RESUMEN

BACKGROUND: Juvenile Idiopathic Arthritis (JIA) is a complex autoimmune disease and the most common chronic rheumatological disease affecting children under the age of 16. The etiology of JIA remains poorly understood, but evidence suggests a significant genetic predisposition. METHODS: We analyzed a Swedish cohort of 329 JIA patients and 728 healthy adult controls using the Illumina OmniExpress array for genotyping. HLA alleles were imputed from GWAS data using the SNP2HLA algorithm. RESULTS: Case-control analysis yielded 12 SNPs with genome-wide significant association to JIA, all located on chromosome 6 within the MHC class II gene region. Notably, the top SNP (rs28421666) was located adjacent to HLA-DQA1 and HLA-DRB1. HLA-DRB1*08:01, HLA-DQA1*04:01, and HLA-DQB1*04:02 were the haplotypes most strongly associated with an increased risk of JIA in the overall cohort. When analyzing disease specific subtypes, these alleles were associated with oligoarthritis and RF-negative polyarthritis. Within the complex linkage disequilibrium of the HLA-DRB1-DQA1-DQB1 haplotype, our analysis suggests that HLA-DRB1*08 might be the primary allele linked to JIA susceptibility. The HLA-DRB1*11 allele group was also independently associated with JIA and specifically enriched in the oligoarthritis patient group. Additionally, our study revealed a significant correlation between antinuclear antibody (ANA) positivity and specific HLA alleles. The ANA-positive JIA group showed stronger associations with the HLA-DRB1-DQA1-DQB1 haplotype, HLA-DRB1*11, and HLA-DPB1*02, suggesting a potential connection between genetic factors and ANA production in JIA. Furthermore, logistic regression analysis reaffirmed the effects of HLA alleles, female sex, and lower age at onset on ANA positivity. CONCLUSIONS: This study identified distinct genetic associations between HLA alleles and JIA subtypes, particularly in ANA-positive patients. These findings contribute to a better understanding of the genetic basis of JIA and provide insights into the genetic control of autoantibody production in ANA-positive JIA patients. This may inform future classification and personalized treatment approaches for JIA, ultimately improving patient outcomes and management of this disease.

Asunto(s)

Anticuerpos Antinucleares , Artritis Juvenil , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple , Humanos , Artritis Juvenil/genética , Artritis Juvenil/inmunología , Suecia , Masculino , Femenino , Anticuerpos Antinucleares/sangre , Adolescente , Niño , Estudios de Casos y Controles , Estudios de Cohortes , Alelos , Haplotipos , Adulto , Estudio de Asociación del Genoma Completo , Genotipo , Cadenas alfa de HLA-DQ/genética , Cadenas HLA-DRB1/genética , Preescolar , Desequilibrio de Ligamiento

RESUMEN

The cytokine storm syndrome (CSS) associated with systemic juvenile idiopathic arthritis (sJIA) has widely been referred to as macrophage activation syndrome (MAS). In this chapter, we use the term sJIA-associated CSS (sJIA-CSS) when referring to this syndrome and use the term MAS when referencing publications that specifically report on sJIA-associated MAS.

Asunto(s)

Artritis Juvenil , Síndrome de Liberación de Citoquinas , Humanos , Artritis Juvenil/complicaciones , Artritis Juvenil/inmunología , Síndrome de Liberación de Citoquinas/etiología , Síndrome de Liberación de Citoquinas/inmunología , Síndrome de Activación Macrofágica/diagnóstico , Síndrome de Activación Macrofágica/etiología , Citocinas/metabolismo , Niño

