Bach1 increased pIgR mRNA stability. These results demonstrate that Bach1 deficiency causes abnormal secretion of IgA into the intestinal lumen via suppression of pIgR expression.NEW & NOTEWORTHY The transcriptional repressor Bach1 has been implicated in diverse intestinal functions, but the effects of Bach1 on IgA-mediated mucosal immunity remain unclear. We demonstrate here that Bach1 deficiency causes abnormal secretion of IgA into the intestinal lumen, although the proportions of IgA-producing cells were not altered. Furthermore, Bach1 regulates the expression of pIgR, which plays an important role in the transepithelial transport of IgA, at the posttranscriptional level.
Asunto(s)
Factores de Transcripción con Cremalleras de Leucina de Carácter Básico , Mucosa Intestinal , Ratones Noqueados , Receptores de Inmunoglobulina Polimérica , Animales , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/metabolismo , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/deficiencia , Receptores de Inmunoglobulina Polimérica/genética , Receptores de Inmunoglobulina Polimérica/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/inmunología , Ratones , Humanos , Inmunoglobulina A/metabolismo , Inmunidad Mucosa , Ratones Endogámicos C57BL , Inmunoglobulina A Secretora/metabolismo , Ganglios Linfáticos Agregados/metabolismo , Ganglios Linfáticos Agregados/inmunología , Regulación de la Expresión GénicaRESUMEN
BACKGROUND: Intestinal epithelial cells (IECs) serve as robust barriers against potentially hostile luminal antigens and commensal microbiota. Epithelial barrier dysfunction enhances intestinal permeability, leading to leaky gut syndrome (LGS) associated with autoimmune and chronic inflammatory disorders. However, a causal relationship between LGS and systemic disorders remains unclear. Ap1m2 encodes clathrin adaptor protein complex 1 subunit mu 2, which facilitates polarized protein trafficking toward the basolateral membrane and contributes to the establishment of epithelial barrier functions. METHODS: We generated IEC-specific Ap1m2-deficient (Ap1m2ΔIEC) mice with low intestinal barrier integrity as an LSG model and examined the systemic impact. FINDINGS: Ap1m2ΔIEC mice spontaneously developed IgA nephropathy (IgAN)-like features characterized by the deposition of IgA-IgG immune complexes and complement factors in the kidney glomeruli. Ap1m2 deficiency markedly enhanced aberrantly glycosylated IgA in the serum owing to downregulation and mis-sorting of polymeric immunoglobulin receptors in IECs. Furthermore, Ap1m2 deficiency caused intestinal dysbiosis by attenuating IL-22-STAT3 signaling. Intestinal dysbiosis contributed to the pathogenesis of IgAN because antibiotic treatment reduced aberrantly glycosylated IgA production and renal IgA deposition in Ap1m2ΔIEC mice. INTERPRETATION: IEC barrier dysfunction and subsequent dysbiosis by AP-1B deficiency provoke IgA deposition in the mouse kidney. Our findings provide experimental evidence of a pathological link between LGS and IgAN. FUNDING: AMED, AMED-CREST, JSPS Grants-in-Aid for Scientific Research, JST CREST, Fuji Foundation for Protein Research, and Keio University Program for the Advancement of Next Generation Research Projects.
