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PURPOSE: Evaluating the presence of class 3, 4, and 5 genetic variants in inherited retinal disease (IRD) genes in patients with retinopathy of unknown origin (RUO). METHODS: Multicentric retrospective study of RUO cases diagnosed between January 2012 and February 2022. General and ophthalmologic history, complete ophthalmologic examination, antiretinal antibodies, and IRD gene panel results were analyzed in every patient. Four RUO categories were defined: nonparaneoplastic autoimmune retinopathy, unilateral pigmentary retinopathy, asymmetrical pigmentary retinopathy, and acute zonal occult outer retinopathy. RESULTS: The authors included 12 patients (9 females) across these four RUO categories. Mean age at inclusion was 45.6 years (20-68 years). Seven patients demonstrated class 3 variants in IRD genes. Of these, two also demonstrated class 5 variants in other IRD genes. The remaining five patients had negative panel results. IRD gene panel analysis allowed diagnosis refinement in 1 (8.3%) nonparaneoplastic autoimmune retinopathy patient in the RUO cohort. When considering the nonparaneoplastic autoimmune retinopathy subpopulation only, a higher diagnostic yield of 20% (1/5 patients) was achieved. CONCLUSION: Every suspected nonparaneoplastic autoimmune retinopathy patient should benefit from gene panel testing to not overlook undiagnosed IRDs. By contrast, unilateral pigmentary retinopathy, asymmetrical pigmentary retinopathy, and acute zonal occult outer retinopathy subpopulations did not benefit from genetic testing in this study.
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Enfermedades de la Retina , Humanos , Femenino , Estudios Retrospectivos , Masculino , Persona de Mediana Edad , Adulto , Enfermedades de la Retina/genética , Enfermedades de la Retina/diagnóstico , Anciano , Adulto Joven , Pruebas Genéticas/métodos , Mutación , Proteínas del Ojo/genéticaRESUMEN
BACKGROUND: Tissue expression of endothelial cell (EC) markers of microcirculatory changes in CSU is poorly investigated. OBJECTIVE: to explore the expression of specific EC markers (stem cell factor (SCF), vascular endothelial growth factor (VEGF) and membrane attack complex (MAC)) in CSU-L and CSU-NL skin through immunohistochemistry (IHC) and in serum. METHODS: Lesional (L) and non-lesional (NL) skin biopsies from CSU patients and HCs were studied for the IHC expression of SCF, VEGF and MAC in CSU patients (n = 23) and healthy controls (HCs, n = 9). In this population, we also investigated blood levels of VEGF and SCF. Patients were also assessed for clinical characteristics, disease activity, and markers of autoimmune CSU (aiCSU). RESULTS: Epidermal SCF reactivity was significantly higher in CSU-L skin compared to HC skin (p=0.026). In the dermis, SCF immunoreactivity was seen particularly on endothelial, perivascular and epithelial cells. In CSU-L skin, mean perivascular SCF stainings were significantly more intense compared to HCs (p<0.001). Furthermore, CSU-NL skin also showed significantly higher SCF stainings on dermal perivascular cells compared to HCs (p<0.001). CSU patients had the highest SCF immunoreactivity scores in the epidermis and/or on dermal ECs. These patients did not have significantly higher SCF serum levels. CONCLUSION: This is the first study to show elevated cutaneous expression of SCF in chronic spontaneous urticaria. These findings underline the potential therapeutic possibilities of anti-KIT antibodies in CSU treatment.
