RESUMEN
Dysregulation of mucosal immune system has been proposed to be critical in the pathogenesis of inflammatory bowel diseases (IBDs). Regulatory T cells (Tregs) play an important role in regulating immune responses. Tregs are involved in maintaining intestinal homeostasis and exerting suppressive function in colitis. Our previous studies showed that a novel forkhead box protein P3 (Foxp3) negative Tregs (Treg-of-B cells), induced by culturing naïve CD4+ T cells with B cells, could protect against colitis and downregulate T helper (Th) 1 and Th17 cell cytokines in T cell-mediated colitis. In the present study, we aimed to induce Treg-of-B cells in the CD8+ T-cell population and investigate their characteristics and immunomodulatory functions. Our results showed that CD8+ Treg-of-B cells expressed Treg-associated markers, including lymphocyte-activation gene-3 (LAG3), inducible co-stimulator (ICOS), programmed death-1 (PD-1), cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), tumor necrosis factor receptor superfamily member-4 (TNFRSF4, OX40), and tumor necrosis factor receptor superfamily member-18 (TNFRSF18, GITR), but did not express Foxp3. CD8+ Treg-of-B cells produced higher concentration of inhibitory cytokine interleukin (IL)-10, and expressed higher levels of cytotoxic factor granzyme B and perforin after stimulation, compared to those of CD8+CD25- T cells. Moreover, CD8+ Treg-of-B cells suppressed T cell proliferation in vitro and alleviated colonic inflammation in chronic dextran sulfate sodium (DSS)-induced colitis. In conclusion, our study identified a novel subpopulation of CD8+ Tregs with suppressive effects through cell contact. These CD8+ Treg-of-B cells might have therapeutic potential for IBDs.
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Linfocitos T CD8-positivos , Modelos Animales de Enfermedad , Enfermedades Inflamatorias del Intestino , Ratones Endogámicos C57BL , Linfocitos T Reguladores , Animales , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Ratones , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Enfermedades Inflamatorias del Intestino/inmunología , Enfermedades Inflamatorias del Intestino/patología , Colitis/inmunología , Colitis/patología , Colitis/inducido químicamente , Sulfato de Dextran , Factores de Transcripción Forkhead/metabolismo , Interleucina-10/metabolismo , Interleucina-10/inmunologíaRESUMEN
Peyer's patches, splenic, and peritoneal B cells induce regulatory T (Treg-of-B) cells in vitro without exogenous chemicals and cytokines. Treg-of-B cells exert suppressive function both in vitro and in vivo. Here, we demonstrate experimental procedures for the generation and characterization of Treg-of-B cells. We describe steps for isolating B220+ B cells, isolating CD4+CD25- T cells, inducing Treg-of-B cells, identifying Treg-of-B cells by flow cytometry, cytokine analyzing by ELISA, and functional testing by suppression assay. For complete details on the use and execution of this protocol, please refer to Chien et al.1 and Chu et al.2.
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Linfocitos B , Citometría de Flujo , Linfocitos T Reguladores , Animales , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/citología , Ratones , Linfocitos B/inmunología , Linfocitos B/citología , Citometría de Flujo/métodos , Citocinas/metabolismoRESUMEN
Palpable purpura, gastrointestinal symptoms, joint involvement, and renal disease characterize immunoglobulin A vasculitis (IgAV). Renal involvement ranging from mild proteinuria to severe nephritic or nephrotic syndrome highlights the importance of monitoring kidney function in patients with IgAV. Recognizing these key features is crucial for early diagnosis and appropriate management to prevent long-term complications related to kidney disease. However, the pathogenesis of IgAV remains unclear. Disease mechanisms involve various factors, including the interplay of aberrantly glycosylated IgA, anti-endothelial cell antibodies, and neutrophils following infection triggers, which are the main pathogenic mechanisms of IgAV. Insights from cases of IgAV related to Coronavirus disease 2019 have offered additional understanding of the connection between infection and IgAV pathogenesis. This review provides a valuable resource for healthcare professionals and rheumatology researchers seeking a better understanding of the clinical features and pathophysiology of IgAV.
