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1.
Scand J Immunol ; 100(5): e13407, 2024 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-39285602

RESUMEN

Long-COVID caused by SARS-CoV-2 infection has significant and increasing effects on human health worldwide. Although a unifying molecular or biological explanation is lacking, several pathophysiological mechanisms have been proposed. Involvement of mast cells-evolutionary old "multipurpose" innate immune cells-was reported recently in studies of acute infection and post-acute-COVID-19 syndrome. Mast cell activity has been suggested in long-COVID. In this case-control study, we compared data from 24 individuals with long-COVID (according to the NICE criteria) and 24 age- and sex-matched healthy individuals with a history of SARS-CoV-2 infection without developing sequelae. Serum levels of the proteases beta-tryptase (TPSB2) and carboxypeptidase (CPA3), which are mast cell specific, were measured using immunoassays. The values were compared between the two groups and correlated to measures of physical exertional intolerance. TPSB2 and CPA3 levels were median (range) 26.9 (2.0-1000) and 5.8 (1.5-14.0) ng/mL, respectively, in the long-COVID group. The corresponding values in the control group were 10.9 (2.0-1000) (p = 0.93) and 5.3 (3.5-12.9) ng/mL (p = 0.82). No significant correlations between TPSB2 or CPA3 levels and scores on the ten physical subscales of SF-36, 3.1-3.10 were revealed. We found no significant differences in the levels of mast cell activation markers TPSB2 and CPA3 between the long-COVID and control groups and no correlations with proxy markers of exercise intolerance. Mast cell activation does not appear to be part of long-term pathogenesis of long-COVID, at least in the majority of patients.


Asunto(s)
COVID-19 , Carboxipeptidasas A , Mastocitos , SARS-CoV-2 , Triptasas , Humanos , Mastocitos/inmunología , COVID-19/inmunología , COVID-19/sangre , Masculino , Estudios de Casos y Controles , Femenino , Persona de Mediana Edad , Triptasas/sangre , SARS-CoV-2/inmunología , Adulto , Anciano , Carboxipeptidasas A/metabolismo , Síndrome Post Agudo de COVID-19
2.
Mol Med ; 29(1): 81, 2023 06 26.
Artículo en Inglés | MEDLINE | ID: mdl-37365509

RESUMEN

BACKGROUND: Fatigue is common in patients with chronic inflammatory and autoimmune diseases, often with a severe impact on the patient's daily life. From a biological point of view, fatigue can be regarded as an element of the sickness behavior response, a coordinated set of responses induced by pathogens to enhance survival during an infection and immunological danger. The mechanisms are not fully understood but involve activation of the innate immune system, with pro-inflammatory cytokines, in particular interleukin (IL)-1ß, acting on cerebral neurons. These mechanisms are also active during chronic inflammatory conditions. High mobility group box 1 (HMGB1) protein has interleukin-1 like properties and is a strong inducer of innate immune responses. Its role in generation of fatigue is not clarified. Emerging evidence indicates that also other biomolecules may influence sickness behavior. We aimed to elucidate how HMGB1 influences fatigue in patients with Crohn's disease, and how the protein interacts with other candidate biomarkers of fatigue. METHODS: In 56 patients with newly diagnosed Crohn's disease, fatigue was evaluated using three different fatigue instruments: the fatigue visual analog scale (fVAS), Fatigue Severity Scale (FSS), and the vitality subscale of Medical Outcomes Study Short-Form Health Survey (SF-36vs). The biochemical markers IL-1 receptor antagonist (RA), soluble IL-1 receptor type 2 (sIL-RII), heat shock protein 90 alpha (HSP90α), HMGB1, anti-fully reduced (fr)HMGB1 antibodies (abs), hemopexin (HPX), and pigment epithelium-derived factor (PEDF) were measured in plasma. Multivariable regression and principal component analyses (PCA) were applied. RESULTS: Multivariable regression analyses revealed significant contributions to fatigue severity for HMGB1 in the FSS model, HSP90α in the fVAS model and IL-1RA in the SF-36vs model. Depression and pain scores contributed to all three models. In PCA, two components described 53.3% of the variation. The "inflammation and cellular stress dimension" was dominated by IL-1RA, sIL-1RII, HSP90α, HPX, and PEDF scores, where the "HMGB1 dimension" was dominated by HMGB1, anti-frHMGB1 abs, and fVAS scores. CONCLUSION: This study supports the hypothesis that HMGB1 and a network of other biomolecules influence fatigue severity in chronic inflammatory conditions. The well-known association with depression and pain is also acknowledged.