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BACKGROUND: Chronic urticaria (CSU) is a chronic inflammatory mast cell-driven disorder of which reliable clinical data in Belgium are lacking. This study focusses on clinical characteristics of CSU patients presenting at an urban Immunology-Allergology department. METHODS: Outpatients with CSU were included from 2018 to 2021. Clinical characteristics, Dermatology Life Quality Index (DLQI) and Urticaria activity score (UAS7) were collected by thorough anamnesis and questionnaires. Furthermore, patients underwent provocational testing, an autologous serum skin test (ASST) and a blood analysis. RESULTS: The study included 49 CSU patients and 20 non-CSU subjects. CSU was distributed differently with age and sex, showing higher numbers in female patients below the age of 46 years. 67% of CSU patients had accompanying angioedema of which 9% were reported genital. CSU patients scored a mean 8/30 on their DLQI questionnaire. There was no significant difference in immunoglobulin E (IgE), C-reactive protein, and tryptase levels between CSU patients and controls. Oral glucocorticosteroids were prescribed in 23% of CSU patients during their disease course though only half of these patients had a severity grade 4 CSU. In 82% of the included CSU patients, Urticaria Control Test (UCT) scores were below 12. When we hypothetically considered low IgE levels and high IgG anti-thyroid peroxidase levels as differentiation marker for autoimmune (ai)CSU and non-aiCSU, we found that 4% of all included CSU patients could be considered aiCSU. CONCLUSION: Generally, the inner-city population displayed the same clinical characteristics, as previous cohorts from Northern Europe. The relatively high rate of CSU patients receiving oral glucocorticosteroid treatment for their disease though not always classified as severe, underlines the need to train doctors of various specialties in the treatment algorithms of CSU. Furthermore, by looking at potential autoimmune characteristics, our findings open perspectives on the identification of new routinely used clinical parameters for the detection of aiCSU, a relatively small immunological subtype of CSU.
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Urticaria Crónica , Urticaria , Humanos , Femenino , Persona de Mediana Edad , Bélgica , Urticaria Crónica/tratamiento farmacológico , Urticaria/tratamiento farmacológico , Progresión de la Enfermedad , Inmunoglobulina E , Enfermedad CrónicaRESUMEN
Many biomarkers have been proposed for the diagnosis of secondary hemophagocytic lymphohistiocytosis (HLH) in adults, but comparative studies are lacking. We analyzed ferritin, glycosylated ferritin, soluble CD25, CD163 and CD14, IL-6, IFN-γ, IL-18, IL-10, IL-1ß, IL-12p70, IL-17α, IP-10, and CXCL9 levels to differentiate HLH from sepsis in critically ill patients. Of 120 patients, HLH was confirmed for 14 patients. Among the biomarkers tested, ferritin, IL-18, and glycosylated ferritin were the most efficient parameters for early diagnosis of HLH. With a sensitivity set at 85%, ferritin, IL-18, and glycosylated ferritin were the biomarkers with the highest specificity: 84, 79, and 71% respectively. Combining IL-18 with the HScore provided a new score with an increased specificity compared to the HScore alone, 86% compared to 70% with a sensitivity set at 100%. A distinct cytokine pattern was highlighted in patients with malignancy-triggered HLH, with highly increased levels of INF-É£ and CXCL9, compared to HLH secondary to infection. This is the largest study available to date, comparing diagnostic biomarkers for HLH on a cohort of critically ill adult patients. Serum ferritin was the most discriminating parameter for early diagnosis of secondary HLH. IL18*HScore was identified as a highly potential score.
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Biomarcadores , Enfermedad Crítica , Linfohistiocitosis Hemofagocítica/diagnóstico , Linfohistiocitosis Hemofagocítica/etiología , Adulto , Anciano , Bélgica , Biomarcadores/sangre , Citocinas/sangre , Manejo de la Enfermedad , Susceptibilidad a Enfermedades , Diagnóstico Precoz , Femenino , Humanos , Mediadores de Inflamación , Linfohistiocitosis Hemofagocítica/sangre , Masculino , Persona de Mediana Edad , Curva ROC , Evaluación de SíntomasRESUMEN
BACKGROUND: A 3-week short-course of adjuvant-free hydrolysates of Lolium perenne peptide (LPP) immunotherapy for rhinoconjunctivitis with or without asthma over 4 physician visits is safe, well tolerated, and effective. OBJECTIVE: We sought to investigate immunologic mechanisms of LPP immunotherapy in a subset of patients who participated in a phase III, multicenter, randomized, double-blind, placebo-controlled trial (clinical.govNCT02560948). METHODS: Participants were randomized to receive LPP (n = 21) or placebo (n = 11) for 3 weeks over 4 visits. Grass pollen-induced basophil, T-cell, and B-cell responses were evaluated before treatment (visit [V] 2), at the end of treatment (V6), and after the pollen season (V8). RESULTS: Combined symptom and rescue medication scores (CSMS) were lower during the peak pollen season (-35.1%, P = .03) and throughout the pollen season (-53.7%, P = .03) in the LPP-treated group compared with those in the placebo-treated group. Proportions of CD63+ and CD203cbrightCRTH2+ basophils were decreased following LPP treatment at V6 (10 ng/mL, P < .0001) and V8 (10 ng/mL, P < .001) compared to V2. No change in the placebo-treated group was observed. Blunting of seasonal increases in levels of grass pollen-specific IgE was observed in LPP-treated but not placebo-treated group. LPP immunotherapy, but not placebo, was associated with a reduction in proportions of IL-4+ TH2 (V6, P = .02), IL-4+ (V6, P = .003; V8, P = .004), and IL-21+ (V6, P = .003; V8, P = .002) follicular helper T cells. Induction of FoxP3+, follicular regulatory T, and IL-10+ regulatory B cells were observed at V6 (all P < .05) and V8 (all P < .05) in LPP-treated group. Induction of regulatory B cells was associated with allergen-neutralizing IgG4-blocking antibodies. CONCLUSION: For the first time, we demonstrate that the immunologic mechanisms of LPP immunotherapy are underscored by immune modulation in the T- and B-cell compartments, which is necessary for its effect.