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COVID-19 , Inmunoglobulina A , Humanos , Inmunoglobulina A/inmunología , COVID-19/inmunología , COVID-19/fisiopatología , COVID-19/virología , COVID-19/complicaciones , Vasculitis/inmunología , Vasculitis/fisiopatología , SARS-CoV-2/inmunología , Vasculitis por IgA/inmunología , Vasculitis por IgA/fisiopatología , Vasculitis por IgA/diagnóstico , Autoanticuerpos/inmunología , Neutrófilos/inmunologíaRESUMEN
Background: The aim of this study was to investigate whether quantitative changes in lymphocyte subsets and gene expression in peripheral blood (PB) cells are related to the clinical manifestations and pathogenesis of lupus nephritis (LN). Methods: We enrolled 95 pediatric-onset SLE patients with renal involvement who presented with 450 clinical episodes suspicious for LN flare. Percentages of lymphocyte subsets at each episode were determined. We stratified 55 of 95 patients as high or low subset group according to the median percentage of each lymphocyte subset and the association with changes in the eGFR (ΔeGFR) were analyzed. Peripheral blood bulk RNA-seq to identify differentially expressed genes (DEGs) in 9 active LN vs. 9 inactive LN patients and the DEG-derived network was constructed by Ingenuity Pathway Analysis (IPA). Results: The mean ΔeGFR of low NK-low memory CD4+ T-high naive CD4+ T group (31.01 mL/min/1.73 m2) was significantly greater than that of high NK-high memory CD4+ T-low naive CD4+ T group (11.83 mL/min/1.73 m2; P = 0.0175). Kaplan-Meier analysis showed that the median time for ΔeGFR decline to mean ΔeGFR is approximately 10 years for high NK-high memory CD4+ T-low naive CD4+ T group and approximately 5 years for low NK-low memory CD4+ T-high naive CD4+ T group (log-rank test P = 0.0294). Conclusions: Our study highlighted important connections between DEG-derived network, lymphocyte subset composition, and disease status of LN and GN. A novel scoring system based on lymphocyte subset proportions effectively stratified patients into groups with differential risks for declining renal function.
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BACKGROUND: Juvenile idiopathic arthritis (JIA), an autoimmune disease affecting children or adolescents and causing joint or systemic symptoms, reportedly has a negative effect on the patients' body height. This study aimed to identify factors attributable to substantially reduced adult height (SRAH) in JIA patients. METHODS: This single-center retrospective cohort study included patients from 2009 to 2019 in Taiwan. We collected JIA patients aged > 18 years at enrollment with a definite diagnosis and undergoing regular outpatient clinic follow-up or disease remission. Target height difference (THD), defined by adult height minus mid-parental height, was calculated for each patient. The calculation results yielded two groups, of which positive THD was defined as the optimal height (OH group) and those with THD below two standardized deviations as the SRAH group. Descriptive statistics and logistic regression analysis were used to analyze the data. RESULTS: Of 92 JIA patients, 57 and 12 were in the OH and the SRAH groups. Earlier disease onset, especially before the six-year-old, was noted in the SRAH group (p = 0.026). The distribution of JIA subtypes differed significantly between the two groups (p < 0.001); enthesis-related arthritis was the commonest subtype in the OH group, and systemic JIA was the commonest in the SRAH group. Half of the patients in the SRAH group had an active disease status at enrollment, which was higher than the OH group (50.0% vs. 21.1%, p = 0.066). More patients in the SRAH group had received orthopedic surgery due to JIA (25% vs. 3.5%, p = 0.034). Multiple logistic regression analysis showed that SRAH was independently related to systemic JIA (OR = 37.6, 95%CI 1.2-1210.5; p = 0.041). CONCLUSION: The subtype of systemic JIA, with its characteristics of early disease onset and active disease status, was the essential factor that significantly impacted adult height.