Asunto(s)
Enfermedad de Crohn , Proteína HMGB1 , Humanos , Enfermedad Crónica , Enfermedad de Crohn/complicaciones , Fatiga/etiología , Fatiga/diagnóstico , Proteína HMGB1/metabolismo , Inflamación , Proteína Antagonista del Receptor de Interleucina 1 , Dolor , Receptores de Interleucina-1
3.
Rheumatology (Oxford) ; 62(9): 3213-3218, 2023 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-37004177

RESUMEN

OBJECTIVE: To identify and genetically characterize subgroups of patients with ANCA-associated vasculitides (AAV) based on sex and ANCA subtype. METHODS: A previously established SNP dataset derived from DNA sequencing of 1853 genes and genotyping of 1088 Scandinavian cases with AAV and 1589 controls was stratified for sex and ANCA subtype and analysed for association with five top AAV SNPs. rs9274619, a lead variant at the HLA-DQB1/HLA-DQA2 locus previously associated with AAV positive for myeloperoxidase (MPO)-ANCA, was analysed for association with the cumulative disease involvement of ten different organ systems. RESULTS: rs9274619 showed a significantly stronger association to MPO-ANCA-positive females than males [P = 2.0 × 10-4, OR = 2.3 (95% CI 1.5, 3.5)], whereas proteinase 3 (PR3)-ANCA-associated variants rs1042335, rs9277341 (HLA-DPB1/A1) and rs28929474 (SERPINA1) were equally associated with females and males with PR3-ANCA. In MPO-ANCA-positive cases, carriers of the rs9274619 risk allele were more prone to disease engagement of eyes [P = 0.021, OR = 11 (95% CI 2.2, 205)] but less prone to pulmonary involvement [P = 0.026, OR = 0.52 (95% CI 0.30, 0.92)]. Moreover, AAV with both MPO-ANCA and PR3-ANCA was associated with the PR3-ANCA lead SNP rs1042335 [P = 0.0015, OR = 0.091 (95% CI 0.0022, 0.55)] but not with rs9274619. CONCLUSIONS: Females and males with MPO-ANCA-positive AAV differ in genetic predisposition to disease, suggesting at least partially distinct disease mechanisms between the sexes. Double ANCA-positive AAV cases are genetically similar to PR3-ANCA-positive cases, providing clues to the clinical follow-up and treatment of these patients.


Asunto(s)
Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos , Anticuerpos Anticitoplasma de Neutrófilos , Femenino , Humanos , Masculino , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/genética , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/inmunología , Anticuerpos Anticitoplasma de Neutrófilos/inmunología , Mieloblastina/genética , Mieloblastina/inmunología , Peroxidasa/genética , Peroxidasa/inmunología , Caracteres Sexuales
4.
Rheumatology (Oxford) ; 61(8): 3461-3470, 2022 08 03.
Artículo en Inglés | MEDLINE | ID: mdl-34888651

RESUMEN

OBJECTIVE: To identify and characterize genetic loci associated with the risk of developing ANCA-associated vasculitides (AAV). METHODS: Genetic association analyses were performed after Illumina sequencing of 1853 genes and subsequent replication with genotyping of selected single nucleotide polymorphisms in a total cohort of 1110 Scandinavian cases with granulomatosis with polyangiitis or microscopic polyangiitis, and 1589 controls. A novel AAV-associated single nucleotide polymorphism was analysed for allele-specific effects on gene expression using luciferase reporter assay. RESULTS: PR3-ANCA+ AAV was significantly associated with two independent loci in the HLA-DPB1/HLA-DPA1 region [rs1042335, P = 6.3 × 10-61, odds ratio (OR) 0.10; rs9277341, P = 1.5 × 10-44, OR 0.22] and with rs28929474 in the SERPINA1 gene (P = 2.7 × 10-10, OR 2.9). MPO-ANCA+ AAV was significantly associated with the HLA-DQB1/HLA-DQA2 locus (rs9274619, P = 5.4 × 10-25, OR 3.7) and with a rare variant in the BACH2 gene (rs78275221, P = 7.9 × 10-7, OR 3.0), the latter a novel susceptibility locus for MPO-ANCA+ granulomatosis with polyangiitis/microscopic polyangiitis. The rs78275221-A risk allele reduced luciferase gene expression in endothelial cells, specifically, as compared with the non-risk allele. CONCLUSION: We identified a novel susceptibility locus for MPO-ANCA+ AAV and propose that the associated variant is of mechanistic importance, exerting a regulatory function on gene expression in specific cell types.