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Alérgenos/inmunología , Asma/terapia , Conjuntivitis/terapia , Lolium/inmunología , Péptidos/uso terapéutico , Polen/inmunología , Rinitis Alérgica Estacional/terapia , Adulto , Asma/inmunología , Linfocitos B Reguladores/inmunología , Conjuntivitis/inmunología , Desensibilización Inmunológica , Método Doble Ciego , Femenino , Humanos , Inmunoglobulina E/sangre , Inmunoglobulina G/sangre , Masculino , Péptidos/inmunología , Rinitis Alérgica Estacional/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Reguladores/inmunología , Adulto JovenRESUMEN
PURPOSE OF REVIEW: Continuous expansion of our knowledge in the pathogenesis of membranous nephropathy possible by the identification of antibodies recognized specific podocytes antigens results in unprecedent patient management strategy. RECENT FINDINGS: Circulating anti-phospholipase A2 receptor (PLA2R) and anti-thrombospondin domain 7A (THSD7A) antibodies strongly relate with the modifications of podocytes biology leading to the new molecular diagnosis of membranous nephropathy. Immunization against THSD7A involves extra-renal mechanism. However, the pathway of anti-PLA2R immunization still remains unresolved. Experimental data highlight the crucial role of THSD7A in the attachment of podocytes to the glomerular basement membrane, rewarding the THSD7A pathogenicity, whereas the third of Koch's postulates is still not fulfilled for anti-PLA2R antibodies. The anti-PLA2R antibodies epitope spreading will possibly be even more specific marker improving the molecular classification of membranous nephropathy. Two immune epitopes have been identified in the N-terminal tail of THSD7A but without evidence of epitope spreading as for anti-PLA2R. SUMMARY: In 2019, the Kidney Diseases: Improving Global Outcomes guidelines recognized anti-PLA2R antibodies (but not anti-THSD7A antibodies) as a valuable molecular risk factor for the pejorative evolution of kidney function and recommended their monitoring for the diagnosis and the assessment of membranous nephropathy immune activity. Screening for malignancy is particularly advised in THSD7A-mediated membranous nephropathy.
