RESUMEN
Although the role of T lymphocytes in sarcoidosis (SA) and lung cancer (LC) is quite well reported, the occurrence of B cells in disease microenvironments may suggest their potential role as natural modifiers of the immune response. The aim of this study was to investigate the B-cell profile and lymphocyte-related hematological parameters between patients with SA, LC and healthy controls (HCs). The cells were assessed by flow cytometry and a hematological analyzer in peripheral blood (PB) and material from lymph nodes (LNs) obtained by the EBUS/TBNA method. We showed that in SA patients, there were higher percentages of naïve B and CD21low B cells and a lower percentage of class-switched memory B cells than LC patients in LNs. We observed a higher median proportion of non-switched memory and transitional B cells in the PB of SA patients than in LC patients. We noticed the lowest median proportion of class-switched memory B cells in the PB from SA patients. LC patients had a higher percentage of RE-LYMP and AS-LYMP than SA patients. Our study presented a different profile of B-cell subpopulations in SA and LC patients, distinguishing dominant subpopulations, and showed the relocation from distant compartments of the circulation to the disease microenvironment, thus emphasizing their role.
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Neoplasias Pulmonares , Sarcoidosis , Microambiente Tumoral , Humanos , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/sangre , Masculino , Femenino , Persona de Mediana Edad , Sarcoidosis/inmunología , Sarcoidosis/patología , Sarcoidosis/sangre , Microambiente Tumoral/inmunología , Subgrupos de Linfocitos B/inmunología , Adulto , Anciano , Ganglios Linfáticos/patología , Ganglios Linfáticos/inmunología , Linfocitos B/inmunología , Estudios de Casos y ControlesRESUMEN
Sarcoidosis is a systemic granulomatous disease characterized by non-caseating epithelioid cell granulomas. One of its immunological hallmarks is the differentiation of CD4 + naïve T cells into Th1/Th17 cells, accompanied by the release of numerous pro-inflammatory cytokines. The TL1A/DR3 signaling pathway plays a crucial role in activating effector lymphocytes, thereby triggering pro-inflammatory responses. The primary aim of this investigation was to scrutinize the impact of anti-TL1A monoclonal antibody on the dysregulation of Th1/Th17 cells and granuloma formation in sarcoidosis. Initially, the abnormal activation of the TL1A/DR3 signaling pathway in pulmonary tissues of sarcoidosis patients was confirmed using qPCR and immunohistochemistry techniques. Subsequently, employing a murine model of sarcoidosis, the inhibitory effects of anti-TL1A monoclonal antibody on the TL1A/DR3 signaling pathway in sarcoidosis were investigated through qPCR, immunohistochemistry, and Western blot experiments. The influence of anti-TL1A monoclonal antibody on granulomas was assessed through HE staining, while their effects on sarcoidosis Th1/Th17 cells and associated cytokine mRNA levels were evaluated using flow cytometry and qPCR, respectively. Immunofluorescence and Western blot experiments corroborated the inhibitory effects of anti-TL1A monoclonal antibody on the aberrant activation of the PI3K/AKT signaling pathway in sarcoidosis. The findings of this study indicate that the TL1A/DR3 signaling pathway is excessively activated in sarcoidosis. Anti-TL1A monoclonal antibody effectively inhibit this abnormal activation in sarcoidosis, thereby alleviating the dysregulation of Th1/Th17 cells and reducing the formation of pulmonary granulomas. This effect may be associated with the inhibition of the downstream PI3K/AKT signaling pathway. Anti-TL1A monoclonal antibody hold promise as a potential novel therapeutic intervention for sarcoidosis.