Asunto(s)
Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos , Granulomatosis con Poliangitis , Poliangitis Microscópica , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/complicaciones , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/genética , Anticuerpos Anticitoplasma de Neutrófilos , Células Endoteliales , Granulomatosis con Poliangitis/complicaciones , Granulomatosis con Poliangitis/genética , Humanos , Poliangitis Microscópica/complicaciones , Poliangitis Microscópica/genética , Mieloblastina/genética , Peroxidasa
5.
Scand J Gastroenterol ; 57(3): 290-297, 2022 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-34846950

RESUMEN

OBJECTIVE: The relationship between the disease activity of ulcerative colitis and fatigue is unclear. We investigated how reaching deep remission versus remaining in active disease influenced the severity of fatigue. MATERIALS AND METHODS: We included 149 consecutive patients in a longitudinal study. Patients were re-examined after 3 months of conventional treatment and dichotomized into A: Active disease or B: Deep remission. The Partial Mayo Score (PMS) was recorded in all patients. Fatigue was rated using the fatigue visual analog scale (fVAS), Fatigue Severity Scale (FSS), and Short Form-36 Vitality Subscale (SF-36vs). A control group of 22 age and sex-matched healthy subjects were included as controls for patients reaching deep remission. RESULTS: After 3 months there were no significant differences in fVAS, FSS and SF-36vs scores in patients with active disease compared to patients reaching deep remission, when adjusting for baseline fatigue scores. Patients in remission based on MES-UC scores had no significant reduction in fatigue scores, whereas patients in remission based on PMS had all three fatigue scores reduced. However, patients reaching deep remission still had higher fVAS and lower SF-36vs scores compared to healthy control subjects. CONCLUSIONS: After 3 months of conventional treatment there were no differences in fatigue severity in patients reaching deep remission compared with patients still having active disease. Fatigue was more pronounced in patients in deep remission than in healthy subjects, and was associated with subjective and not objective measures of disease activity. This indicates that other potent factors than inflammation influence fatigue in UC.


Asunto(s)
Colitis Ulcerosa , Colitis Ulcerosa/complicaciones , Fatiga/etiología , Humanos , Estudios Longitudinales , Dimensión del Dolor , Inducción de Remisión , Índice de Severidad de la Enfermedad
6.
Clin Exp Dermatol ; 47(6): 1068-1077, 2022 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-34921435

RESUMEN

BACKGROUND: Chronic fatigue is common in patients with psoriasis, and heat-shock proteins (HSPs) have been suggested to influence fatigue. AIM: To evaluate gene expression patterns of selected HSPs in patients with psoriasis with high vs. low fatigue. METHODS: Fatigue was assessed using the fatigue Visual Analogue Scale, and disease activity by the Psoriasis Area and Severity Index. Peripheral blood transcriptional profiling was performed using RNA sequencing (RNA-seq) of HSP genes from 10 patients with high fatigue, and compared with 10 patients with low fatigue. HSPB11, HSPBAP1, HSPA14, HSPA9P1, HSP90B1 and HSP90AB1 contributed most to separation of the two groups in a principal components analysis. Four of these genes (HSPB11, HSPA14, HSP90B1 and HSP90AB1) were further investigated by real-time reverse transcription quantitative PCR (RT-qPCR) in 20 patients with high- and 20 patients with low-fatigue scores. RESULTS: Both RNA-seq and RT-qPCR analyses revealed a tendency to higher expression levels of HSPB11 and lower expression of HSP90B1 in the high- vs. the low-fatigue group. Psoriasis disease activity had no influence on the expression levels of the studied HSP genes. CONCLUSION: Overall, the results suggest that some HSPs are involved in generation of fatigue in psoriasis, supporting the hypothesis that downregulatory innate immune responses influence fatigue.


Asunto(s)
Proteínas de Choque Térmico , Psoriasis , Proteínas HSP70 de Choque Térmico/genética , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Humanos , Psoriasis/genética
7.
Ann Rheum Dis ; 80(1): 109-117, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33037003

RESUMEN

OBJECTIVES: Systemic lupus erythematosus (SLE) is an autoimmune disease with extensive heterogeneity in disease presentation between patients, which is likely due to an underlying molecular diversity. Here, we aimed at elucidating the genetic aetiology of SLE from the immunity pathway level to the single variant level, and stratify patients with SLE into distinguishable molecular subgroups, which could inform treatment choices in SLE. METHODS: We undertook a pathway-centred approach, using sequencing of immunological pathway genes. Altogether 1832 candidate genes were analysed in 958 Swedish patients with SLE and 1026 healthy individuals. Aggregate and single variant association testing was performed, and we generated pathway polygenic risk scores (PRS). RESULTS: We identified two main independent pathways involved in SLE susceptibility: T lymphocyte differentiation and innate immunity, characterised by HLA and interferon, respectively. Pathway PRS defined pathways in individual patients, who on average were positive for seven pathways. We found that SLE organ damage was more pronounced in patients positive for the T or B cell receptor signalling pathways. Further, pathway PRS-based clustering allowed stratification of patients into four groups with different risk score profiles. Studying sets of genes with priors for involvement in SLE, we observed an aggregate common variant contribution to SLE at genes previously reported for monogenic SLE as well as at interferonopathy genes. CONCLUSIONS: Our results show that pathway risk scores have the potential to stratify patients with SLE beyond clinical manifestations into molecular subsets, which may have implications for clinical follow-up and therapy selection.