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Glomerulonefritis Membranosa/etiología , Autoanticuerpos/inmunología , Glomerulonefritis Membranosa/diagnóstico , Glomerulonefritis Membranosa/inmunología , Humanos , Podocitos/inmunología , Receptores de Fosfolipasa A2/inmunología , Factores de Riesgo , Trombospondinas/inmunología , Trombospondinas/fisiologíaRESUMEN
BACKGROUND: Most of the findings related to the noxious effect of mold sensitization on asthma come from investigations based on Alternaria alternata, Cladosporium herbarum, and Aspergillus fumigatus. However, species such as Penicillium spp, Cladosporium sphaerospermum, Cladosporium cladosporioides, or Aspergillus versicolor display a more pronounced indoor tropism, and their potential harmful respiratory effects cannot be neglected. OBJECTIVE: The goal of this work was to relate mold sensitizations with asthma severity and with the level of indoor mold contamination among mold-sensitized patients with asthma and nonsensitized patients with asthma. METHODS: A case-control study was conducted and several asthma severity markers were compared between patients with asthma with and without mold sensitization. Indoor contamination of patients' dwellings was also investigated. RESULTS: Our findings confirmed the association between sensitization to A fumigatus and severity for patients with asthma in contrast with sensitization to other species. Indoor mold contamination was detected in approximately 90% of dwellings. Overall mold exposure was not associated with asthma severity. However, regardless of the sensitization, exposure to A fumigatus and Penicillium spp in dust was linked to an increased risk of severe asthma. CONCLUSION: The harmful nature of mold sensitization and mold exposure for patients with asthma was not confirmed in this study. However, sensitization to A fumigatus was associated with an increased risk for severe asthma. A better investigation of the properties of Penicillium spp is recommended because its exposure was found to be associated with a more pronounced impairment of lung function.
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Contaminación del Aire Interior/efectos adversos , Alérgenos/inmunología , Alternaria/inmunología , Aspergillus fumigatus/inmunología , Asma/inmunología , Cladosporium/inmunología , Penicillium/inmunología , Adulto , Anciano , Estudios de Casos y Controles , Polvo/análisis , Femenino , Humanos , Inmunoglobulina E/sangre , Inmunoglobulina E/inmunología , Masculino , Persona de Mediana EdadRESUMEN
The persistence of latently infected cells in patients under combinatory antiretroviral therapy (cART) is a major hurdle to HIV-1 eradication. Strategies to purge these reservoirs are needed and activation of viral gene expression in latently infected cells is one promising strategy. Bromodomain and Extraterminal (BET) bromodomain inhibitors (BETi) are compounds able to reactivate latent proviruses in a positive transcription elongation factor b (P-TEFb)-dependent manner. In this study, we tested the reactivation potential of protein kinase C (PKC) agonists (prostratin, bryostatin-1 and ingenol-B), which are known to activate NF-κB signaling pathway as well as P-TEFb, used alone or in combination with P-TEFb-releasing agents (HMBA and BETi (JQ1, I-BET, I-BET151)). Using in vitro HIV-1 post-integration latency model cell lines of T-lymphoid and myeloid lineages, we demonstrated that PKC agonists and P-TEFb-releasing agents alone acted as potent latency-reversing agents (LRAs) and that their combinations led to synergistic activation of HIV-1 expression at the viral mRNA and protein levels. Mechanistically, combined treatments led to higher activations of P-TEFb and NF-κB than the corresponding individual drug treatments. Importantly, we observed in ex vivo cultures of CD8+-depleted PBMCs from 35 cART-treated HIV-1+ aviremic patients that the percentage of reactivated cultures following combinatory bryostatin-1+JQ1 treatment was identical to the percentage observed with anti-CD3+anti-CD28 antibodies positive control stimulation. Remarkably, in ex vivo cultures of resting CD4+ T cells isolated from 15 HIV-1+ cART-treated aviremic patients, the combinations bryostatin-1+JQ1 and ingenol-B+JQ1 released infectious viruses to levels similar to that obtained with the positive control stimulation. The potent effects of these two combination treatments were already detected 24 hours post-stimulation. These results constitute the first demonstration of LRA combinations exhibiting such a potent effect and represent a proof-of-concept for the co-administration of two different types of LRAs as a potential strategy to reduce the size of the latent HIV-1 reservoirs.