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Artritis Juvenil , Estatura , Humanos , Estudios Retrospectivos , Femenino , Masculino , Adolescente , Niño , Taiwán , Trastornos del Crecimiento/etiología , Factores de Riesgo , Adulto , PreescolarRESUMEN
CD200 is an anti-inflammatory protein that facilitates signal transduction through its receptor, CD200R, in cells, resulting in immune response suppression. This includes reducing M1-like macrophages, enhancing M2-like macrophages, inhibiting NK cell cytotoxicity, and downregulating CTL responses. Activation of CD200R has been found to modulate dendritic cells, leading to the induction or enhancement of Treg cells expressing Foxp3. However, the precise mechanisms behind this process are still unclear. Our previous study demonstrated that B cells in Peyer's patches can induce Treg cells, so-called Treg-of-B (P) cells, through STAT6 phosphorylation. This study aimed to investigate the role of CD200 in Treg-of-B (P) cell generation. To clarify the mechanisms, we used wild-type, STAT6 deficient, and IL-24 deficient T cells to generate Treg-of-B (P) cells, and antagonist antibodies (anti-CD200 and anti-IL-20RB), an agonist anti-CD200R antibody, CD39 inhibitors (ARL67156 and POM-1), a STAT6 inhibitor (AS1517499), and soluble IL-20RB were also applied. Our findings revealed that Peyer's patch B cells expressed CD200 to activate the CD200R on T cells and initiate the process of Treg-of-B (P) cells generation. CD200 and CD200R interaction triggers the phosphorylation of STAT6, which regulated the expression of CD200R, CD39, and IL-24 in T cells. CD39 regulated the expression of IL-24, which sustained the expression of CD223 and IL-10 and maintained the cell viability. In summary, the generation of Treg-of-B (P) cells by Peyer's patch B cells was through the CD200R-STAT6-CD39-IL-24 axis pathway.
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Linfocitos B , Factor de Transcripción STAT6 , Linfocitos T Reguladores , Animales , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Ratones , Linfocitos B/inmunología , Linfocitos B/metabolismo , Factor de Transcripción STAT6/metabolismo , Ratones Endogámicos C57BL , Receptores de Orexina/metabolismo , Receptores de Orexina/genética , Antígenos CD/metabolismo , Antígenos CD/genética , Antígenos CD/inmunología , Transducción de Señal , Fosforilación , Ganglios Linfáticos Agregados/inmunología , Ganglios Linfáticos Agregados/metabolismo , Ganglios Linfáticos Agregados/citología , Apirasa/metabolismo , Apirasa/inmunología , Glicoproteínas de MembranaRESUMEN
OBJECTIVES: Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease that can result in high morbidity if not treated. This retrospective study aimed to evaluate the outcomes of rituximab treatment in a paediatric SLE cohort in Taiwan. METHODS: The medical records of paediatric patients diagnosed with SLE at the National Taiwan University Hospital between January 1992 and August 2022 who received rituximab as maintenance therapy between January 2015 and August 2022 were retrospectively reviewed. To enhance our analysis, we included a contemporary comparison group, matching in case number and demographic characteristics. This study aimed to describe the indications, efficacy and safety of rituximab in the treatment of paediatric SLE and to analyse the factors associated with disease outcomes. RESULTS: The study included 40 rituximab-treated patients with a median age of 14.3 years at the time of disease diagnosis. In the rituximab-treated cohort, the median score on the Systemic Lupus Erythematosus Disease Activity Index 2000 decreased from 8 before rituximab administration to 4 after 2 years. The levels of C3 and C4 increased and anti-double stranded DNA (anti-dsDNA) levels decreased significantly within 6 months. The equivalent oral prednisolone dose halved after 6 months. Finally, 8 (20%) patients achieved disease control and 35 (87.5%) patients had no flare-ups during the follow-up period (median, 2 years). Those patients who achieved disease control had a significantly shorter interval between diagnosis and rituximab administration. In terms of adverse effects, only one patient developed hypogammaglobulinaemia that required intravenous immunoglobulin (IVIG) replacement. Compared with the comparison group (n=53), the rituximab-treated cohort exhibited superior disease outcomes and a reduced incidence of flare-ups. CONCLUSIONS: This study provides real-world data and illuminates rituximab's role in maintaining disease stability among patients with paediatric-onset SLE who are serologically active without major clinical deterioration. Most importantly, no mortality or development of end-stage renal disease was observed in the rituximab-treated cohort.