Asunto(s)
Presentación de Antígeno/genética , Inmunidad Innata/genética , Interferón Tipo I/inmunología , Lupus Eritematoso Sistémico/genética , Linfopoyesis/genética , Linfocitos T/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Coagulación Sanguínea/genética , Estudios de Casos y Controles , Análisis por Conglomerados , Activación de Complemento/genética , Femenino , Humanos , Quinasas Janus/genética , Lupus Eritematoso Sistémico/inmunología , Masculino , Persona de Mediana Edad , Herencia Multifactorial , Polimorfismo de Nucleótido Simple , Factores de Transcripción STAT/genética , Análisis de Secuencia de ADN , Transducción de Señal/genética , Suecia , Población Blanca , Adulto Joven
8.
Rheumatology (Oxford) ; 60(7): 3099-3106, 2021 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-30815693

RESUMEN

Chronic fatigue, pain and depression are common in patients with primary Sjögren's syndrome. These phenomena mutually affect each other and have a considerable impact on the patients' quality of life. While pain is usually regarded as a fairly somatic phenomenon, both fatigue and depression have traditionally been regarded as more-or-less of psychological origin. There is an increasing understanding that this picture is multifaceted; that there is a genetic foundation, and that biological mechanisms regulate the clinical expression through activation of evolutionary, deeply conserved neuronal pathways in the brain. This pattern is evident not only in primary Sjögren's syndrome, but also in other systemic inflammatory autoimmune diseases, in cancer and in neurodegenerative diseases like Parkinson's disease. This article will mainly focus on the biology of pain and fatigue. We describe how these factors influence each other, and act with the overarching purpose of defending the organism against harm and danger.

9.
Rheumatology (Oxford) ; 60(2): 837-848, 2021 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-32889544

RESUMEN

OBJECTIVES: Clinical presentation of primary Sjögren's syndrome (pSS) varies considerably. A shortage of evidence-based objective markers hinders efficient drug development and most clinical trials have failed to reach primary endpoints. METHODS: We performed a multicentre study to identify patient subgroups based on clinical, immunological and genetic features. Targeted DNA sequencing of 1853 autoimmune-related loci was performed. After quality control, 918 patients with pSS, 1264 controls and 107 045 single nucleotide variants remained for analysis. Replication was performed in 177 patients with pSS and 7672 controls. RESULTS: We found strong signals of association with pSS in the HLA region. Principal component analysis of clinical data distinguished two patient subgroups defined by the presence of SSA/SSB antibodies. We observed an unprecedented high risk of pSS for an association in the HLA-DQA1 locus of odds ratio 6.10 (95% CI: 4.93, 7.54, P=2.2×10-62) in the SSA/SSB-positive subgroup, while absent in the antibody negative group. Three independent signals within the MHC were observed. The two most significant variants in MHC class I and II respectively, identified patients with a higher risk of hypergammaglobulinaemia, leukopenia, anaemia, purpura, major salivary gland swelling and lymphadenopathy. Replication confirmed the association with both MHC class I and II signals confined to SSA/SSB antibody positive pSS. CONCLUSION: Two subgroups of patients with pSS with distinct clinical manifestations can be defined by the presence or absence of SSA/SSB antibodies and genetic markers in the HLA locus. These subgroups should be considered in clinical follow-up, drug development and trial outcomes, for the benefit of both subgroups.


Asunto(s)
Autoanticuerpos/sangre , Cadenas alfa de HLA-DQ/genética , Síndrome de Sjögren , Edad de Inicio , Autoinmunidad/genética , Correlación de Datos , Femenino , Marcadores Genéticos/genética , Predisposición Genética a la Enfermedad , Variación Genética , Humanos , Masculino , Persona de Mediana Edad , Noruega/epidemiología , Polimorfismo de Nucleótido Simple , Análisis de Secuencia de ADN/métodos , Síndrome de Sjögren/clasificación , Síndrome de Sjögren/genética , Síndrome de Sjögren/inmunología , Síndrome de Sjögren/fisiopatología , Suecia/epidemiología
10.
Curr Opin Neurol ; 33(3): 391-396, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32304437