RESUMEN

OBJECTIVES: To measure regulatory T cell (Treg) levels in the peripheral blood of children with juvenile idiopathic arthritis (JIA) and analyse the association of this measure with disease activity, quality of life, adjustment of treatment, and hospitalisation. METHODS: We conducted a two-phase study (cross-sectional and prospective), including consecutive children with a JIA diagnosis according to ILAR criteria. Our independent variables were Tregs, Th1, Th2, and cytokines in peripheral blood, and our dependent variables in the cross-sectional phase were arthritis category, JIA activity, and patient-reported outcomes. To test associations, we used Spearman's correlation coefficient and the Mann-Whitney U test. In the prospective phase, we explored the probability of treatment adjustment and hospitalisation for JIA during follow-up according to Tregs levels at baseline, using Cox proportional regression. RESULTS: Our sample included 87 participants (median age 11 years, 63.2% girls). Tregs were not associated with most variables of interest. However, we found that higher Tregs concentration was associated with lower erythrocyte sedimentation rate (ESR) and better subjective disease status and course, while higher IL-10 and TGF-ß levels were associated with lower ESR, less pain, and better subjective disease status We found no association between Tregs and treatment adjustments or hospitalisation. CONCLUSIONS: Higher baseline Treg levels in the peripheral blood of children with JIA may be associated with reduced disease activity and better quality of life, though were not informative on the inflammatory progression on the follow-up.

Asunto(s)

Artritis Juvenil , Calidad de Vida , Linfocitos T Reguladores , Humanos , Artritis Juvenil/sangre , Artritis Juvenil/inmunología , Niño , Femenino , Masculino , Linfocitos T Reguladores/inmunología , Estudios Transversales , Estudios Prospectivos , Adolescente , Sedimentación Sanguínea , Hospitalización/estadística & datos numéricos , Índice de Severidad de la Enfermedad , Preescolar

RESUMEN

Macrophage activation syndrome (MAS) is a life-threatening episode of hyperinflammation driven by excessive activation and expansion of T cells (mainly CD8) and hemophagocytic macrophages producing proinflammatory cytokines. MAS has been reported in association with almost every rheumatic disease, but it is by far most common in systemic juvenile idiopathic arthritis (SJIA). Clinically, MAS is similar to familial or primary hemophagocytic lymphohistiocytosis (pHLH), a group of rare autosomal recessive disorders linked to various genetic defects all affecting the perforin-mediated cytolytic pathway employed by NK cells and cytotoxic CD8 T lymphocytes. Decreased cytolytic activity in pHLH patients leads to prolonged survival of target cells associated with increased production of proinflammatory cytokines that overstimulate macrophages. The resulting cytokine storm is believed to be responsible for the frequently fatal multiorgan system failure seen in MAS. Whole exome sequencing as well as targeted sequencing of pHLH-associated genes in patients with SJIA-associated MAS demonstrated increased "burden" of rare protein-altering variants affecting the cytolytic pathway compared to healthy controls, suggesting that as in pHLH, genetic variability in the cytolytic pathway contributes to MAS predisposition. Functional studies of some of the novel variants have shown that even in a heterozygous state, their presence partially reduces cytolytic activity that may lead to increased cytokine production.

Asunto(s)

Artritis Juvenil , Síndrome de Activación Macrofágica , Humanos , Síndrome de Activación Macrofágica/genética , Síndrome de Activación Macrofágica/inmunología , Artritis Juvenil/genética , Artritis Juvenil/inmunología , Artritis Juvenil/complicaciones , Predisposición Genética a la Enfermedad , Células Asesinas Naturales/inmunología , Citocinas/genética , Citocinas/metabolismo , Linfohistiocitosis Hemofagocítica/genética , Linfohistiocitosis Hemofagocítica/inmunología , Macrófagos/inmunología , Macrófagos/metabolismo

RESUMEN

In the past two decades, there has been a great deal of work aimed to devise diagnostic guidelines, classification criteria, and diagnostic scores for cytokine storm syndromes (CSSs). The most notable effort has been the large-scale multinational study that led to the development of the 2016 classification criteria for macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (JIA). Future studies should scrutinize the validity of the proposed criteria, particularly in systemic JIA patients treated with biologics, in children with subtle or incomplete forms of MAS, and in patients with MAS complicating other rheumatologic disorders. More generic CSS criteria are also available but often lack sensitivity and specificity in a wide variety of patient populations and CSSs of different etiologies. The coronavirus disease 2019 (COVID-19)-related lung disease led to an evolution of the concept of a "cytokine storm." Emerging and unsolved challenges in the diagnosis of the different forms of CSSs highlight the need for diagnostic tools and well-established classification criteria to enable timely recognition and correct classification of patients.