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Anticuerpos Monoclonales , Granuloma , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Sarcoidosis , Transducción de Señal , Células TH1 , Células Th17 , Miembro 15 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral , Animales , Células TH1/inmunología , Células Th17/inmunología , Transducción de Señal/efectos de los fármacos , Humanos , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Fosfatidilinositol 3-Quinasas/metabolismo , Fosfatidilinositol 3-Quinasas/inmunología , Granuloma/inmunología , Granuloma/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-akt/inmunología , Femenino , Miembro 15 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/metabolismo , Miembro 15 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/inmunología , Masculino , Sarcoidosis/inmunología , Sarcoidosis/tratamiento farmacológico , Ratones , Adulto , Persona de Mediana Edad , Miembro 25 de Receptores de Factores de Necrosis Tumoral/metabolismo , Miembro 25 de Receptores de Factores de Necrosis Tumoral/inmunología , Pulmón/inmunología , Pulmón/patología , Citocinas/metabolismo , Citocinas/inmunología , Modelos Animales de Enfermedad , Ratones Endogámicos BALB CRESUMEN
Sarcoidosis is a chronic immune disease of unknown origin for which we still lack an immunological framework unifying causal agents, host factors, and natural history of disease. Here, we discuss the initial triggers of disease, and how myeloid cells drive granuloma formation and contribute to immunopathogenesis. We highlight recent advances in our understanding of innate immune memory and propose the hypothesis that maladaptive innate immune training connects previous environmental exposure to granuloma maintenance and expansion. Lastly, we consider how this hypothesis may open novel therapeutic avenues, while corticosteroids remain the front-line treatment.
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Inmunidad Innata , Memoria Inmunológica , Sarcoidosis , Humanos , Sarcoidosis/inmunología , Inmunidad Innata/inmunología , Animales , Granuloma/inmunología , Células Mieloides/inmunología , Inmunidad EntrenadaRESUMEN
The differential diagnosis of inflammatory arthritis as an immune-related adverse event can be challenging as patients with cancer can present with musculoskeletal symptoms that can mimic arthritis because of localized or generalized joint pain. In addition, immune checkpoint inhibitors can exacerbate joint conditions such as crystal-induced arthritis or osteoarthritis, or induce systemic disease that can affect the joints such as sarcoidosis. This distinction is important as the treatment of these conditions can be different from that of immune-related inflammatory arthritis.
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Artritis , Inhibidores de Puntos de Control Inmunológico , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Diagnóstico Diferencial , Artritis/diagnóstico , Artritis/inducido químicamente , Artritis/tratamiento farmacológico , Sarcoidosis/inducido químicamente , Sarcoidosis/diagnóstico , Sarcoidosis/inmunología , Neoplasias/tratamiento farmacológico , Neoplasias/inmunología , Osteoartritis/tratamiento farmacológico , Osteoartritis/inmunología , Artropatías por Depósito de Cristales/diagnóstico , Artropatías por Depósito de Cristales/inmunologíaRESUMEN
Sarcoidosis, a systemic inflammatory disease, poses challenges in understanding its etiology and variable clinical courses. Despite ongoing uncertainty about causative agents and genetic predisposition, granuloma formation remains its hallmark feature. To address this, we developed a validated in vitro human granuloma model using patient-derived peripheral blood mononuclear cells (PBMCs), offering a dynamic platform for studying early granuloma formation and sarcoidosis pathogenesis. However, a current limitation of this model is its dependence on freshly isolated PBMCs obtained from whole blood. While cryopreservation is a common method for long-term sample preservation, the biological effects of freezing and thawing PBMCs on granuloma formation remain unclear. This study aimed to assess the viability and functionality of cryopreserved sarcoidosis PBMCs within the granuloma model, revealing similar granulomatous responses to fresh cells and highlighting the potential of cryopreserved PBMCs as a valuable tool for studying sarcoidosis and related diseases.