Asunto(s)
Modelos Animales de Enfermedad , Inmunoglobulina A , Mucosa Intestinal , Glomérulos Renales , Ratones Noqueados , Animales , Ratones , Inmunoglobulina A/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Glomérulos Renales/metabolismo , Glomérulos Renales/patología , Disbiosis , Glomerulonefritis por IGA/metabolismo , Glomerulonefritis por IGA/etiología , Glomerulonefritis por IGA/patología , Complejo 1 de Proteína Adaptadora/metabolismo , Complejo 1 de Proteína Adaptadora/genética , Transducción de Señal , Factor de Transcripción STAT3/metabolismoRESUMEN
Immunoglobulin A1 (IgA1) protease is a critical virulence factor of Haemophilus influenzae that facilitates bacterial mucosal infection. This study investigates the effect of iga gene polymorphism on the enzymatic activity of H. influenzae IgA1 protease. The IgA1 protease activity was examined in the H. influenzae Rd KW20 strain and 51 isolates. Genetic variations in iga and deduced amino acid substitutions affecting IgA1 protease activity were assessed. Machine learning tools and functional complementation assays were used to analyze the effects of identified substitutions on the stability and activity of IgA1 protease, respectively. All 51 isolates exhibited similar iga expression levels. No igaB expression was detected. According to comparisons with the reference Rd KW20 strain, four substitutions in the protease domain, 26 in the nonprotease passenger domain, and two in the ß-barrel domain were associated with the change in IgA1 protease activity. No substitutions in the catalytic site of IgA1 protease were observed. Logistic regression, receiver operating characteristic curves, Venn diagrams, and protein stability analyses revealed that the substitutions Asn352Lys, Pro353Ala, Lys356Asn, Gln916Lys, and Gly917Ser, which were located in the nonactive site of the passenger domain, were associated with decreases in IgA1 protease activity and stability, whereas Asn914Lys was associated with an increase in these events. Functional complementation assays revealed that the Asn914Lys substitution increased IgA1 protease activity in the Rd KW20 strain. This study identified substitutions in the nonactive site of the passenger domain that affect both the activity and stability of H. influenzae IgA1 protease.
Asunto(s)
Haemophilus influenzae , Haemophilus influenzae/genética , Haemophilus influenzae/enzimología , Humanos , Sustitución de Aminoácidos , Serina Endopeptidasas/genética , Serina Endopeptidasas/metabolismo , Serina Endopeptidasas/química , Inmunoglobulina A/metabolismo , Infecciones por Haemophilus/microbiología , Infecciones por Haemophilus/inmunología , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/químicaRESUMEN
Introduction: Equine asthma (EA) is a common lower airway disease in horses, but whether its pathogenesis is allergic is ambiguous. Extrinsic stimuli like hay dust induce acute exacerbation of clinical signs and sustained local neutrophilic inflammation in susceptible horses. Aspergillus fumigatus is an EA stimulus, but it is unclear if it merely acts as an IgE-provoking allergen. We aimed to comprehensively analyze immunoglobulin (Ig) isotypes in EA, elucidating their binding to different A. fumigatus antigens, and their quantities systemically in serum and locally in bronchoalveolar lavage fluid (BALF). Methods: Serum and BALF from healthy horses (HE, n = 18) and horses with mild-moderate asthma (MEA, n = 20) or severe asthma (SEA, n = 24) were compared. Ig isotype (IgG1, IgG3/5, IgG4/7, IgG6, IgA, and IgE) binding to nine antigens (A. fumigatus lysate, and recombinant Asp f 1, Asp f 7, Asp f 8, dipeptidyl-peptidase 5, class II aldolase/adducin domain protein, glucoamylase, beta-hexosaminidase, and peptide hydrolase) was compared by enzyme-linked immunosorbent assays. Total Ig isotype contents were determined by bead-based assays. Results: MEA and SEA differed from HE but hardly from each other. Compared to HE, asthmatic horses showed increased anti-A. fumigatus binding of IgG (BALF and serum) and IgA (BALF). Serum and BALF IgE binding and total IgE contents were similar between HE and EA. Single antigens, as well as A. fumigatus lysate, yielded similar Ig binding patterns. Serum and BALF IgG1 binding to all antigens was increased in SEA and to several antigens in MEA. Serum IgG4/7 binding to two antigens was increased in SEA. BALF IgA binding to all antigens was increased in SEA and MEA. Total BALF IgG1 and IgG4/7 contents were increased in SEA, and serum IgG4/7 content was increased in MEA compared to HE. Yet, total isotype contents differentiated EA and HE less clearly than antigen-binding Ig. Discussion: A. fumigatus immunogenicity was confirmed without identification of single dominant antigens here. A. fumigatus provoked elevated BALF IgG1 and IgA binding, and these isotypes appear relevant for neutrophilic EA, which does not support allergy. BALF Ig isotype differentiation beyond IgE is crucial for a comprehensive analysis of immune responses to fungi in EA pathogenesis.