RESUMEN

PURPOSE OF REVIEW: Chronic fatigue is common in cancer, neurodegenerative, and chronic inflammatory diseases and is regarded by many patients as their absolutely worst problem. Lately, fatigue is increasingly understood to have a genetic and molecular basis. RECENT FINDINGS: Biologically, fatigue occurs as part of the sickness behavior response, a complex and automated behavior triggered by the activation of innate immunity and neuroinflammation. IL-1ß causes neuronal activation in the brain and subsequent fatigue. In addition to proinflammatory molecules, potential partners in the complex brain signaling of fatigue include downregulatory mechanisms for inflammation and cellular stress responses and the neuropeptide hypocretin-1. These mechanisms all become constantly activated in chronic conditions. Genetic studies indicate that fatigue may have evolved to enhance survival during infection and injury. SUMMARY: Fatigue is a major clinical problem. Finding the right treatment is challenging, as no specific options exist and only a few of the mechanisms contributing to fatigue are known. Because fatigue is generated in the brain, further studies should focus on proteomics and specific candidate proteins in cerebrospinal fluid. Studies on genetic variants, gene activation, and epigenetics are also required.


Asunto(s)
Encéfalo/inmunología , Síndrome de Fatiga Crónica/inmunología , Fatiga/inmunología , Inmunidad Innata/fisiología , Inflamación/inmunología , Animales , Encéfalo/metabolismo , Fatiga/metabolismo , Síndrome de Fatiga Crónica/metabolismo , Humanos , Inflamación/metabolismo , Neuronas/inmunología , Neuronas/metabolismo
11.
Ann Intern Med ; 170(7): 453-464, 2019 04 02.
Artículo en Inglés | MEDLINE | ID: mdl-30856652

RESUMEN

Background: Hashimoto disease is a chronic autoimmune thyroiditis. Despite adequate hormone substitution, some patients have persistent symptoms that may be the result of immunologic pathophysiology. Objective: To determine whether thyroidectomy improves symptoms in patients with Hashimoto thyroiditis who still have symptoms despite having normal thyroid gland function while receiving medical therapy. Design: Randomized trial. (ClinicalTrials.gov: NCT02319538). Setting: Secondary care hospital in Norway. Patients: 150 patients aged 18 to 79 years with persistent Hashimoto-related symptoms despite euthyroid status while receiving hormone replacement therapy and with serum antithyroid peroxidase (anti-TPO) antibody titers greater than 1000 IU/mL. Intervention: Total thyroidectomy or medical management with hormone substitution to secure euthyroid status in both groups. Measurements: The primary outcome was general health score on the Short Form-36 Health Survey (SF-36) at 18 months. Secondary outcomes were adverse effects of surgery, the other 7 SF-36 subscores, fatigue questionnaire scores, and serum anti-TPO antibody titers at 6, 12, and 18 months. Results: During follow-up, only the surgical group demonstrated improvement: Mean general health score increased from 38 to 64 points, for a between-group difference of 29 points (95% CI, 22 to 35 points) at 18 months. Fatigue score decreased from 23 to 14 points, for a between-group difference of 9.3 points (CI, 7.4 to 11.2 points). Chronic fatigue frequency decreased from 82% to 35%, for a between-group difference of 39 percentage points (CI, 23 to 53 percentage points). Median serum anti-TPO antibody titers decreased from 2232 to 152 IU/mL, for a between-group difference of 1148 IU/mL (CI, 1080 to 1304 IU/mL). In multivariable regression analyses, the adjusted treatment effects remained similar to the unadjusted effects. Limitation: Results are applicable only to a subgroup of patients with Hashimoto disease, and follow-up was limited to 18 months. Conclusion: Total thyroidectomy improved health-related quality of life and fatigue, whereas medical therapy did not. This improvement, along with concomitant elimination of serum anti-TPO antibodies, may elucidate disease mechanisms. Primary Funding Source: Telemark Hospital.


Asunto(s)
Enfermedad de Hashimoto/fisiopatología , Enfermedad de Hashimoto/terapia , Terapia de Reemplazo de Hormonas , Glándula Tiroides/fisiología , Tiroidectomía , Tiroxina/uso terapéutico , Adolescente , Adulto , Anciano , Anticuerpos/sangre , Quimioterapia Combinada , Fatiga/prevención & control , Femenino , Estudios de Seguimiento , Enfermedad de Hashimoto/inmunología , Enfermedad de Hashimoto/cirugía , Humanos , Yoduro Peroxidasa/inmunología , Masculino , Persona de Mediana Edad , Medición de Resultados Informados por el Paciente , Complicaciones Posoperatorias , Calidad de Vida , Tiroidectomía/efectos adversos , Triyodotironina/uso terapéutico , Adulto Joven
13.
Anal Chem ; 91(14): 9323-9329, 2019 07 16.
Artículo en Inglés | MEDLINE | ID: mdl-31260261