Asunto(s)

COVID-19 , Síndrome de Liberación de Citoquinas , Humanos , COVID-19/inmunología , COVID-19/diagnóstico , COVID-19/complicaciones , Síndrome de Liberación de Citoquinas/inmunología , Síndrome de Liberación de Citoquinas/diagnóstico , Síndrome de Liberación de Citoquinas/etiología , Síndrome de Activación Macrofágica/diagnóstico , Síndrome de Activación Macrofágica/clasificación , Síndrome de Activación Macrofágica/inmunología , Artritis Juvenil/diagnóstico , Artritis Juvenil/clasificación , Artritis Juvenil/inmunología , Artritis Juvenil/tratamiento farmacológico , SARS-CoV-2/inmunología , Niño , Citocinas/metabolismo

RESUMEN

OBJECTIVE: Diagnosing juvenile idiopathic arthritis (JIA) is challenging. Our study aimed to investigate the clinical significance of anti-α-1,4-D-polygalacturonic acid (PGA) antibodies in JIA, focusing on their role in diagnosis and assessing disease activity. METHODS: In this prospective case-control study, we examined variations in serum levels of PGA-IgA and PGA-IgG among children with different types of JIA and healthy controls. Serum PGA-IgA and PGA-IgG levels were assessed concurrently in children with active and inactive JIA. RESULTS: This study included 126 patients diagnosed with JIA, 13 neonates, and 76 healthy children. Serum PGA-IgA and PGA-IgG levels were assessed, which revealed significant differences in PGA-IgA levels between various JIA subtypes and controls. An analysis of PGA-IgA levels in various JIA states revealed a statistically significant difference. Receiver operating characteristic (ROC) analysis demonstrated the robust predictive capability of PGA-IgA, with an AUC of 0.879 (p < 0.001), along with a specificity of 0.842 and sensitivity of 0.848. CONCLUSION: Increased levels of anti-PGA antibodies, particularly PGA-IgA, were significantly associated with JIA. PGA-IgA may serve as a sensitive biomarker for disease activity in JIA and could potentially aid in the diagnosis of JIA. Key Points • This study found a significant correlation between blood levels of PGA-IgA and juvenile idiopathic arthritis (JIA), which may provide valuable diagnostic insights. • PGA-IgA shows potential as a sensitive biomarker for the assessment of disease activity in JIA patients, helping to determine disease activity.

Asunto(s)

Artritis Juvenil , Biomarcadores , Humanos , Artritis Juvenil/sangre , Artritis Juvenil/inmunología , Artritis Juvenil/diagnóstico , Femenino , Masculino , Biomarcadores/sangre , Niño , Estudios de Casos y Controles , Preescolar , Estudios Prospectivos , Adolescente , Inmunoglobulina G/sangre , Inmunoglobulina A/sangre , Pectinas/inmunología , Curva ROC , Autoanticuerpos/sangre , Lactante , Recién Nacido , Sensibilidad y Especificidad

RESUMEN

We review the abnormal bone turnover that is the basis of idiopathic inflammatory or rheumatoid arthritis and bone loss, with emphasis on Tumor Necrosis Factor-alpha (TNFα)-related mechanisms. We review selected data on idiopathic arthritis in juvenile human disease, and discuss mouse models focusing on induction of bone resorbing cells by TNFα and Receptor Activator of Nuclear Factor kappa B Ligand (RANKL). In both humans and animal models, macrophage-derived cells in the joint, particularly in the synovium and periosteum, degrade bone and cartilage. Mouse models of rheumatoid arthritis share with human disease bone resorbing cells and strong relation to TNFα expression. In humans, differences in therapy and prognosis of arthritis vary with age, and results from early intervention for inflammatory cytokines in juvenile patients are particularly interesting. Mechanisms that contribute to inflammatory arthritis reflect, in large part, inflammatory cytokines that play minor roles in normal bone turnover. Changes in inflammatory cytokines, particularly TNFα, are many times larger, and presented in different locations, than cytokines that regulate normal bone turnover. Recent data from in vitro and mouse models include novel mechanisms described in differentiation of bone resorbing cells in inflammatory arthritis dependent on the Transient Receptor Potential Channel (TRPC) family of calcium channels. Low-molecular weight (MW) inhibitors of TRPC channels add to their potential importance. Associations with inflammatory arthritis unrelated to TNFα are briefly summarized as pointing to alternative mechanisms. We suggest that early detection and monoclonal antibodies targeting cytokines mediating disease progression deserves emphasis.