Asunto(s)
Antígenos Fúngicos , Aspergillus fumigatus , Asma , Líquido del Lavado Bronquioalveolar , Enfermedades de los Caballos , Inmunoglobulina A , Inmunoglobulina G , Animales , Caballos/inmunología , Aspergillus fumigatus/inmunología , Líquido del Lavado Bronquioalveolar/inmunología , Asma/inmunología , Asma/microbiología , Inmunoglobulina G/inmunología , Inmunoglobulina G/sangre , Inmunoglobulina A/inmunología , Inmunoglobulina A/sangre , Inmunoglobulina A/metabolismo , Enfermedades de los Caballos/inmunología , Enfermedades de los Caballos/microbiología , Antígenos Fúngicos/inmunología , Masculino , Neutrófilos/inmunología , Neutrófilos/metabolismo , Femenino , Inmunoglobulina E/inmunología , Inmunoglobulina E/sangre , Anticuerpos Antifúngicos/inmunología , Anticuerpos Antifúngicos/sangreRESUMEN
Intestinal homeostasis involves the collaboration of gut barrier components, such as goblet cells and IgA-microbiota complexes, that are under the control of stress that promotes inflammatory responses addressed primarily in the colon. The aim of this study was to evaluate the effect of stress on mucins, goblet cells, and proinflammatory parameters in the proximal and distal regions of the small intestine. A group (n = 6) of female 8-week-old BALB/c mice underwent board immobilization stress (2 h per day for 4 days) and were sacrificed with isoflurane. Samples from proximal and distal small segments were collected to analyze the following: 1) goblet cells stained with periodic acid-Schiff (PAS) and with alcian blue (AB) to visualize histologically neutral and acidic mucins, respectively; 2) IgA-microbiota complexes identified by flow cytometry in intestinal lavages; and 3) MUC2, MUC5AC, and IL-18 mRNA levels in whole mucosal scrapings by reverse transcription-qPCR. Regarding the unstressed group, in the proximal region of small intestine both PAS+ and AB+ goblet cells were unchanged; however, MUC5AC and IL-18 mRNA levels were increased, and the percentage of IgA-microbiota complexes was reduced. In the distal segment, the number of PAS+ goblet cells was increased, whereas the number of AB+ goblet cells was reduced and did not affect the remaining parameters. The data suggest that stress induces inflammation in the proximal small intestine; these findings may provide an experimental reference for human diseases that may affect the proximal small intestine, such as Crohn's disease, in which stress contributes to the progression of intestinal inflammation or relapse.
Asunto(s)
Células Caliciformes , Intestino Delgado , Ratones Endogámicos BALB C , Mucinas , Animales , Intestino Delgado/metabolismo , Intestino Delgado/microbiología , Intestino Delgado/patología , Femenino , Ratones , Células Caliciformes/metabolismo , Células Caliciformes/patología , Mucinas/metabolismo , Estrés Psicológico/metabolismo , Estrés Psicológico/inmunología , Interleucina-18/metabolismo , Mucina 5AC/metabolismo , Estrés Fisiológico , Inmunoglobulina A/metabolismo , Mucina 2/metabolismo , Mucina 2/genéticaRESUMEN
Circadian rhythm plays an important role in intestinal homeostasis and intestinal immune function. Circadian rhythm dysregulation was reported to induce intestinal microbiota dysbiosis, intestinal barrier disruption, and trigger intestinal inflammation. However, the relationship between intestinal microbiota metabolites and the circadian rhythm of the intestinal barrier was still unclear. Urolithin A (UA), a kind of intestinal microbial metabolite, was selected in this study. Results showed UA influenced on the expression rhythm of the clock genes BMAL1 and PER2 in intestinal epithelial cells. Furthermore, the study investigated the effects of UA on the expression rhythms of clock genes (BMAL1 and PER2) and tight junctions (OCLN, TJP1, and CLND1), all of which were dysregulated by inflammation. In addition, UA pre-treatment by oral administration to female C57BL/6 mice showed the improvement in the fecal IgA concentrations, tight junction expression (Clnd1 and Clnd4), and clock gene expression (Bmal1 and Per2) in a DSS-induced colitis model induced using DSS treatment. Finally, the Nrf2-SIRT1 signaling pathway was confirmed to be involved in UA's effect on the circadian rhythm of intestinal epithelial cells by antagonist treatment. This study also showed evidence that UA feeding showed an impact on the central clock, which are circadian rhythms in SCN. Therefore, this study highlighted the potential of UA in treating diseases like IBD with sleeping disorders by improving the dysregulated circadian rhythms in both the intestinal barrier and the SCN.