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Brioestatinas/farmacología , Linfocitos T CD4-Positivos/virología , Regulación Viral de la Expresión Génica/efectos de los fármacos , VIH-1/efectos de los fármacos , Linfocitos T CD4-Positivos/efectos de los fármacos , Diterpenos/metabolismo , VIH-1/fisiología , Humanos , Factor B de Elongación Transcripcional Positiva/metabolismo , Activación Viral/efectos de los fármacos , Latencia del Virus/efectos de los fármacosAsunto(s)
COVID-19 , Eritema Pernio , Esclerodermia Sistémica , Humanos , Angioscopía Microscópica , Eritema Pernio/diagnóstico , Eritema Pernio/etiología , Estudios Transversales , Factor A de Crecimiento Endotelial Vascular , COVID-19/complicaciones , Uñas/diagnóstico por imagen , Capilares/diagnóstico por imagen , Factores de Crecimiento Endotelial VascularRESUMEN
BACKGROUND: Data on mould sensitization in the general population are scarce and mostly on Aspergillus fumigatus, Alternaria alternata and Cladosporium herbarum. OBJECTIVES: To validate a dot-blot assay for the detection of specific IgE and evaluate the prevalence of mould sensitization in a healthy population. METHODS: The dot-blot assay was validated against the CAP test. Sensitization rate to ten common indoor and outdoor mould species in 344 serum samples was calculated. For each serum with more than one reactivity, the "major sensitization" defined as the strongest response against a single mould species was calculated. RESULTS: Intra- and inter-assay variations were both below 20%, and the positivity threshold of the test was of 0.418 kU/L for A. fumigatus. Correlation with CAP results was strong. The overall prevalence of sensitization was 32.8%, and the commonest sensitizations were against A. alternaria, A. flavus and A. niger (around 15%). The most frequent "major reactivities" were against A. niger and A. alternata (20-30%). In 25.1% of the samples, "major reactivities" were directed against a group of moulds commonly found indoor (Penicillium spp., Aspergillus versicolor, Cladosporium sphaerospermum and Cladosporium cladosporioides). CONCLUSIONS: The dot-blot assay was validated for the detection of mould-specific IgE. In the general population, sensitization to indoor species was common and accounted for 25% of overall mould sensitizations.
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Anticuerpos Antifúngicos/sangre , Hongos/inmunología , Immunoblotting/métodos , Inmunoglobulina E/sangre , Adulto , Bélgica , Femenino , Humanos , Masculino , Adulto JovenRESUMEN
AIMS: In drug development, the anti-inflammatory properties of new molecules in the lung are currently tested using the inhaled lipopolysaccharide (LPS) model. The total and regional lung bioavailability of inhaled particles depends significantly on their size. The objective of the present study was to compare inflammatory responses in healthy volunteers after the inhalation of LPS of varying droplet size. METHODS: Three nebulizers were characterized by different droplet size distributions [mean mass median aerodynamic diameters: Microcirrus (2.0 µm), MB2 (3.2 µm) and Pari (7.9 µm)]. Participants inhaled three boluses of a 20 µg (technetium 99 m-labelled) solution of LPS, randomly delivered by each nebulizer. We measured the lung deposition of the nebulized LPS by gamma-scintigraphy, while blood and sputum biomarkers were evaluated before and after challenges. RESULTS: MB2 and Pari achieved greater lung deposition than Microcirrus [171.5 (±72.9) and 217.6 (±97.8) counts pixel-1 , respectively, vs. 67.9 (±20.6) counts pixel-1 ; P < 0.01]. MB2 and Pari caused higher levels of blood C-reactive protein and more total cells and neutrophils in sputum compared with Microcirrus (P < 0.05). C-reactive protein levels correlated positively with lung deposition (P < 0.01). CONCLUSIONS: Inhalation of large droplets of LPS gave rise to greater lung deposition and induced a more pronounced systemic and bronchial inflammatory response than small droplets. The systemic inflammatory response correlated with lung deposition. NCT01081392.