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Lupus Eritematoso Sistémico , Humanos , Niño , Adolescente , Rituximab/efectos adversos , Lupus Eritematoso Sistémico/complicaciones , Lupus Eritematoso Sistémico/tratamiento farmacológico , Lupus Eritematoso Sistémico/diagnóstico , Estudios Retrospectivos , Anticuerpos Monoclonales de Origen Murino/efectos adversos , Resultado del TratamientoRESUMEN
OBJECTIVES: We clarified the characteristics and risk factors of CVEs in young SLE patients. METHOD: We retrospectively reviewed the medical records of patients younger than 50 years of age diagnosed with SLE and first CVEs from 1995 to 2020 in a tertiary medical center in Taiwan. We collected data on the patient characteristics before the CVE and reviewed the laboratory data obtained during the period. At a ratio of 1:3, cases and controls were matched with sex, SLE diagnosis age, diagnosis year, and SLE duration. RESULTS: We enrolled 43 CVE SLE patients and matched 129 non-CVE SLE controls. The median age at the time of the CVE was 39 years. Around 70% of young-aged CVE involved the cerebral lobes of frontal (â¼30%), parietal (â¼20%), occipital (â¼10%), and temporal (â¼10%). The peak incidence period for hemorrhagic CVE was within 1st year of SLE diagnosis (37%); in contrast, during the 2nd to 5th year of SLE diagnosis (25%) for ischemia CVEs. Hyperlipidemia (odds ratio [OR] = 19.36, p = 0.002), anti-phospholipid syndrome (APS) (OR = 41.9, p = 0.0068), a lower hemoglobin level (OR = 0.66, p = 0.0192), and a higher SLE Disease Activity Index (SLEDAI-2k) score (OR = 1.22, p = 0.0019) were independent risk factors for CVEs in young SLE patients. CONCLUSION: Hyperlipidemia, APS, low Hb level, and high SLEDAI-2k significantly increase the risk of young-aged SLE patients developing CVE.
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Enfermedades Cardiovasculares , Hiperlipidemias , Lupus Eritematoso Sistémico , Humanos , Anciano , Adulto , Estudios de Casos y Controles , Enfermedades Cardiovasculares/epidemiología , Estudios Retrospectivos , Lupus Eritematoso Sistémico/complicaciones , Lupus Eritematoso Sistémico/epidemiología , Factores de RiesgoRESUMEN
BACKGROUND: Human enteroviruses A71 (EV-A71) and D68 (EV-D68) are the suspected causative agents of hand-foot-and-mouth disease, aseptic meningitis, encephalitis, acute flaccid myelitis, and acute flaccid paralysis in children. Until now, no cure nor mucosal vaccine existed for EV-A71 and EV-D68. Novel mucosal bivalent vaccines are highly important for preventing EV-A71 and EV-D68 infections. METHODS: In this study, formalin-inactivated EV-A71 and EV-D68 were used as antigens, while PS-G, a polysaccharide from Ganoderma lucidum, was used as an adjuvant. Natural polysaccharides have the characteristics of intrinsic immunomodulation, biocompatibility, low toxicity, and safety. Mice were immunized intranasally with PBS, EV-A71, EV-D68, or EV-A71 + EV-D68, with or without PS-G as an adjuvant. RESULTS: The EV-A71 + EV-D68 bivalent vaccine generated considerable EV-A71- and EV-D68-specific IgG and IgA titres in the sera, nasal washes, saliva, bronchoalveolar lavage fluid, and feces. These antibodies neutralized EV-D68 and EV-A71 infectivity. They also cross-neutralized infections by different EV-D68 and EV-A71 sub-genotypes. Furthermore, compared with the PBS group, EV-A71 + EV-D68 + PS-G-vaccinated mice exhibited an increased number of EV-D68- and EV-A71-specific IgA- and IgG-producing cells. In addition, T-cell proliferative responses, and IFN-γ and IL-17 secretion in the spleen were substantially induced when PS-G was used as an adjuvant with EV-A71 + EV-D68. Finally, in vivo challenge experiments demonstrated that the immune sera induced by EV-A71 + EV-D68 + PS-G conferred protection in neonate mice against lethal EV-A71 and EV-D68 challenges as indicated by the increased survival rate and decreased clinical score and viral RNA tissue expression. Taken together, all EV-A71/EV-D68 + PS-G-immunized mice developed potent specific humoral, mucosal, and cellular immune responses to EV-D68 and EV-A71 and were protected against them. CONCLUSIONS: These findings demonstrated that PS-G can be used as a potential adjuvant for EV-A71 and EV-D68 bivalent mucosal vaccines. Our results provide useful information for the further preclinical and clinical development of a mucosal bivalent enterovirus vaccine against both EV-A71 and EV-D68 infections.