RESUMEN

Low levels of hypocretin-1 (Hcrt1) in cerebrospinal fluid (CSF) are associated with narcolepsy type 1 (NT1). Although immunoassays are prone to antibody batch differences, detection methods and variation between laboratories, the standard method for Hcrt1 measurement is a radioimmunoassay (RIA). Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) is an antibody- and radioactive free alternative for precise measurement of Hcrt1. We developed an LC-MS/MS method for measurement of Hcrt1 in CSF with automated sample preparation by solid-phase extraction (SPE). The LC-MS/MS method was compared with the RIA method for Hcrt1 detection. CSF samples from healthy subjects and NT1 patients was obtained by lumbar puncture. NT1 patients were diagnosed according to the minimal criteria by the International Classification of Sleep Disorders (ICSD). The LC-MS/MS method showed linearity across the range of calibrators and had a limit of detection (LOD) of 2.5 pg/mL and a limit of quantitation (LOQ) of 3.6 pg/mL. Comparison of the LC-MS/MS method with RIA revealed a 19 times lower level in healthy controls and 22 times lower level in NT1 patients with the LC-MS/MS method than with RIA. Bland-Altman analysis demonstrated agreement between the methods. These results question what is detected by RIA and strongly suggest that the physiological concentrations of the peptide are much lower than previously believed. LC-MS/MS proves to be an alternative for detection of Hcrt1 for diagnosis of narcolepsy.


Asunto(s)
Cromatografía Liquida/métodos , Orexinas/líquido cefalorraquídeo , Espectrometría de Masas en Tándem/métodos , Adulto , Secuencia de Aminoácidos , Humanos , Límite de Detección , Narcolepsia/líquido cefalorraquídeo , Narcolepsia/diagnóstico , Radioinmunoensayo , Reproducibilidad de los Resultados , Extracción en Fase Sólida
14.
J Neuroinflammation ; 16(1): 102, 2019 May 17.
Artículo en Inglés | MEDLINE | ID: mdl-31101054

RESUMEN

BACKGROUND: Fatigue is a common and sometimes debilitating phenomenon in primary Sjögren's syndrome (pSS) and other chronic inflammatory diseases. We aimed to investigate how IL-1 ß-related molecules and the neuropeptide hypocretin-1 (Hcrt1), a regulator of wakefulness, influence fatigue. METHODS: Hcrt1 was measured by radioimmunoassay (RIA) in cerebrospinal fluid (CSF) from 49 patients with pSS. Interleukin-1 receptor antagonist (IL-1Ra), IL-1 receptor type 2 (IL-1RII), IL-6, and S100B protein were measured by enzyme-linked immunosorbent assay (ELISA). Fatigue was rated by the fatigue visual analog scale (fVAS). RESULTS: Simple univariate regression and multiple regression analyses with fatigue as a dependent variable revealed that depression, pain, and the biochemical variable IL-1Ra had a significant association with fatigue. In PCA, two significant components were revealed. The first component (PC1) was dominated by variables related to IL-1ß activity (IL-1Ra, IL-1RII, and S100B). PC2 showed a negative association between IL-6 and Hcrt1. fVAS was then introduced as an additional variable. This new model demonstrated that fatigue had a higher association with the IL-1ß-related PC1 than to PC2. Additionally, a third component (PC3) became significant between low Hcrt1 concentrations and fVAS scores. CONCLUSIONS: The main findings of this study indicate a functional network in which several IL-1ß-related molecules in CSF influence fatigue in addition to the classical clinical factors of depression and pain. The neuropeptide Hcrt1 seems to participate in fatigue generation, but likely not through the IL-1 pathway.


Asunto(s)
Fatiga/líquido cefalorraquídeo , Fatiga/diagnóstico , Interleucina-1/líquido cefalorraquídeo , Orexinas/líquido cefalorraquídeo , Síndrome de Sjögren/líquido cefalorraquídeo , Síndrome de Sjögren/diagnóstico , Adulto , Anciano , Biomarcadores/líquido cefalorraquídeo , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad
16.
Rheumatol Int ; 39(6): 1083-1090, 2019 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-30923955