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Proteína C-Reactiva/metabolismo , Inflamación/inducido químicamente , Lipopolisacáridos/farmacocinética , Neutrófilos/efectos de los fármacos , Tamaño de la Partícula , Tecnecio/farmacocinética , Administración por Inhalación , Adolescente , Adulto , Recuento de Células , Femenino , Voluntarios Sanos , Humanos , Inflamación/metabolismo , Lipopolisacáridos/administración & dosificación , Pulmón/metabolismo , Masculino , Persona de Mediana Edad , Nebulizadores y Vaporizadores , Cintigrafía , Esputo/citología , Tecnecio/administración & dosificación , Adulto JovenAsunto(s)
Angioscopía Microscópica , Esclerodermia Sistémica , Capilares , Estudios de Casos y Controles , Humanos , UñasRESUMEN
OBJECTIVES: To investigate associated dimensions of fatigue regarding cognitive impairment, psychomotor performances, muscular effort power and circulating cytokine levels and their relations to symptom intensity in a sample of pure chronic fatigue syndrome (CFS) patients without overlapping objective sleepiness or sleep disorders. METHODS: 16 CFS patients were compared to 14 matched controls. We assessed structured symptom-scales, polysomnography, multiple sleep latency tests, attention (Zazzo-Cancellation ZCT, digit-symbol-substitution DSST), psychomotor vigilance and speed (PVT, finger tapping test, FTT), dynamometer handgrip force (tonic and phasic trials) and circulating cytokines (IFN-γ, IL-1b, IL-6, IL-8, IL-10, TNF-α). RESULTS: In addition to fatigue, CFS patients presented with higher affective symptom intensity and worse perceived sleep quality. Polysomnography showed more slow-wave sleep and microarousals in CFS but similar sleep time, efficiency and light-sleep durations than controls. Patients presented with impaired attention (DSST, ZCT), slower reaction times (PVT) but not with lower hit rates (FTT). Notwithstanding lower grip strength during tonic and phasic trials, CFS also presented with higher fatigability during phasic trials. Cytokine levels were increased for IL-1b, IL-8, IL-10 and TNF-α and fatigue intensity was correlated to grip strength and IL-8. CONCLUSIONS: In contrast to sleepiness, chronic fatigue is a more complex phenomenon that cannot be reduced to one single measured dimension (i.e., sleep propensity). Showing its relations to different measurements, our study reflects this multidimensionality, in a psychosomatic disorder such as CFS. To obtain objective information, routine assessments of fatigue should rule out sleepiness, combine aspects of mental and physical fatigue and focus on fatigability.
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Atención , Cognición , Síndrome de Fatiga Crónica/fisiopatología , Sueño , Adulto , Estudios de Casos y Controles , Citocinas/sangre , Síndrome de Fatiga Crónica/sangre , Femenino , Fuerza de la Mano , Humanos , Masculino , Tiempo de ReacciónRESUMEN
An increasing number of studies have highlighted the existence of a sex-specific immune response, wherein men experience a worse prognosis in cases of acute inflammatory diseases. Initially, this sex-dependent inflammatory response was attributed to the influence of sex hormones. However, a growing body of evidence has shifted the focus toward the influence of chromosomes rather than sex hormones in shaping these inflammatory sex disparities. Notably, certain pattern recognition receptors, such as Toll-like receptors (TLRs), and their associated immune pathways have been implicated in driving the sex-specific immune response. These receptors are encoded by genes located on the X chromosome. TLRs are pivotal components of the innate immune system, playing crucial roles in responding to infectious diseases, including bacterial and viral pathogens, as well as trauma-related conditions. Importantly, the TLR-mediated inflammatory responses, as indicated by the production of specific proteins and cytokines, exhibit discernible sex-dependent patterns. In this review, we delve into the subject of sex bias in TLR activation and explore its clinical implications relatively to both the X chromosome and the hormonal environment. The overarching objective is to enhance our understanding of the fundamental mechanisms underlying these sex differences.
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Inflamación , Receptores Toll-Like , Animales , Femenino , Humanos , Masculino , Hormonas Esteroides Gonadales/metabolismo , Hormonas Esteroides Gonadales/inmunología , Inmunidad Innata , Inflamación/inmunología , Factores Sexuales , Transducción de Señal , Receptores Toll-Like/metabolismo , Receptores Toll-Like/inmunologíaRESUMEN
The enduring impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its disease manifestation, COVID-19, on public health remains significant. Postacute sequelae of SARS-CoV-2 infection (PASC) affect a considerable number of patients, impairing their quality of life. While the role of the cytokine storm in acute COVID-19 is well established, its contribution to the pathophysiology of PASC is not fully understood. This study aimed to analyze the cytokine profile of patients with PASC following in vitro stimulation of Toll-like receptor (TLR) pathways, comparing them with a healthy control group. From October 2020 till March 2021, Brugmann University Hospital's clinical research unit included patients with PASC in the study. Whole blood samples were collected from 50 patients and 25 healthy volunteers. After in vitro stimulation under five different conditions, cytokine levels were measured using a multiplex method. Significantly decreased cytokine levels were observed in patients with PASC compared with healthy volunteers, particularly after TLR4 (interleukin [IL]-1α, IL-1ß, IL-2, IL-10, interferon (IFN)α, IFNγ, IFNω, and tumor necrosis factor (TNF)α) and TLR7/8 (IL-1α, IL-1ß, IFNα, IFNω, IFNγ, and TNFα) pathway stimulation. Principal component analysis identified two distinct clusters, suggesting a likely dysregulation of immunity involving TLR4 and TLR7/8 pathways in patients with PASC. Our study suggests that TLR4 and TLR7/8 pathways play a role in the pathophysiology of PASC. Continuous basal activation of immunity could explain the high basal concentrations of cytokines described in these patients and the decreased amplitude of response of these signaling pathways following specific stimulation.