Asunto(s)
Ritmo Circadiano , Colitis , Cumarinas , Mucosa Intestinal , Ratones Endogámicos C57BL , Animales , Ritmo Circadiano/efectos de los fármacos , Femenino , Mucosa Intestinal/metabolismo , Mucosa Intestinal/efectos de los fármacos , Colitis/inducido químicamente , Colitis/tratamiento farmacológico , Colitis/metabolismo , Ratones , Cumarinas/farmacología , Microbioma Gastrointestinal/efectos de los fármacos , Inflamación , Factor 2 Relacionado con NF-E2/metabolismo , Factores de Transcripción ARNTL/metabolismo , Factores de Transcripción ARNTL/genética , Proteínas Circadianas Period/metabolismo , Proteínas Circadianas Period/genética , Uniones Estrechas/metabolismo , Uniones Estrechas/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Modelos Animales de Enfermedad , Humanos , Sulfato de Dextran , Regulación de la Expresión Génica/efectos de los fármacos , Inmunoglobulina A/metabolismo , Sirtuina 1RESUMEN
Pancreas-derived islet amyloid polypeptide (IAPP) aggregates and deposits in the pancreas and periphery of Type 2 Diabetes (T2D) patients, contributing to diabetic complications. The excess IAPP can be removed by autoantibodies, and increased levels of immunoglobulin (Ig) G against IAPP have been reported in T2D patients. However, whether other Ig classes are also affected and if the levels can be managed is less known. This pre-post study examines IgA levels against IAPP oligomers (IAPPO-IgA) in T2D patients and assesses the impact of the Okinawa-based Nordic (O-BN) diet-a low-carbohydrate, high-fiber diet-on these levels after following the diet for 3 months. IAPP, IAPPO-IgA, and total IgA levels were measured in plasma and fecal samples from n = 30 T2D patients collected at baseline, after 3 months of diet, and after additional 4 months of unrestricted diets (a clinical follow-up). The IAPP and IAPPO-IgA levels were significantly lower after 3 months, with the latter also being significantly reduced at the clinical follow-up. The reduction in plasma IAPP and IAPPO-IgA levels correlated with reductions in plasma levels of metabolic and inflammatory markers. Hence, following the O-BN diet for at least 3 months is sufficient to reduce circulating IAPP and IAPPO-IgA levels, which may be principal in managing T2D.