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Criopreservación , Granuloma , Leucocitos Mononucleares , Sarcoidosis , Humanos , Sarcoidosis/inmunología , Sarcoidosis/patología , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/metabolismo , Granuloma/patología , Granuloma/inmunología , Antígenos/inmunología , Supervivencia Celular , Células Cultivadas , Masculino , Femenino , AdultoAsunto(s)
Vacunas contra la COVID-19 , COVID-19 , Sarcoidosis , Enfermedades de la Piel , Humanos , Sarcoidosis/diagnóstico , Sarcoidosis/inmunología , COVID-19/prevención & control , COVID-19/inmunología , Enfermedades de la Piel/patología , Enfermedades de la Piel/inmunología , Enfermedades de la Piel/inducido químicamente , Vacunas contra la COVID-19/efectos adversos , Vacunas contra la COVID-19/administración & dosificación , SARS-CoV-2/inmunología , Femenino , Vacunación/efectos adversos , Piel/patología , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Chronic rhinosinusitis is a very common condition. IgG4-related disease (IgG4-RD) and sarcoidosis are systemic diseases which can contribute to the development of chronic rhinosinusitis in select patients. OBJECTIVE: Characterize the presenting features, diagnostic criteria, workup, and management of sinonasal IgG4-RD and sarcoidosis as they are encountered in otolaryngology clinics. METHODS: Full length manuscripts published 2000 or later were reviewed. A separate search was conducted for each disease. Pertinent clinical features related to sinonasal manifestations of IgG4-RD and sarcoidosis were collected and reported in this review. RESULTS: 404 references were discovered during literature review process. In total, 42 references for IgG4-RD and 34 references for sarcoidosis were included in this review. CONCLUSION: IgG4-RD and sarcoidosis are autoimmune inflammatory conditions that can affect many systems of the body. For both disease entities, sinonasal disease is a less common presentation which can lead to delayed diagnosis. Sinonasal IgG4-RD commonly presents in the setting of multisystem disease. All with other clinical features, biopsy plays a key role in the diagnosis for both diseases. Treatment for IgG4-RD consists primarily of steroids and rituximab which can lead to excellent and durable remission. A variety of immunosuppressive agents are used in the management of sarcoidosis. Surgery for IgG4-RD is primarily utilized for tissue biopsy, although resection or debulking may be considered. For sarcoidosis, surgery can be used for tissue biopsy and functional sinus surgery can offer symptomatic relief in many patients.
Asunto(s)
Enfermedad Relacionada con Inmunoglobulina G4 , Sarcoidosis , Sinusitis , Humanos , Sarcoidosis/diagnóstico , Sarcoidosis/inmunología , Enfermedad Relacionada con Inmunoglobulina G4/diagnóstico , Enfermedad Relacionada con Inmunoglobulina G4/terapia , Enfermedad Relacionada con Inmunoglobulina G4/complicaciones , Sinusitis/inmunología , Sinusitis/diagnóstico , Rinitis/inmunología , Rinitis/diagnóstico , Rinitis/terapia , Enfermedad Crónica , Inflamación/inmunología , Inflamación/diagnóstico , Inmunoglobulina G/inmunología , Inmunoglobulina G/sangre , Rituximab/uso terapéutico , Inmunosupresores/uso terapéutico , Femenino , MasculinoRESUMEN
BACKGROUND: Early detection and initiation of treatment in cardiac sarcoidosis (CS) is believed to be crucial to reduce morbidity and mortality. The diagnosis of CS is challenging, especially in isolated CS (ICS). Certain human leukocyte antigen (HLA-DRB1) alleles associate with different phenotypes of sarcoidosis. Phenotypic and genotypic characterization of patients with CS may improve our ability to identify patients being at risk for developing CS. METHODS: 87 patients with CS, identified at two Swedish university hospitals were included. Phenotypic characteristics were extracted from the medical records and the patients were HLA-DRB1 typed. RESULTS: Median age at diagnosis was 55 years, 37% were women. HLA-DRB1 distribution was similar to a general sarcoidosis population. A majority of patients (51/87) had CS as the first sarcoidosis presentation. They were younger (p = 0.04), more often presenting with ventricular tachycardia (VT) or atrioventricular block (AVB) grade II or III (p < 0.001), had lower left ventricular ejection fraction (LVEF) (p = 0.002), lower serum angiotensin converting enzyme (s-ACE) (p = 0.025), and fewer extra cardiac manifestations (ECM) (p = 0.02) than those presenting with CS later. CONCLUSIONS: Of Swedish CS patients, 59% presented with cardiac involvement as first manifestation. They had more severe cardiac symptoms than patients presenting with CS later. This phenotype disclosed less ECM and lower s-ACE thus diagnosis can be missed or delayed. We did not observe significant differences in HLA-DRB1 allele frequency between patients with CS compared to sarcoidosis in general. Awareness of CS as a primary manifestation can enable early detection and adequate intervention.