RESUMEN

Rituximab, an anti-CD20 monoclonal antibody causing selective B-cell depletion, is used for various systemic inflammatory and autoimmune diseases (SIADs). Long-term safety data on rituximab are limited. The objectives of this study were to evaluate the long-term safety and tolerability of rituximab treatment for SIADs. A retrospective, single-center observational study including all patients ≥ 16 years treated with rituximab for SIADs was performed. The electronic medical records were reviewed, and data concerning indication and duration of rituximab treatment, prior and concurrent immunosuppressive therapy, and adverse events such as infections requiring hospitalization, dysgammaglobulinemia and end organ damage, were collected. A total of 70 patients were included, with a median treatment duration of 54 months, ranging 30-138 months. The most common indications for rituximab treatment were granulomatosis with polyangiitis (22.9%), primary Sjögren's syndrome (20.0%) and systemic lupus erythematosus (14.3%). Infections and persistent dysgammaglobulinemia were the most common adverse events, occurring in 34.3% and 25.7%, respectively. A total of 64 infections were observed in 24 (34.3%) patients, including 1 case of fatal infection. Seventeen patients performed B-cell quantitation during the first 2 years following discontinuation, of which only four (19.0%) demonstrated B-cell reconstitution. End organ damage occurred in two patients, presenting as pyoderma gangrenosum and interstitial pneumonitis. No opportunistic infections were observed. Three patients died during the observational period, of which one was due to lethal infection. This study presents observational data with long treatment duration. It demonstrates that long-term rituximab treatment is relatively well tolerated, and that no cumulative side effects were observed.


Asunto(s)
Antirreumáticos/efectos adversos , Enfermedades Autoinmunes/tratamiento farmacológico , Disgammaglobulinemia/inducido químicamente , Infecciones/etiología , Inflamación/tratamiento farmacológico , Rituximab/administración & dosificación , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Quimioterapia Combinada , Femenino , Granulomatosis con Poliangitis/tratamiento farmacológico , Hospitalización , Humanos , Inmunosupresores/uso terapéutico , Enfermedades Pulmonares Intersticiales/inducido químicamente , Lupus Eritematoso Sistémico/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Piodermia Gangrenosa/inducido químicamente , Estudios Retrospectivos , Rituximab/uso terapéutico , Síndrome de Sjögren/tratamiento farmacológico , Factores de Tiempo , Adulto Joven
17.
Tidsskr Nor Laegeforen ; 139(8)2019 May 07.
Artículo en Noruego | MEDLINE | ID: mdl-31062556

RESUMEN

BACKGROUND: Uveitis and acute renal failure can be seen in various immune-mediated systemic diseases. Here we present a case of a young man with a rare inflammatory oculorenal syndrome. CASE REPORT: A man in his thirties was admitted with a constellation of fatigue, flank pain, weight loss and bilateral acute anterior uveitis. Laboratory tests showed anaemia, leukocytosis with eosinophilia, as well as elevated creatinine and C-reactive protein, and urine analyses demonstrated mild proteinuria. Work-up excluded sarcoidosis, Sjögren's syndrome, systemic lupus erythematosus, ANCA-associated vasculitides, Behçet disease, spondyloarthritis and infection. Renal biopsy showed severe tubulointerstitial nephritis. INTERPRETATION: Following exclusion of the abovementioned disorders, a diagnosis of tubulointerstitial nephritis and uveitis (TINU) syndrome was made. TINU syndrome is a rare inflammatory disorder which can be diagnosed in patients presenting with uveitis and tubulointerstitial nephritis after exclusion of other causes of similar oculorenal involvement.


Asunto(s)
Nefritis Intersticial/diagnóstico , Uveítis/diagnóstico , Adulto , Humanos , Masculino , Nefritis Intersticial/tratamiento farmacológico , Nefritis Intersticial/patología , Uveítis/tratamiento farmacológico , Uveítis/patología
18.
Scand J Gastroenterol ; 53(12): 1453-1458, 2018 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-30625276

RESUMEN

OBJECTIVE: The aim of the study was to investigate whether heat shock protein (HSP)90α plasma concentrations were associated with disease activity in patients with Crohn's disease. MATERIALS AND METHODS: This cross-sectional study included 53 patients who were newly diagnosed with Crohn's disease. Demographic data and disease distribution were recorded, and disease activity was rated using the Simple Endoscopic Score for Crohn's Disease (SES-CD) and the Harvey Bradshaw Index (HBI). Faecal calprotectin and plasma concentrations of CRP and HSP90α were measured. RESULTS: The median SES-CD was 7, and the median HSP90α level was 17.2 ng/mL. The HSP90α level was significantly correlated with SES-CD, CRP, and faecal calprotectin, but not with HBI. Linear regression analysis revealed that HSP90α was significantly associated with SES-CD (r2 = 0.27, p < .001) and with CRP (r2 = 0.18, p = .002). HSP90α concentrations were significantly higher in the 10 patients with the highest SES-CD scores compared to the 10 patients with the lowest SES-CD scores. CONCLUSIONS: Objective measures of disease activity and inflammation in Crohn's disease - SES-CD and CRP - were closely associated with HSP90α concentrations in plasma, suggesting that HSP90α may be a biomarker of Crohn's disease.