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Enterovirus Humano A , Enterovirus Humano D , Infecciones por Enterovirus , Enterovirus , Reishi , Niño , Animales , Humanos , Ratones , Enterovirus Humano D/genética , Enterovirus Humano A/genética , Vacunas Combinadas , Antígenos Virales , Inmunoglobulina A , Inmunoglobulina GRESUMEN
Background: Infants with respiratory-syncytial virus bronchiolitis hospitalization are more likely to develop wheezing and subsequent asthma. Reportedly, palivizumab prophylaxis effectively prevents respiratory-syncytial virus hospitalization in high-risk children-such as premature infants or infants with bronchopulmonary dysplasia (BPD). Objective: We sought to explore the effect of respiratory-syncytial virus immunoprophylaxis on the risk of asthma development in premature infants with BPD in subtropical areas. Methods: This case-control study included preterm children with BPD born at Mackay Memorial Hospital, Taipei, Taiwan, from 1999 to 2015. Overall, medical records of 616 eligible participants were retrospectively collected from their birth to the time they attained an age of 5 to 20 years. The primary outcome was onset of active asthma. Results: Overall, 576 consecutive cases met the inclusion criteria. Of these, 306 (53.2%) patients had palivizumab exposure and 191 (33.2%) were diagnosed with asthma. Patients with history of respiratory-syncytial virus bronchiolitis hospitalization had a higher risk of developing asthma in the future (adjusted odds ratio, 3.77; 95% CI, 2.30-6.20, P < .001; hazard ratio, 2.56; 95% CI, 1.81-3.62, P < .001). Palivizumab prophylaxis reduced future asthma development through the inhibition of respiratory-syncytial virus bronchiolitis hospitalization (coefficient, -0.021; 95% CI, -0.031 to -0.011, P = .027). Asthmatic children who received palivizumab immunoprophylaxis had a lesser active asthma duration than those who did not (P = .005). Conclusions: Children with BPD with hospitalization for respiratory-syncytial virus bronchiolitis had higher risk of developing asthma compared with those without respiratory-syncytial virus infection. Prophylactic palivizumab might reduce later asthma development through inhibition of respiratory-syncytial virus bronchiolitis hospitalization. For those already developing asthma, palivizumab could reduce active asthma duration.
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BACKGROUND: Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels that may be responsible for cancer cell proliferation, epithelial-mesenchymal transition (EMT), and immune regulation. However, little is known about the associations of different nAChR subunits with tumor microenvironment in oral squamous cell carcinoma (OSCC). METHODS: We retrospectively reviewed pathology samples from 75 OSCC patients by immunohistochemistry. In addition, a cohort of 307 OSCC patients in The Cancer Genome Atlas was analyzed. RESULTS: Subunit α1 was specific to peri-OSCC skeletal muscle. Increased α1 was associated with increased CD44 (cancer stem cells), increased CD3 and 8 (T cells), increased CD56 and 16 (natural killer cells), a decreased T stage, and an increased N stage. Increased α3 was associated with increased CD56 and 16. Increased α5 was associated with decreased CD3, 8, and 56, a decreased T stage, an increased N stage, worse survival, and decreased epithelial features. Increased α7 was associated with increased CD3, 8, 56, and 16, decreased tumor/peritumor ratios of CD3, 8, and 56 immune cells, and increased epithelial features. Increased local immune cells were associated with a better prognosis. CONCLUSIONS: α5 is the only subunit associated with decreased local immune cells and worse survival, while α1, α3, and α7 are associated with increased local immune cells in OSCC. α5 and α7 are correlated with different EMT states to be mesenchymal-like and epithelial-like OSCC, respectively. Protein expression data of the nAChR subunits, complementary to gene expression data, could provide meaningful information regarding the EMT status of OSCC associated with immune responses and prognosis.