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Cadenas HLA-DRB1 , Miocarditis , Sarcoidosis , Alelos , Femenino , Cadenas HLA-DRB1/genética , Cadenas HLA-DRB1/inmunología , Humanos , Masculino , Miocarditis/genética , Miocarditis/inmunología , Fenotipo , Sarcoidosis/genética , Sarcoidosis/inmunología , Volumen Sistólico , Suecia , Función Ventricular IzquierdaRESUMEN
BACKGROUND: Blau syndrome (BS) is an autoinflammatory disease associated with mutations in nucleotide-binding oligomerization domain 2. Although treatments with anti-TNF agents have been reported to be effective, the underlying molecular mechanisms remain unclear. OBJECTIVE: We aimed to elucidate the mechanisms of autoinflammation in patients with BS and to clarify how anti-TNF treatment controls the disease phenotype at the cellular level in clinical samples. METHODS: Macrophages were differentiated from monocytes of 7 BS patients, and global transcriptional profiles of 5 patients were analyzed with or without IFN-γ stimulation. Macrophages were also generated from BS-specific induced pluripotent stem cells (iPSCs), and their transcriptome was examined for comparison. RESULTS: Aberrant inflammatory responses were observed upon IFN-γ stimulation in macrophages from untreated BS patients, but not in those from patients treated with anti-TNF. iPSC-derived macrophages carrying a disease-associated mutation also showed IFN-γ-dependent accelerated inflammatory responses. Comparisons of peripheral blood- and iPSC-derived macrophages revealed the upregulation of nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB) targets in unstimulated macrophages as a common feature. CONCLUSIONS: IFN-γ stimulation is one of the key signals driving aberrant inflammatory responses in BS-associated macrophages. However, long-term treatment with anti-TNF agents ameliorates such abnormalities even in the presence of IFN-γ stimulation. Our data thus suggest that preexposure to TNF or functionally similar cytokines inducing NF-κB-driven proinflammatory signaling during macrophage development is a prerequisite for accelerated inflammatory responses upon IFN-γ stimulation in BS.
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Artritis/inmunología , Interferón gamma/inmunología , Macrófagos/inmunología , Sarcoidosis/inmunología , Sinovitis/inmunología , Inhibidores del Factor de Necrosis Tumoral/farmacología , Uveítis/inmunología , Adulto , Artritis/tratamiento farmacológico , Artritis/genética , Línea Celular , Niño , Preescolar , Femenino , Humanos , Células Madre Pluripotentes Inducidas/citología , Masculino , FN-kappa B/inmunología , Sarcoidosis/tratamiento farmacológico , Sarcoidosis/genética , Sinovitis/tratamiento farmacológico , Sinovitis/genética , Transcriptoma , Inhibidores del Factor de Necrosis Tumoral/uso terapéutico , Uveítis/tratamiento farmacológico , Uveítis/genética , Adulto JovenRESUMEN
Sarcoidosis is a systemic inflammatory disorder of unknown etiology characterized by tissue infiltration with macrophages and lymphocytes and associated non-caseating granuloma formation. The disease primarily affects the lungs. Patients suffering from sarcoidosis show a wide range of clinical symptoms, natural history and disease outcomes. Originally described as a Th1-driven disease, sarcoidosis involves a complex interplay among diverse immune cells. This review highlights recent advances in the pathogenesis of sarcoidosis, with emphasis on the role of different immune cells. Accumulative evidence suggests Th17 cells, IFN-γ-producing Th17 cells or Th17.1 cells, and regulatory T (Treg) cells play a critical role. However, their specific actions, whether protective or pathogenic, remain to be clarified. Macrophages are also involved in granuloma formation, and M2 polarization may be predictive of fibrosis. Previously neglected cells including B cells, dendritic cells (DCs), natural killer (NK) cells and natural killer T (NKT) cells were studied more recently for their contribution to sarcoid granuloma formation. Despite these advances, the pathogenesis remains incompletely understood, indicating an urgent need for further research to reveal the distinct immunological events in this process, with hope to open up new therapeutic avenues and if possible, to develop preventive measures.