Asunto(s)
Proteína C-Reactiva/análisis , Enfermedad de Crohn/diagnóstico , Proteínas HSP90 de Choque Térmico/sangre , Complejo de Antígeno L1 de Leucocito/análisis , Adulto , Biomarcadores/análisis , Colonoscopía , Enfermedad de Crohn/sangre , Estudios Transversales , Heces/química , Femenino , Humanos , Modelos Lineales , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Adulto Joven
19.
Hum Mol Genet ; 24(2): 582-96, 2015 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-25205108

RESUMEN

Exploiting genotyping, DNA sequencing, imputation and trans-ancestral mapping, we used Bayesian and frequentist approaches to model the IRF5-TNPO3 locus association, now implicated in two immunotherapies and seven autoimmune diseases. Specifically, in systemic lupus erythematosus (SLE), we resolved separate associations in the IRF5 promoter (all ancestries) and with an extended European haplotype. We captured 3230 IRF5-TNPO3 high-quality, common variants across 5 ethnicities in 8395 SLE cases and 7367 controls. The genetic effect from the IRF5 promoter can be explained by any one of four variants in 5.7 kb (P-valuemeta = 6 × 10(-49); OR = 1.38-1.97). The second genetic effect spanned an 85.5-kb, 24-variant haplotype that included the genes IRF5 and TNPO3 (P-valuesEU = 10(-27)-10(-32), OR = 1.7-1.81). Many variants at the IRF5 locus with previously assigned biological function are not members of either final credible set of potential causal variants identified herein. In addition to the known biologically functional variants, we demonstrated that the risk allele of rs4728142, a variant in the promoter among the lowest frequentist probability and highest Bayesian posterior probability, was correlated with IRF5 expression and differentially binds the transcription factor ZBTB3. Our analytical strategy provides a novel framework for future studies aimed at dissecting etiological genetic effects. Finally, both SLE elements of the statistical model appear to operate in Sjögren's syndrome and systemic sclerosis whereas only the IRF5-TNPO3 gene-spanning haplotype is associated with primary biliary cirrhosis, demonstrating the nuance of similarity and difference in autoimmune disease risk mechanisms at IRF5-TNPO3.


Asunto(s)
Factores Reguladores del Interferón/genética , Lupus Eritematoso Sistémico/genética , beta Carioferinas/genética , Enfermedades Autoinmunes/genética , Teorema de Bayes , Estudios de Casos y Controles , Estudios de Cohortes , Proteínas de Unión al ADN/genética , Haplotipos , Humanos , Masculino , Polimorfismo de Nucleótido Simple , Regiones Promotoras Genéticas
20.
Scand J Gastroenterol ; 52(4): 420-424, 2017 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-28040992

RESUMEN

OBJECTIVE: Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) may be involved in the pathogenesis of inflammatory bowel disease. The aim was to investigate if TWEAK may reflect disease activity in inflammatory bowel disease. MATERIALS AND METHODS: In this cohort study, 139 consecutive patients with newly diagnosed and previously untreated inflammatory bowel disease - 95 with ulcerative colitis (UC) and 44 with Crohn's disease (CD) - underwent colonoscopy. Disease activity was assessed by the Mayo score and the Mayo endoscopic score (MES) for UC, or the Simple Endoscopic Score (SES) for CD. Serum C-reactive protein (CRP) and fecal calprotectin were measured in IBD patients, as were plasma TWEAK levels in patients and 85 healthy subjects. Associations between TWEAK levels and disease activity markers were explored. RESULTS: In the total IBD group, the median (interquartile range) TWEAK level was 430 pg/ml (109-6570), in UC 502 pg/ml (109-4547) and in CD patients 352 pg/ml (101-9179), respectively. Healthy subjects had a median (IQR) TWEAK of 307 pg/ml (63-3492). There were no significant differences in TWEAK levels between the total IBD group and healthy control subjects, nor between UC and CD, or between UC/CD and healthy subjects. Furthermore, we found no significant associations between Mayo scores, MES-UC, SES-CD, CRP, and fecal calprotectin with plasma TWEAK levels. CONCLUSIONS: Plasma TWEAK levels do not reflect disease activity or the grade of inflammation in patients with newly diagnosed inflammatory bowel disease. NCT01551563.


Asunto(s)
Colitis Ulcerosa/sangre , Enfermedad de Crohn/sangre , Factores de Necrosis Tumoral/sangre , Adolescente , Adulto , Anciano , Biomarcadores/sangre , Proteína C-Reactiva/análisis , Estudios de Casos y Controles , Colonoscopía , Citocina TWEAK , Heces/química , Femenino , Humanos , Complejo de Antígeno L1 de Leucocito/análisis , Modelos Lineales , Masculino , Persona de Mediana Edad , Noruega , Estudios Prospectivos , Índice de Severidad de la Enfermedad , Adulto Joven
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