Asunto(s)

Artritis Juvenil , Modelos Animales de Enfermedad , Factor de Necrosis Tumoral alfa , Animales , Artritis Juvenil/metabolismo , Artritis Juvenil/inmunología , Humanos , Factor de Necrosis Tumoral alfa/metabolismo , Ratones , Remodelación Ósea , Ligando RANK/metabolismo , Osteoclastos/metabolismo

RESUMEN

Introduction: Polyarticular juvenile idiopathic arthritis (pJIA) is a childhood-onset autoimmune disease. Immune cells contribute to persistent inflammation observed in pJIA. Despite the crucial role of monocytes in arthritis, the precise involvement of classical monocytes in the pathogenesis of pJIA remains uncertain. Here, we aimed to uncover the transcriptomic patterns of classical monocytes in pJIA, focusing on their involvement in disease mechanism and heterogeneity. Methods: A total of 17 healthy subjects and 18 premenopausal women with pJIA according to ILAR criteria were included. Classical monocytes were isolated, and RNA sequencing was performed. Differential expression analysis was used to compare pJIA patients and healthy control group. Differentially expressed genes (DEGs) were identified, and gene set enrichment analysis (GSEA) was performed. Using unsupervised learning approach, patients were clustered in two groups based on their similarities at transcriptomic level. Subsequently, these clusters underwent a comparative analysis to reveal differences at the transcriptomic level. Results: We identified 440 DEGs in pJIA patients of which 360 were upregulated and 80 downregulated. GSEA highlighted TNF-α and IFN-γ response. Importantly, this analysis not only detected genes targeted by pJIA therapy but also identified new modulators of immuno-inflammation. PLAUR, IL1B, IL6, CDKN1A, PIM1, and ICAM1 were pointed as drivers of chronic hyperinflammation. Unsupervised learning approach revealed two clusters within pJIA, each exhibiting varying inflammation levels. Conclusion: These findings indicate the pivotal role of immuno-inflammation driven by classical monocytes in pJIA and reveals the existence of two subclusters within pJIA, regardless the positivity of rheumatoid factor and anti-CCP, paving the way to precision medicine.

Asunto(s)

Artritis Juvenil , Perfilación de la Expresión Génica , Inflamación , Monocitos , Transcriptoma , Adulto , Niño , Femenino , Humanos , Anticuerpos Antiproteína Citrulinada , Artritis Juvenil/clasificación , Artritis Juvenil/genética , Artritis Juvenil/inmunología , Artritis Juvenil/patología , Estudios de Casos y Controles , Enfermedad Crónica , Análisis por Conglomerados , Inflamación/genética , Inflamación/inmunología , Inflamación/patología , Mediadores de Inflamación/inmunología , Interferón gamma/inmunología , Monocitos/inmunología , Monocitos/metabolismo , Fenotipo , Medicina de Precisión , Premenopausia , Unión Proteica , Mapas de Interacción de Proteínas , Factor Reumatoide , Análisis de Secuencia de ARN , Transcriptoma/genética , Factor de Necrosis Tumoral alfa/inmunología , Aprendizaje Automático no Supervisado

RESUMEN

Recurrent exposures to a pathogenic antigen remodel the CD8+ T cell compartment and generate a functional memory repertoire that is polyclonal and complex. At the clonotype level, the response to the conserved influenza antigen, M158-66 has been well characterized in healthy individuals, but not in patients receiving immunosuppressive therapy or with aberrant immunity, such as those with juvenile idiopathic arthritis (JIA). Here we show that patients with JIA have a reduced number of M158-66 specific RS/RA clonotypes, indicating decreased clonal richness and, as a result, have lower repertoire diversity. By using a rank-frequency approach to analyze the distribution of the repertoire, we found several characteristics of the JIA T cell repertoire to be akin to repertoires seen in healthy adults, including an amplified RS/RA-specific antigen response, representing greater clonal unevenness. Unlike mature repertoires, however, there is more fluctuation in clonotype distribution, less clonotype stability, and more variable IFNy response of the M158-66 specific RS/RA clonotypes in JIA. This indicates that functional clonal expansion is altered in patients with JIA on immunosuppressive therapies. We propose that the response to the influenza M158-66 epitope described here is a general phenomenon for JIA patients receiving immunosuppressive therapy, and that the changes in clonal richness and unevenness indicate a retarded and uneven generation of a mature immune response.