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BACKGROUND: Chronic spontaneous urticaria (CSU) is a chronic inflammatory skin disease where activation of endothelial cells (ECs) at sites of skin lesions leads to increased blood flow, leakage of fluid into the skin, cellular infiltration, and vascular remodeling. To understand the disease duration and the sometimes vague systemic symptoms accompanying flares, the objective of this study was to examine if CSU comes with systemic vascular changes at the microcirculatory level. METHODS: We investigated CSU patients (n = 49) and healthy controls (HCs, n = 44) for microcirculatory differences by nailfold videocapillaroscopy (NVC) and for blood levels of the soluble EC biomarkers serum vascular endothelial growth factor (VEGF), soluble E-selectin, and stem cell factor (SCF). Patients were also assessed for clinical characteristics, disease activity, and markers of autoimmune CSU (aiCSU). RESULTS: CSU patients had significantly lower capillary density, more capillary malformations, and more irregular capillary dilations than HCs on NVC. Serum levels of VEGF, soluble E selectin and SCF were similar in CSU patients and HCs. CSU patients with higher VEGF levels had significantly more abnormal capillaries. Patients with markers of aiCSU, that is, low IgE levels or increased anti-TPO levels, had significantly more capillaries and less capillary dilations than those without. CONCLUSION: Our results suggest that CSU comes with systemic microcirculatory changes, which may be driven, in part, by VEGF.
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BACKGROUND: The acute inhalation of endotoxin mimicks several aspects of the inflammation related to chronic obstructive pulmonary disease (COPD). The aim of the current study was to identify and to validate biomarkers of endotoxin-induced airways' inflammation. METHODS: The cellular count in the induced-sputum, was measured before and after an inhalation of 20 mcg endotoxin, in 8 healthy volunteers. A proteomic analysis was applied to identify the more relevant proteins expression, before measurement by ELISA. The amplitude and the repeatability of the markers were evaluated among another population of 12 healthy subjects. RESULTS: There was a significant rise of viable cells (p <0.01), macrophages (p <0.05), and neutrophils (p <0.02) 24 hours after endotoxin inhalation, and of neutrophils (p <0.02) and lymphocytes (p <0.05) at 6 hours. Among the highest amplitude responses, the two dimensional electrophoretic separation shown proteolytic activity and overexpression of protein spots. By MALDI-TOF mass spectrometry, the last were identified as calgranulin A and B. The expression of the bioactive A/B heterodimeric complex was confirmed by ELISA both in the sputum (p <0.01) and at the blood level (p <0.01). The intra-subject repeatability of the sputum calgranulin A/B was highly significant (p <0.0001). CONCLUSION: In healthy subjects, the inhalation of endotoxin induced expression of sputum calgranulin A/B that could be a biomarker of the endotoxin response/exposure.
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Calgranulina A/metabolismo , Calgranulina B/metabolismo , Exposición por Inhalación , Lipopolisacáridos/inmunología , Sistema Respiratorio/metabolismo , Adolescente , Adulto , Biomarcadores/metabolismo , Calgranulina A/sangre , Calgranulina B/sangre , Femenino , Humanos , Inflamación/inmunología , Recuento de Linfocitos , Linfocitos , Macrófagos/metabolismo , Masculino , Persona de Mediana Edad , Neutrófilos/metabolismo , Reproducibilidad de los Resultados , Sistema Respiratorio/inmunología , Sistema Respiratorio/patología , Esputo/citología , Adulto JovenRESUMEN
Autoimmune encephalopathy is a rare but potentially reversible cause of cognitive deterioration and neuropsychiatric disturbances. We describe two older female patients with subacute cognitive decline and marked neuropsychiatric disturbances in the presence of high serum anti-thyroid peroxidase antibodies and with normal dosage of free thyroxine 4. One patient recovered almost completely after oral corticotherapy. Differential diagnosis and the role of biomarkers, in particular, are discussed. We support a pragmatic approach involving a short empirical therapeutic trial with intravenous or oral corticoids; this should be considered in all patients with subacute encephalopathy and with laboratory arguments for an underlying autoimmune aetiology.