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Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Neoplasias de la Boca , Receptores Nicotínicos , Humanos , Receptores Nicotínicos/genética , Receptores Nicotínicos/metabolismo , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas de Cabeza y Cuello , Estudios Retrospectivos , Neoplasias de la Boca/genética , Transición Epitelial-Mesenquimal/genética , Línea Celular Tumoral , Pronóstico , Microambiente Tumoral/genéticaRESUMEN
Gamma-delta (γδ) T cells play an essential role in allergic diseases and have emerged as a potential treatment target in recent decades. To clarify the effects of γδ T cells on atopic illnesses, we reviewed the literature on the physical roles and functions of various subsets of γδ T cells, including type 1 T helper (Th1)-like, type 2 T helper- (Th2)-like, and type 17 T helper (Th17)-like γδ T cells. Mouse Vγ1 T cells increase interleukin (IL)-4 levels and trigger B cell class switching and immunoglobulin E production. Meanwhile, mouse Vγ4 T cells and human CD8lowVδ1 T cells secrete interferon-γ and exert an anti-allergy effect similar to that of Th1 cells. Moreover, mouse Vγ6 T cells produce IL-17A, while Th17-like γδ T cells enhance neutrophil and eosinophil infiltration in the acute phase of inflammation, but exert anti-inflammatory effects in the chronic phase. Human Vγ9δ2 T cells may exhibit Th1- or Th2-like characteristics in response to certain types of stimulation. In addition, the microbiota can modulate epithelial γδ T cell survival through aryl hydrocarbon receptors; these γδ T cells play crucial roles in the repair of epithelial damage, antibacterial protection, antigen tolerance, and effects of dysbiosis on allergic diseases.
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Hipersensibilidad , Receptores de Antígenos de Linfocitos T gamma-delta , Ratones , Animales , Humanos , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismo , Células TH1 , Interferón gamma/metabolismo , Hipersensibilidad/metabolismo , Inflamación/metabolismo , Subgrupos de Linfocitos TRESUMEN
Our group have demonstrated that splenic B cells contributed to the CD4+ CD25- naive T cells conversion into CD4+ CD25+ Foxp3- regulatory T cells without adding appended cytokines, named Treg-of-B cells which were potent suppressors of adaptive immunity. We like to investigate whether Treg-of-B cells could promote alternatively activated macrophage (M2 macrophages) polarization and alleviate inflammatory disease, psoriasis. In this study, we co-cultured the bone marrow-derived macrophages (BMDMs) with Treg-of-B cells under LPS/IFN-γ stimulation and analyzed the M2-associated gene and protein using qPCR, western blotting, and immunofluorescence staining. We also examined the therapeutic effect of Treg-of-B cell-induced M2 macrophage for skin inflammation using imiquimod (IMQ)-induced psoriatic mouse model. Our results showed that BMDMs co-cultured with Treg-of-B cells upregulated typical M2-associated molecules, including Arg-1, IL-10, Pdcd1lg2, MGL-1, IL-4, YM1/2 and CD206. In an inflammatory environment, TNF-α and IL-6 production by macrophages co-cultured with Treg-of-B cells was decreased significantly. The molecular mechanism revealed that Treg-of-B cells promoted M2 macrophage polarization via STAT6 activation in a cell contact-dependent manner. Moreover, the treatment with Treg-of-B cell-induced M2 macrophages attenuated the clinical manifestations of psoriasis, such as scaling, erythema and thickening in the IMQ-induced psoriatic mouse model. T cell activation in draining lymph nodes was decreased in the Treg-of-B cell-induced M2 macrophage group after IMQ application. In conclusion, our findings suggested that Foxp3- Treg-of-B cells could induce alternatively activated M2 macrophages through STAT6 activation, providing a cell-based therapeutic strategy for psoriasis.