Asunto(s)

Artritis Juvenil , Linfocitos T CD8-positivos , Vacunas contra la Influenza , Gripe Humana , Humanos , Artritis Juvenil/inmunología , Linfocitos T CD8-positivos/inmunología , Vacunas contra la Influenza/inmunología , Gripe Humana/inmunología , Femenino , Niño , Masculino , Adolescente , Vacunación , Células Clonales/inmunología , Preescolar , Memoria Inmunológica , Adulto Joven

RESUMEN

OBJECTIVE: The objective is to characterize transcriptomic profiles and immune cell composition and distribution in juvenile idiopathic arthritis (JIA) synovial biopsies, assess for associations of these features with clinical parameters, and compare JIA and rheumatoid arthritis (RA) synovial features. METHODS: RNA sequencing (RNASeq) was performed on 24 samples, with pathway analysis and inference of relative abundance of immune cell subsets based on gene expression data. Two multiplex fluorescence immunohistochemistry (IHC) panels were performed on 28 samples (including 13 on which RNASeq was performed), staining for CD206- classical and CD206+ nonclassical macrophages, and CD8+ and CD4+ T and B lymphocytes. Data were compared to a published series of early RA synovial biopsies. RESULTS: Pathway analysis of the most variably expressed genes (n = 339) identified a B and plasma cell signature as the main driver of heterogeneity in JIA synovia, with strong overlap between JIA and RA synovitis. Multiplex IHC confirmed heterogeneity of immune cell infiltration. M1-like macrophage-rich synovial lining was associated with greater lining hypertrophy and higher (CD45+) pan-immune cell and CD8+ T cell infiltration. CONCLUSION: Our study indicates significant similarities between JIA and RA synovitis. Similar to RA, JIA synovia may be broadly categorized into two groups: (1) those with an inflammatory/adaptive immune transcriptomic signature, M1-like macrophage and CD8+ T cell infiltration, and thicker, M1-like macrophage-rich synovial lining, and (2) those with an M2-like macrophage transcriptomic signature, greater M2/M1-like macrophage ratios, and thinner, M2-like macrophage-rich synovial lining. Synovial features were not significantly associated with clinical parameters, likely because of group size and heterogeneity.

Asunto(s)

Artritis Juvenil , Artritis Reumatoide , Linfocitos B , Macrófagos , Membrana Sinovial , Humanos , Artritis Juvenil/patología , Artritis Juvenil/inmunología , Membrana Sinovial/patología , Membrana Sinovial/inmunología , Artritis Reumatoide/patología , Artritis Reumatoide/inmunología , Artritis Reumatoide/genética , Macrófagos/patología , Macrófagos/inmunología , Biopsia , Masculino , Femenino , Niño , Linfocitos B/patología , Linfocitos B/inmunología , Transcriptoma , Adolescente , Linfocitos T CD8-positivos/patología , Linfocitos T CD8-positivos/inmunología , Sinovitis/patología , Sinovitis/inmunología , Sinovitis/genética , Células Plasmáticas/patología , Células Plasmáticas/inmunología , Inmunohistoquímica , Linfocitos T CD4-Positivos/patología , Linfocitos T CD4-Positivos/inmunología