Asunto(s)
Diabetes Mellitus Tipo 2 , Inmunoglobulina A , Polipéptido Amiloide de los Islotes Pancreáticos , Humanos , Diabetes Mellitus Tipo 2/dietoterapia , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/metabolismo , Inmunoglobulina A/sangre , Inmunoglobulina A/metabolismo , Polipéptido Amiloide de los Islotes Pancreáticos/sangre , Polipéptido Amiloide de los Islotes Pancreáticos/metabolismo , Masculino , Femenino , Persona de Mediana Edad , Anciano , Japón , AdultoRESUMEN
Skin is the most prominent tissue and organ, as well as the first line of defence, of the body. Because it is situated on the body's surface, it is constantly exposed to microbial, chemical, and physical factors such as mechanical stimulation. Therefore, skin has evolved substantial immune defences, regenerative ability, and anti-injury capacity. Epidermal cells produce antibacterial peptides that play a role in immune defence under physiological conditions. Additionally, IgG or IgA in the skin also participates in local anti-infective immunity. However, based on the classical theory of immunology, Ig can only be produced by B cells which should be derived from local B cells. This year, thanks to the discovery of Ig derived from non B cells (non B-Ig), Ig has also been found to be expressed in epidermal cells and contributes to immune defence. Epidermal cell-derived IgG and IgA have been demonstrated to have potential antibody activity by binding to pathogens. However, these epidermal cell-derived Igs show different microbial binding characteristics. For instance, IgG binds to Staphylococcus aureus and IgA binds to Staphylococcus epidermidis. Epidermal cells producing IgG and IgA may serve as an effective defense mechanism alongside B cells, providing a novel insight into skin immunity.
Asunto(s)
Inmunoglobulina A , Piel , Humanos , Inmunoglobulina A/inmunología , Inmunoglobulina A/metabolismo , Piel/inmunología , Animales , Inmunoglobulina G/inmunología , Inmunoglobulina G/metabolismo , Linfocitos B/inmunología , Inmunoglobulinas/inmunología , Inmunoglobulinas/metabolismo , Staphylococcus aureus/inmunología , Staphylococcus epidermidis/inmunología , Epidermis/inmunología , Epidermis/metabolismo , Células Epidérmicas/inmunología , Células Epidérmicas/metabolismoRESUMEN
Nasal vaccination elicits a humoral immune response that provides protection from airborne pathogens1, yet the origins and specific immune niches of antigen-specific IgA-secreting cells in the upper airways are unclear2. Here we define nasal glandular acinar structures and the turbinates as immunological niches that recruit IgA-secreting plasma cells from the nasal-associated lymphoid tissues (NALTs)3. Using intact organ imaging, we demonstrate that nasal vaccination induces B cell expansion in the subepithelial dome of the NALT, followed by invasion into commensal-bacteria-driven chronic germinal centres in a T cell-dependent manner. Initiation of the germinal centre response in the NALT requires pre-expansion of antigen-specific T cells, which interact with cognate B cells in interfollicular regions. NALT ablation and blockade of PSGL-1, which mediates interactions with endothelial cell selectins, demonstrated that NALT-derived IgA-expressing B cells home to the turbinate region through the circulation, where they are positioned primarily around glandular acinar structures. CCL28 expression was increased in the turbinates in response to vaccination and promoted homing of IgA+ B cells to this site. Thus, in response to nasal vaccination, the glandular acini and turbinates provide immunological niches that host NALT-derived IgA-secreting cells. These cellular events could be manipulated in vaccine design or in the treatment of upper airway allergic responses.