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Citocinas/inmunología , Células Dendríticas/inmunología , Linfocitos/inmunología , Macrófagos/inmunología , Sarcoidosis/inmunología , Animales , Citocinas/metabolismo , Células Dendríticas/efectos de los fármacos , Células Dendríticas/metabolismo , Humanos , Factores Inmunológicos/uso terapéutico , Linfocitos/efectos de los fármacos , Linfocitos/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Fenotipo , Sarcoidosis/tratamiento farmacológico , Sarcoidosis/metabolismo , Sarcoidosis/patología , Transducción de SeñalRESUMEN
PURPOSE OF THE STUDY: The involvement of the IL-23/IL23R pathway is well known in the disease pathogenesis of sarcoidosis and other inflammatory diseases. To date, the pathogenic mechanism of IL-23 is most notably described on CD4+ Th17 lymphocytes. However, the function of the IL23R on myeloid cells in sarcoidosis is poorly understood. Thus, the aim of the study is to investigate the role of the IL23R on myeloid cell in pulmonary granuloma formation. Methods: We generated IL23RLysMCre mice lacking the IL23R gene in myeloid cells. The importance of IL23R in myeloid cells for the development of sarcoidosis was studied in a mouse model of inflammatory lung granuloma formation through embolization of PPD from Mycobacterium bovis-coated Sepharose beads into previously PPD-immunized mice. In addition the function of IL23R on myeloid cells was studied in LPS or IFNγ stimulated BMDMs and BMDCs. The mRNA and protein expression levels of relevant cytokines were analyzed by RT-PCR (TaqMan) and ELISA. The composition of immune cells in BALF was quantified by flow cytometry and alteration in granuloma sizes were observed by H&E stained lung sections. Results: Mycobacterium Ag-elicted pulmonary granulomas tend to be smaller in IL23RLysMCre mice and NF-κB dependent Th1 cytokines in the murine lungs are reduced compared to wildtype mice. In line, we observed that IL23R-deficient bone marrow-derived macrophages show a reduced production of Th1 cytokines after LPS stimulation. Conclusion: We here for the first time demonstrate a role for IL23R on myeloid cells in pulmonary inflammation and granuloma formation. Our findings provide essential insights in the pathogenesis of inflammatory lung diseases like sarcoidosis, which might be useful for the development of novel therapeutics targeting distinct immunological pathways like IL-23/IL23R.
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Granuloma , Neumonía , Receptores de Interleucina/inmunología , Sarcoidosis/inmunología , Animales , Citocinas , Granuloma/inmunología , Pulmón , Macrófagos , Ratones , Neumonía/inmunologíaRESUMEN
Löfgren's syndrome (LS) is an acute form of sarcoidosis characterized by a genetic association with HLA-DRB1*03 (HLA-DR3) and an accumulation of CD4+ T cells of unknown specificity in the bronchoalveolar lavage (BAL). Here, we screened related LS-specific TCRs for antigen specificity and identified a peptide derived from NAD-dependent histone deacetylase hst4 (NDPD) of Aspergillus nidulans that stimulated these CD4+ T cells in an HLA-DR3-restricted manner. Using ELISPOT analysis, a greater number of IFN-γ- and IL-2-secreting T cells in the BAL of DR3+ LS subjects compared with DR3+ control subjects was observed in response to the NDPD peptide. Finally, increased IgG antibody responses to A. nidulans NDPD were detected in the serum of DR3+ LS subjects. Thus, our findings identify a ligand for CD4+ T cells derived from the lungs of LS patients and suggest a role of A. nidulans in the etiology of LS.
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Aspergillus nidulans/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/microbiología , Epítopos de Linfocito T/inmunología , Sarcoidosis/inmunología , Adulto , Animales , Antígenos Fúngicos/inmunología , Estudios de Casos y Controles , Femenino , Proteínas Fúngicas/inmunología , Antígeno HLA-DR3/química , Antígeno HLA-DR3/genética , Antígeno HLA-DR3/inmunología , Humanos , Hibridomas/inmunología , Inmunoglobulina G , Masculino , Ratones Transgénicos , Persona de Mediana EdadAsunto(s)
Osteítis , Psoriasis/diagnóstico , Sarcoidosis , Enfermedades de la Piel , Falanges de los Dedos del Pie , Heridas y Lesiones/complicaciones , Adolescente , Diagnóstico Diferencial , Progresión de la Enfermedad , Hallux/diagnóstico por imagen , Hallux/patología , Humanos , Masculino , Osteítis/complicaciones , Osteítis/fisiopatología , Osteítis/terapia , Medicina Preventiva , Pronóstico , Sarcoidosis/diagnóstico , Sarcoidosis/inmunología , Sarcoidosis/fisiopatología , Sarcoidosis/terapia , Enfermedades de la Piel/diagnóstico , Enfermedades de la Piel/etiología , Falanges de los Dedos del Pie/diagnóstico por imagen , Falanges de los Dedos del Pie/patologíaRESUMEN
Introduction: Sarcoidosis is a multi-organ disease with a wide range of clinical manifestations and outcomes. A quarter of sarcoidosis patients require long-term treatment for chronic disease. In this group, corticosteroids and cytotoxic agents be insufficient to control diseaseAreas covered: Several biologic agents have been studied for treatment of chronic pulmonary and extra-pulmonary disease. A review of the available literature was performed searching PubMed and an expert opinion regarding specific therapy was developed.Expert opinion: These agents have the potential of treating patients who have progressive disease. Many of these agents have different mechanisms of action, response rates, and toxicity profiles.