RESUMEN

INTRODUCTION: Systemic juvenile idiopathic arthritis (sJIA) is a severe inflammatory condition with onset in childhood. It is sporadic, but elements of its stereotypical innate immune responses are likely genetically encoded by both common variants with small effect sizes and rare variants with larger effects. AREAS COVERED: Genomic investigations have defined the unique genetic architecture of sJIA. Identification of the class II HLA locus as the strongest sJIA risk factor for the first time brought attention to T lymphocytes and adaptive immune mechanisms in sJIA. The importance of the human leukocyte antigen (HLA) locus was reinforced by recognition that HLA-DRB1*15 alleles are strongly associated with development of drug reactions and sJIA-associated lung disease (sJIA-LD). At the IL1RN locus, genetic variation relates to both risk of sJIA and may also predict non-response to anakinra. Finally, rare genetic variants may have critical roles in disease complications, such as homozygous LACC1 mutations in families with an sJIA-like illness, and hemophagocytic lymphohistiocytosis (HLH) gene variants in some children with macrophage activation syndrome (MAS). EXPERT OPINION: Genetic and genomic analysis of sJIA holds great promise for both basic discovery of the course and complications of sJIA, and may help guide personalized medicine and therapeutic decision-making.

Asunto(s)

Artritis Juvenil , Genómica , Humanos , Artritis Juvenil/genética , Artritis Juvenil/inmunología , Predisposición Genética a la Enfermedad , Niño , Cadenas HLA-DRB1/genética , Proteína Antagonista del Receptor de Interleucina 1/genética , Proteína Antagonista del Receptor de Interleucina 1/uso terapéutico , Síndrome de Activación Macrofágica/genética , Síndrome de Activación Macrofágica/inmunología , Inmunidad Innata/genética

Asunto(s)

Artritis Juvenil , Micropartículas Derivadas de Células , Interleucina-1beta , Macrófagos , Humanos , Artritis Juvenil/inmunología , Artritis Juvenil/metabolismo , Interleucina-1beta/metabolismo , Micropartículas Derivadas de Células/metabolismo , Micropartículas Derivadas de Células/inmunología , Macrófagos/inmunología , Macrófagos/metabolismo , Biomarcadores , Trombosis/inmunología , Trombosis/metabolismo , Inflamación/inmunología , Inflamación/metabolismo

RESUMEN

Juvenile Idiopathic Arthritis (JIA) is currently the most common chronic rheumatic disease in children. It is known to have no single identity, but a variety of diagnoses. Under-diagnosis is a barrier to early treatment and reduced complications of the disease. Other immune-mediated diseases may coexist in the same patient, making research in this area relevant. The main objective was to analyse whether links could be established between the molecular basis of JIA and other immune-mediated diseases. Early diagnosis may benefit patients with JIA, which in most cases goes undetected, leading to under-diagnosis, which can have a negative impact on children affected by the disease as they grow up. METHODS: We performed a PRISMA systematic review focusing on immune molecules present in different autoimmune diseases. RESULTS: A total of 13 papers from different countries dealing with the molecular basis of JIA and other immune diseases were evaluated and reviewed. CONCLUSIONS: Most of the autoimmune diseases analysed responded to the same group of drugs. Unfortunately, the reason for the under-diagnosis of these diseases remains unknown, as no evidence has been found to correlate the immunomolecular basis with the under-diagnosis of these immune-mediated diseases. The lack of information in this area means that further research is needed in order to provide a sound basis for preventing the development of immune-mediated diseases, especially in children, and to improve their quality of life through early diagnosis and treatment.

Asunto(s)

Artritis Juvenil , Enfermedades Autoinmunes , Artritis Juvenil/inmunología , Artritis Juvenil/genética , Artritis Juvenil/diagnóstico , Humanos , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/genética , Niño

Asunto(s)

Anticuerpos Antinucleares , Artritis Juvenil , Uveítis Anterior , Humanos , Artritis Juvenil/tratamiento farmacológico , Artritis Juvenil/epidemiología , Artritis Juvenil/inmunología , Progresión de la Enfermedad , Alemania/epidemiología , Factores de Riesgo , Uveítis , Uveítis Anterior/epidemiología , Uveítis Anterior/inmunología

RESUMEN

We have read the article entitled "Similarities in clinical course and outcome between juvenile idiopathic arthritis (JIA)-associated and ANA-positive idiopathic anterior uveitis: data from a population-based nationwide study in Germany" by Heiligenhaus et al. While we appreciate the work conducted by the authors, we have several comments we would like to address. First, the follow-up interval of 2 years is too short to conclude that the clinical course between two chronic pathologies is not significantly different. Second, remission status was determined by uveitis inactivity during the 2-year follow-up visit without any mention of flare frequency or length of remission, which is not a reliable measure of uveitis control. Third, ANA-positive idiopathic anterior uveitis is not a classification with a distinct clinical phenotype, and additional reports of serologic investigations would have been helpful.