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Psoriasis , Linfocitos T Reguladores , Ratones , Animales , Imiquimod/efectos adversos , Linfocitos T Reguladores/metabolismo , Psoriasis/inducido químicamente , Psoriasis/tratamiento farmacológico , Macrófagos/metabolismo , Citocinas/metabolismo , Factores de Transcripción Forkhead/metabolismoRESUMEN
Childhood asthma is a heterogeneous disease characterized by chronic airway inflammation, leading to a broad range of clinical presentations. Nonallergic asthma is asthma without allergic sensitization. Both clinical manifestations and immunopathological mechanisms of nonallergic childhood asthma were rarely investigated. We aimed to compare the clinical features between nonallergic and allergic childhood asthma and apply microRNA to explore the underlying mechanism of nonallergic childhood asthma. We enrolled 405 asthmatic children (76 nonallergic, 52 allergic with total IgE < 150 IU/mL and 277 allergic with total IgE > 150 IU/mL). Clinical characteristics were compared between groups. Comprehensive miRNA sequencing (RNA-seq) was performed using peripheral blood from 11 nonallergic and 11 allergic patients with elevated IgE, respectively. Differentially expressed miRNA (DEmiRNA) were determined with DESeq2. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analysis was performed to determine functional pathways involved. Publicly available mRNA expression data was applied to investigate the predicted target mRNA networks via Ingenuity Pathway Analysis (IPA). The average age of nonallergic asthma was significantly younger (5.614 ± 2.743 vs 6.676 ± 3.118 years-old). Higher severity and worse control were more common in nonallergic asthma (two-way ANOVA, P < 0.0001). Long-term severity was higher, and intermittent attacks persisted in nonallergic patients. We identified 140 top DEmiRNAs based on false discovery rate (FDR) q-value < 0.001. Forty predicted target mRNA gene were associated with nonallergic asthma. The enriched pathway based on GO included Wnt signaling pathway. IgE expression was predicted to be downregulated by a network involving simultaneous interaction with IL-4, activation of IL-10 and inhibition of FCER2. Nonallergic childhood asthma were distinct in their younger age, higher long-term severity and more persistent course. Differentially expressed miRNA signatures associate with downregulation of total IgE expression and predicted target mRNA genes related molecular networks contribute to canonical pathways of nonallergic childhood asthma. We demonstrated the negative role of miRNAs involved in regulating IgE expression indicating differences between asthma phenotypes. Identification of biomarkers of miRNAs could contribute to understand the molecular mechanism of endotypes in nonallergic childhood asthma, which can potentially allow delivery of precision medicine to pediatric asthma.
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Asma , Hipersensibilidad , MicroARNs , Humanos , Niño , MicroARNs/genética , Asma/complicaciones , Hipersensibilidad/complicaciones , Células Sanguíneas , Inmunoglobulina ERESUMEN
BACKGROUND: Lupus nephritis (LN) is a crucial organ involvement in systemic lupus erythematosus (SLE). Patients with LN have higher morbidity and mortality rates than those without. Among all patients with LN, 20-40% had delayed onset, but the data for patients with juvenile-onset SLE (jSLE), who have a higher percentage of LN than patients with adult-onset SLE (aSLE), were limited. This study aimed to determine the risk factors for subsequent LN in patients with jSLE. METHODS: A retrospective cohort study was conducted between 2008 and 2018 in a single tertiary medical centre. Patients with diagnosed jSLE were reviewed. We investigated those without LN at diagnosis and whether they developed LN afterward. The primary outcome was the development of subsequent LN. Clinical manifestations at diagnosis, serial laboratory data, and treatments were reviewed during follow-up periods. RESULTS: Among the 48 patients with jSLE without initial LN, 20 developed subsequent LN later (Group 1), whereas 28 remained free of LN (Group 2). There was no difference in the percentage of initial manifestations except for more discoid rashes in Group 2 patients. In the Cox regression model, elevated average anti-double-stranded DNA (dsDNA) antibody, low average serum complements, and high average erythrocyte sedimentation rate (ESR) levels during follow-up were predictors of subsequent LN. After adjusting for these factors in multivariable analyses, only high average anti-dsDNA antibody and high average ESR levels remained predictive of subsequent LN. For every 100 IU/ml increase in anti-dsDNA antibody, the risk for subsequent LN in jSLE increases by 1.29 times (hazard ratio = 1.29, 95% confidence interval 1.055-1.573). CONCLUSION: Persistently high anti-dsDNA antibody and ESR levels during the follow-up period were risk factors for subsequent LN in patients with jSLE.