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Factores Biológicos/administración & dosificación , Factores Inmunológicos/administración & dosificación , Sarcoidosis/tratamiento farmacológico , Corticoesteroides/uso terapéutico , Animales , Factores Biológicos/efectos adversos , Factores Biológicos/farmacología , Progresión de la Enfermedad , Humanos , Factores Inmunológicos/efectos adversos , Factores Inmunológicos/farmacología , Sarcoidosis/inmunología , Sarcoidosis/fisiopatología , Resultado del TratamientoRESUMEN
Organic and inorganic antigens were studied simultaneously in the same cohort of sarcoidosis patients to investigate whether correlations between clinical characteristics and immunological sensitization could reveal new phenotypes. Sensitization to antigens of mycobacteria, Propionibacterium acnes catalase and vimentin was investigated in 201 sarcoidosis and 51 obstructive sleep apnoea patients, serving as control group. Sensitization to aluminium, beryllium, silica and zirconium was also studied in 105 of the sarcoidosis patients and in 24 of the controls. A significantly higher percentage of sarcoidosis patients (27·6%) than controls (4·2%) had an immunological response to metals or silica (P = 0·014). A higher percentage of these sarcoidosis patients showed fibrosis on chest X-ray 5 years after the diagnosis (69·2 versus 30·3%, P = 0·016). No significant differences in mycobacterial or vimentin enzyme-linked immunospot (ELISPOT) assay results were observed between sarcoidosis and control patients. A significantly lower percentage of sarcoidosis patients (3·5%) than control patients (15·7%) had a positive ELISPOT for P. acnes catalase (P = 0·003). However, sarcoidosis patients sensitized to P. acnes catalase were more likely to have skin involvement, while sarcoidosis patients sensitized to mycobacterial antigens were more likely to have cardiac involvement. Our study suggests a more prominent role for inorganic triggers in sarcoidosis pathogenesis than previously thought. Immunological sensitization to inorganic antigens was associated with development of fibrotic sarcoidosis. No association was found between sensitization to bacterial antigens or vimentin and sarcoidosis in Dutch patients. However, our data suggest that trigger-related phenotypes can exist in the heterogeneous population of sarcoidosis patients.
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Aluminio/inmunología , Antígenos/inmunología , Berilio/inmunología , Sarcoidosis/inmunología , Dióxido de Silicio/inmunología , Circonio/inmunología , Adulto , Aluminio/sangre , Antígenos/sangre , Proteínas Bacterianas/sangre , Proteínas Bacterianas/inmunología , Berilio/sangre , Catalasa/sangre , Catalasa/inmunología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Propionibacterium acnes/inmunología , Propionibacterium acnes/metabolismo , Sarcoidosis/sangre , Dióxido de Silicio/sangre , Apnea Obstructiva del Sueño/sangre , Apnea Obstructiva del Sueño/inmunología , Vimentina/sangre , Vimentina/inmunología , Circonio/sangreRESUMEN
Background: This study aimed to assess the diagnostic relevance of CD4/CD8 ratio in cerebrospinal fluid (CSF) for the etiological diagnosis work-up of uveitis.Methods: We consecutively included patients who were referred to our department for the diagnostic workup of intermediate and/or posterior uveitis. Etiological diagnoses were established in a blind manner regarding CD4/CD8 ratio.Results: Fifty-two patients were included. A diagnosis of ocular sarcoidosis was made in 15 (29%) patients, 21% had another determined diagnosis while 50% remained of undetermined origin. Median CD4/CD8 ratio in CSF was 4.57 (IQR 3.39-5.47) in ocular sarcoidosis, 1.74 (1.60-3.18) in uveitis due to other determined cause (P = .008), and 2.83 (2.34-3.54) in those with uveitis of undetermined origin (P = .007). CD4/CD8 ratio >3.23 was associated with a diagnosis of ocular sarcoidosis.Conclusion: Determination of CD4/CD8 ratio in CSF can be useful for diagnosis work-up since a CD4/CD8 ratio >3.23 in CSF is associated with ocular sarcoidosis.