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Autoanticuerpos/sangre , Encefalopatías/sangre , Encefalopatías/complicaciones , Trastornos del Conocimiento/sangre , Trastornos del Conocimiento/complicaciones , Enfermedad de Hashimoto/sangre , Enfermedad de Hashimoto/complicaciones , Yoduro Peroxidasa/sangre , Anciano , Antiinflamatorios/uso terapéutico , Biomarcadores/sangre , Encefalopatías/tratamiento farmacológico , Trastornos del Conocimiento/tratamiento farmacológico , Diagnóstico Diferencial , Encefalitis , Femenino , Enfermedad de Hashimoto/tratamiento farmacológico , Humanos , Metilprednisolona/uso terapéuticoRESUMEN
Previous studies have reported sex disparity in cystic fibrosis (CF) disease, with females experiencing more pulmonary exacerbations and frequent microbial infections resulting in shorter survival expectancy. This concerns both pubertal and prepubertal females, which is in support to the prominent role of gene dosage rather than the hormonal status. The underlying mechanisms are still poorly understood. The X chromosome codes for a large number of micro-RNAs (miRNAs) that play a crucial role in the post-transcriptional regulation of several genes involved in various biological processes, including inflammation. However, their level of expression in CF males and females has not been sufficiently explored. In this study, we compared in male and female CF patients the expression of selected X-linked miRNAs involved in inflammatory processes. Cytokine and chemokine profiles were also evaluated at both protein and transcript levels and cross-analyzed with the miRNA expression levels. We observed increased expression of miR-223-3p, miR-106a-5p, miR-221-3p and miR-502-5p in CF patients compared to healthy controls. Interestingly, the overexpression of miR-221-3p was found to be significantly higher in CF girls than in CF boys and this correlates positively with IL-1ß. Moreover, we found a trend toward lower expression in CF girls than in CF boys of suppressor of cytokine signaling 1 (SOCS1) and the ubiquitin-editing enzyme PDLIM2, two mRNA targets of miR-221-3p that are known to inhibit the NF-κB pathway. Collectively, this clinical study highlights a sex-bias in X-linked miR-221-3p expression in blood cells and its potential contribution to sustaining a higher inflammatory response in CF girls.
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Fibrosis Quística , MicroARNs , Humanos , Masculino , Femenino , Niño , MicroARNs/metabolismo , Fibrosis Quística/metabolismo , Proyectos Piloto , Citocinas/genética , Cromosomas , Proteínas de Microfilamentos/genética , Proteínas con Dominio LIM/genéticaRESUMEN
Background and objectives: Management of severe allergic transfusion reactions (ATR) is challenging. In this study, we investigate the usefulness of skin tests and basophil activation tests (BAT) in chronically transfused patients for the prevention of future ATR. Materials and methods: BAT and skin tests were carried with the supernatant of red blood cell (RBC) units for a sickle-cell disease patient under chronic exchange transfusion who has presented a severe ATR, in order to prevent potential future ATR. If the results for both BAT and skin tests were negative, the RBC units could be transfused to the patient. If either one of the results was positive, the tested RBC unit was discarded for the patient. Results: 192 RBC units were tested with both tests. The level of results concordance between the two tests was 95%. Out of the 169 negative units with both tests, 118 units were transfused to the patient for which he presented no ATR. Conclusion: In our study, combining both BAT and skin tests was associated with a good negative predictive value since we were able to safely transfuse our patient. Further studies are still necessary to confirm this result but this pilot study indicates that skin tests and BAT might help prevent ATR. When BAT is not available, skin tests may also be useful in preventing ATR.