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Lupus Eritematoso Sistémico , Nefritis Lúpica , Adulto , Humanos , Nefritis Lúpica/complicaciones , Nefritis Lúpica/epidemiología , Estudios Retrospectivos , Lupus Eritematoso Sistémico/complicaciones , Lupus Eritematoso Sistémico/epidemiología , Factores de Riesgo , Modelos de Riesgos ProporcionalesRESUMEN
BACKGROUND: Chronic granulomatous disease (CGD) is a rare primary immunodeficiency disease characterized by defective neutrophil killing of microbial pathogens and recurrent infections. We aimed to investigate the clinical, genetic features, treatment, and outcomes in patients with CGD. METHODS: Pediatric patients diagnosed with CGD from a medical center in Taiwan were enrolled from January 1999 to Oct 2021. RESULTS: Nine pediatric patients with CGD were enrolled: six X-linked (XL) CGD with CYBB gene mutations, three autosomal recessive (AR) CGD with two NCF1 and one CYBA gene mutations. The median age of onset and age of diagnosis was 0.92 and 2.64 years, respectively. Patients with XL-CGD had a younger age of onset (4.6 months vs. 1.83 years, P = 0.06) and age of diagnosis (1.71 vs. 8.86 years, P = 0.024) than AR-CGD patients. The most common sites of infections were skin and soft tissue abscesses. The most common pathogens were Staphylococcus, Serratia, and Salmonella spp. Prophylactic antibiotics, anti-fungal agents, and interferon-gamma (IFN-γ) were given in 9 (100%), 7 (77.8%), and 8 (88.9%) patients, respectively. The mean duration of IFN-γ usage was 5.15 years. One male patient with XL-CGD was successfully treated with hematopoietic stem cell transplantation at 2.2 years. The mortality rate was 11.1%, and the estimated overall survival at 20 years was 66.7%. CONCLUSION: Staphylococcus aureus, Serratia marcescens, and Salmonella infections are important in Taiwanese CGD patients. Patients with XL-CGD have early disease onset. IFN-γ prophylaxis and prophylactic anti-microbial agents might have an effect on alleviating the infection episodes in CGD patients.
Asunto(s)
Antiinfecciosos , Enfermedad Granulomatosa Crónica , Niño , Humanos , Masculino , Lactante , Preescolar , Enfermedad Granulomatosa Crónica/genética , Enfermedad Granulomatosa Crónica/terapia , Enfermedad Granulomatosa Crónica/diagnóstico , Taiwán/epidemiología , Mutación , Neutrófilos , Antiinfecciosos/uso terapéuticoRESUMEN
OBJECTIVE: This study aimed to evaluate the clinical characteristics of children diagnosed with juvenile dermatomyositis (JDM) in a tertiary medical centre in Taiwan and to identify important biomarkers for predicting the disease course and outcomes of JDM. METHODS: We retrospectively reviewed patients with JDM diagnosed at the National Taiwan University Hospital between 1 January 2001 and 31 December 2021. The endpoints for disease assessment included complete clinical response or remission. The JDM courses were divided into monocyclic, polycyclic, and chronic continuous statuses. The significant relationship between the predictors and outcomes was further analysed. RESULTS: A total of 47 patients were included in this study. The mean age at disease onset was 7.5 years. The female-to-male ratio was 1.35. The most common initial presentations were Gottron's sign (74%), followed by muscle weakness (66%) and facial rash (66%). Among all included patients, 35 (74.5%) patients achieved complete clinical remission, 15 (31.9%) had a monocyclic course, six (12.7%) had a polycyclic course, and 24 (51.1%) had a chronic continuous course. Negative facial rash and arthralgia were favourable factors for achieving complete clinical remission. Muscle weakness, higher lactate dehydrogenase (LDH), and higher erythrocyte sedimentation rate (ESR) at disease onset were related to the chronic continuous course. The most common long-term complication was calcinosis (29.8%). CONCLUSION: Juvenile dermatomyositis is a rare disease, and only a few studies have been conducted in Asia. Our results identified the important predictors of the disease course and outcomes. The chronic continuous course requires more attention and aggressive treatment.