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Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Inmunofenotipificación/métodos , Sarcoidosis/inmunología , Uveítis/diagnóstico , Adulto , Biomarcadores/líquido cefalorraquídeo , Relación CD4-CD8 , Femenino , Citometría de Flujo , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Sarcoidosis/líquido cefalorraquídeo , Sarcoidosis/complicaciones , Uveítis/líquido cefalorraquídeo , Uveítis/etiologíaRESUMEN
Purpose: Identify genes associated with ocular sarcoidosis (OS).Methods: We genotyped 1.1 million genetic variants to identify significant OS associations, defined as those that achieved p < 5 × 10-8 in a genome-wide comparison of OS cases to healthy controls in our European- or African-American cohorts (EA, AA). Potential functional roles of all associated variants were assessed.Results: Eight significant non-HLA variants were found in AA OS cases compared to healthy controls and confirmed as at least suggestive when comparing OS to non-OS cases. Seven of these were within MAGI1 and include transcription factor binding sites and expression quantitative trait loci. Our EA cohort, while showing similar effect sizes at variants within MAGI1, had no significant variants. Association analysis of HLA-DRB1 alleles confirmed association to OS in EA to *04:01.Conclusion: Our results support organ-specific genetic risk in OS in a compelling candidate, MAGI1, known to be associated with barrier function and autoimmunity.
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Proteínas Adaptadoras Transductoras de Señales/genética , Negro o Afroamericano/genética , Moléculas de Adhesión Celular/genética , Oftalmopatías/genética , Estudio de Asociación del Genoma Completo/métodos , Guanilato-Quinasas/genética , Cadenas HLA-DRB1/genética , Polimorfismo de Nucleótido Simple , Sarcoidosis/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Adulto , Autoinmunidad/genética , Estudios de Casos y Controles , Moléculas de Adhesión Celular/metabolismo , ADN/genética , Oftalmopatías/etnología , Oftalmopatías/inmunología , Femenino , Estudios de Seguimiento , Genotipo , Guanilato-Quinasas/metabolismo , Cadenas HLA-DRB1/inmunología , Humanos , Masculino , Persona de Mediana Edad , Morbilidad/tendencias , Sarcoidosis/etnología , Sarcoidosis/inmunología , Estados Unidos/epidemiologíaRESUMEN
Purpose: To detect circulating retina-specific autoreactive CD4+ T-cells and antiretinal antibodies (ARA) in latent tuberculosis (TB)-associated uveitis or sarcoid uveitis patients.Methods: The presence of crude retinal extract (RE) autoreactive CD4+ T-cells was determined by a highly sensitive flowcytometric-based technique examining co-expression of CD25 and CD134 (OX40) on RE stimulated PBMC. The presence of ARA in available matched serum samples was assessed by indirect immunofluorescence.Results: No autoreactive CD4+ T-cells against RE could be detected in either latent TB-associated uveitis or sarcoid uveitis patients, while ARA were detected in the serum of the majority (5/6) of latent TB-associated uveitis and all (3/3) sarcoid uveitis patients.Conclusion: Even with the use of this highly sensitive flowcytometric technique circulating retina-specific autoreactive CD4+ T-cells could not be detected. In contrast, ARA were detected in the majority of patients indicating an adaptive humoral immune response toward retinal antigens had occurred.