Asunto(s)
Inmunoglobulina A , Tejido Linfoide , Mucosa Nasal , Células Plasmáticas , Linfocitos T , Cornetes Nasales , Animales , Femenino , Masculino , Ratones , Bacterias/inmunología , Movimiento Celular , Quimiocinas CC/inmunología , Quimiocinas CC/metabolismo , Centro Germinal/inmunología , Centro Germinal/citología , Inmunoglobulina A/inmunología , Inmunoglobulina A/metabolismo , Tejido Linfoide/inmunología , Tejido Linfoide/citología , Ratones Endogámicos C57BL , Mucosa Nasal/citología , Mucosa Nasal/inmunología , Células Plasmáticas/inmunología , Células Plasmáticas/citología , Células Plasmáticas/metabolismo , Linfocitos T/inmunología , Linfocitos T/citología , Linfocitos T/metabolismo , Cornetes Nasales/citología , Cornetes Nasales/inmunología , Vacunación , Administración Intranasal , Vacunas/inmunología , SimbiosisRESUMEN
INTRODUCTION: IgA nephropathy (IgAN) is a kidney disorder characterized by the deposition of circulating immune complexes of IgG bound to galactose-deficient IgA1 (Gd-IgA1) in the mesangial glomeruli. However, limited research has been conducted on the levels of IgA binding in relation to the various sialylation profiles of IgG in IgAN. MATERIALS AND METHODS: Sialylated IgG (SA-IgG) and desialylated IgG (DSA-IgG) were isolated from IgAN patients. The IgG-IgA immune complex (IgG-IgA-IC) was detected using two customized commercial ELISA kits. Additionally, IgG was enzymatically digested with neuraminidase to produce DSA-IgG. Subsequently, the binding capacities of both intact IgG and the neuraminidase-digested DSA-IgG with Gd-IgA1 were determined using ELISA kits. RESULTS: Our research revealed that SA-IgG levels were negatively correlated with Gd-IgA1 (R = -0.16, p = 0.03) in IgAN patients. The optical density (OD) levels of IgG-IgA complexes in SA-IgG samples were significantly lower (0.58 ± 0.09) compared to those in DSA-IgG samples (0.78 ± 0.12) when using the Gd-IgA1 assay kit. These results were confirmed using an IgG assay kit, which showed that the SA-IgG groups had significantly lower IgA indices (0.31 ± 0.12) compared to the DSA-IgG groups (0.57 ± 0.19). Furthermore, we investigated the binding capacity of IgG with different sialic acid levels to Gd-IgA1. The results revealed that neuraminidase digestion of IgG increased its propensity to bind to Gd-IgA1. Additionally, we examined the binding capacity of both intact IgG and DSA-IgG to Gd-IgA1 at different mix ratios (IgG 1.5 µg and Gd-IgA1 1.5 µg, IgG 1.5 µg and Gd-IgA1 3 µg, IgG 3 µg and Gd-IgA1 1.5 µg). Interestingly, DSA-IgG demonstrated significantly higher binding capacity to Gd-IgA1 compared to intact IgG at all mix ratios tested. CONCLUSION: The preliminary findings from our present study indicate that the binding level of IgA in purified sialylated IgG is lower than that in desialylated IgG.
Asunto(s)
Glomerulonefritis por IGA , Inmunoglobulina A , Inmunoglobulina G , Humanos , Glomerulonefritis por IGA/inmunología , Glomerulonefritis por IGA/metabolismo , Inmunoglobulina A/metabolismo , Inmunoglobulina A/inmunología , Inmunoglobulina G/metabolismo , Inmunoglobulina G/inmunología , Inmunoglobulina G/sangre , Masculino , Femenino , Adulto , Persona de Mediana Edad , Complejo Antígeno-Anticuerpo/metabolismo , Complejo Antígeno-Anticuerpo/inmunología , Adulto Joven , Ensayo de Inmunoadsorción Enzimática , Ácido N-Acetilneuramínico/metabolismo , Neuraminidasa/metabolismo , Neuraminidasa/inmunologíaRESUMEN
Maternal breast milk plays a key role in providing newborns with passive immunity and stimulating the maturation of an infant's immune system, protecting them from many diseases. It is known that diet can influence the immune system of lactating mothers and the composition of their breast milk. The aim of this study was to establish if a supplementation during the gestation and lactation of Lewis rats with extra virgin olive oil (EVOO), due to the high proportion of antioxidant components in its composition, has an impact on the mother's immune system and on the breast milk's immune composition. For this, 10 mL/kg of either EVOO, refined oil (control oil) or water (REF group) were orally administered once a day to rats during gestation and lactation periods. Immunoglobulin (Ig) concentrations and gene expressions of immune molecules were quantified in several compartments of the mothers. The EVOO group showed higher IgA levels in both the breast milk and the mammary glands than the REF group. In addition, the gene expression of IgA in mammary glands was also boosted by EVOO consumption. Overall, EVOO supplementation during gestation and lactation is safe and does not negatively affect the mother's immune system while improving breast milk immune composition by increasing the presence of IgA, which could be critical for an offspring's immune health.