Asunto(s)
Autoanticuerpos/sangre , Linfocitos T CD4-Positivos/inmunología , Tuberculosis Latente/inmunología , Retina/inmunología , Sarcoidosis/inmunología , Tuberculosis Ocular/inmunología , Uveítis/inmunología , Adulto , Anciano , Células Cultivadas , Citometría de Flujo , Técnica del Anticuerpo Fluorescente Indirecta , Células Endoteliales de la Vena Umbilical Humana , Humanos , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Persona de Mediana Edad , Receptores OX40/metabolismo , Estudios Retrospectivos , Sarcoidosis/microbiología , Uveítis/microbiologíaRESUMEN
OBJECTIVES: The 2019 ACR/EULAR classification criteria for IgG4-related disease (IgG4-RD) have exclusion criteria including positive disease-specific autoantibodies, and these have been documented to have a high specificity. This study aimed to further validate these criteria as well as identify characteristics of patients showing false-negative results. METHODS: We retrospectively analysed 162 IgG4-RD patients and 130 mimickers. The sensitivity, specificity and fulfilment rates for each criterion were calculated, and intergroup comparisons were performed to characterize the false-negative cases. RESULTS: Both the IgG4-RD patients and mimickers were aged ≥65 years with male predominance. The final diagnoses of mimickers were mainly malignancy, vasculitis, sarcoidosis and aneurysm. The classification criteria had a sensitivity of 72.8% and specificity of 100%. Of the 44 false-negative cases, one did not fulfil the entry criteria, 20 fulfilled one exclusion criterion and 27 did not achieve sufficient inclusion criteria scores. The false-negative cases had fewer affected organs, lower serum IgG4 levels, and were less likely to have received biopsies than the true-positive cases. Notably, positive disease-specific autoantibodies were the most common exclusion criterion fulfilled in 18 patients, only two of whom were diagnosed with a specific autoimmune disease complicated by IgG4-RD. In addition, compared with the true-positive cases, the 18 had comparable serum IgG4 levels, number of affected organs, and histopathology and immunostaining scores despite higher serum IgG and CRP levels. CONCLUSIONS: The ACR/EULAR classification criteria for IgG4-RD have an excellent diagnostic specificity in daily clinical practice. Positive disease-specific autoantibodies may have limited clinical significance for the diagnosis of IgG4-RD.
Asunto(s)
Autoanticuerpos/inmunología , Enfermedad Relacionada con Inmunoglobulina G4/diagnóstico , Anciano , Anticuerpos Antiproteína Citrulinada/inmunología , Anticuerpos Anticitoplasma de Neutrófilos/inmunología , Anticuerpos Antinucleares/inmunología , Aneurisma de la Aorta/diagnóstico , Aneurisma de la Aorta/inmunología , Enfermedades de la Aorta/diagnóstico , Enfermedades de la Aorta/inmunología , Aortitis/diagnóstico , Aortitis/inmunología , Enfermedad de Castleman/diagnóstico , Enfermedad de Castleman/inmunología , Dacriocistitis/diagnóstico , Dacriocistitis/inmunología , Diagnóstico Diferencial , Reacciones Falso Negativas , Femenino , Humanos , Enfermedad Relacionada con Inmunoglobulina G4/inmunología , Enfermedades Renales/diagnóstico , Enfermedades Renales/inmunología , Linfoma/diagnóstico , Linfoma/inmunología , Masculino , Persona de Mediana Edad , Neoplasias/diagnóstico , Neoplasias/inmunología , Enfermedades Pancreáticas/diagnóstico , Enfermedades Pancreáticas/inmunología , Pancreatitis/diagnóstico , Pancreatitis/inmunología , Estudios Retrospectivos , Enfermedades de las Glándulas Salivales/diagnóstico , Enfermedades de las Glándulas Salivales/inmunología , Sarcoidosis/diagnóstico , Sarcoidosis/inmunología , Sialadenitis/diagnóstico , Sialadenitis/inmunologíaRESUMEN
OBJECTIVE: To evaluate the proportion and the long-term prognostic significance of heart failure (HF) in sarcoidosis patients. METHODS: Data extracted from a large Israeli healthcare provider's database were used to study sarcoidosis patients and matched non-sarcoidosis controls since 2000 to 2016. The proportion of HF was compared between the groups, and the associations between sarcoidosis, HF, and all-cause mortality were assessed. RESULTS: Included were 3,993 sarcoidosis patients and 19,856 age- and sex-matched controls. The proportion of HF patients was higher among the former (10.9% and 5.3%, respectively). A logistic regression model for multivariable analysis for covariates found sarcoidosis to be independently associated with HF (Odds Ratio (OR) 2.09 confidence interval (CI) 1.83-2.39). A total of 710 sarcoidosis patients (17.8%) and 2,121 controls (10.7%) died during the study period (p < 0.001). A multivariable survival analysis found an estimated hazard ratio (HR) of 1.84 (95%CI 1.67-2.02), indicating a significant association between sarcoidosis and risk for all-cause mortality. Our analysis also revealed a significant association between HF and risk for all-cause mortality (HR 3.05, 95%CI 2.77-3.36). CONCLUSIONS: Sarcoidosis is independently associated with HF, and both are independently associated with all-cause mortality.