Asunto(s)

Artritis Juvenil , Uveítis Anterior , Uveítis , Humanos , Artritis Juvenil/diagnóstico , Artritis Juvenil/epidemiología , Artritis Juvenil/inmunología , Uveítis Anterior/diagnóstico , Uveítis Anterior/epidemiología , Uveítis/inmunología , Alemania/epidemiología , Progresión de la Enfermedad

RESUMEN

OBJECTIVES: To study the expression levels of CD4+NKG2D+ T cells and NKG2D soluble ligands, the soluble MHC class I chain-related molecules A and B (sMICA/sMICB) in the active stage and stable stage of juvenile idiopathic arthritis (JIA) and their role in the disease activity of JIA. METHODS: Nineteen children with systemic JIA and 20 children with articular JIA who were diagnosed in Children's Hospital of Chongqing Medical University from November 2019 to December 2021 were enrolled in this prospective study. Six healthy children were enrolled as the control group. After peripheral blood samples were collected, ELISA was used to measure the levels of sMICA and sMICB, and flow cytometry was used to measure the percentage of CD4+NKG2D+ T cells. Systemic Juvenile Arthritis Disease Activity Score-27 (sJADAS-27)/Juvenile Arthritis Disease Activity Score-27 (JADAS-27) was used to evaluate the disease activity in children with JIA. The Pearson correlation analysis and the receiver operating characteristic (ROC) curve were used to assess the role of CD4+NKG2D+ T cells, sMICA and sMICB in the disease activity of JIA. RESULTS: The active systemic JIA and active articular JIA groups had a significant increase in the percentage of CD4+NKG2D+ T cells compared with the control group and their corresponding inactive JIA group (P<0.05). The JIA groups had significantly higher levels of sMICA and sMICB than the control group (P<0.05), and the active articular JIA group had a significantly higher level of sMICB than the stable articular JIA group (P<0.05). In the children with JIA, the percentage of CD4+NKG2D+ T cells and the levels of sMICA and sMICB were positively correlated with sJADAS-27/JADAS-27 disease activity scores (P<0.05). The ROC curve analysis showed that sMICB had an area under the curve of 0.755 in evaluating the disease activity of JIA, with a specificity of 0.90 and a sensitivity of 0.64. CONCLUSIONS: The percentage of CD4+NKG2D+ T cells and the levels of sMICA and sMICB increase in children with JIA compared with healthy children and are positively correlated with the disease activity of JIA, suggesting that CD4+NKG2D+ T cells and NKG2D ligands can be used as potential biomarkers for evaluating the disease activity of JIA.

Asunto(s)

Artritis Juvenil , Subfamilia K de Receptores Similares a Lectina de Células NK , Niño , Humanos , Artritis Juvenil/inmunología , Artritis Juvenil/patología , Ligandos , Estudios Prospectivos , Linfocitos T/metabolismo , Linfocitos T/patología

RESUMEN

OBJECTIVE: Systemic juvenile idiopathic arthritis (JIA) is a systemic inflammatory disease with childhood onset. Systemic JIA is associated with neutrophilia, including immature granulocytes, potentially driven by the growth factor granulocyte-colony stimulating factor (G-CSF). This study was undertaken to investigate the role of G-CSF in the pathology of systemic JIA. METHODS: Injection of Freund's complete adjuvant (CFA) in BALB/c mice induces mild inflammation and neutrophilia in wild-type (WT) mice and a more pronounced disease, reminiscent to that of JIA patients, in interferon-γ-knockout (IFNγ-KO) mice. Extramedullary myelopoiesis was studied in CFA-immunized mice by single-cell RNA sequencing, and the effect of G-CSF receptor (G-CSFR) blockage on neutrophil development and systemic JIA pathology was evaluated. Additionally, plasma G-CSF levels were measured in patients. RESULTS: Both in systemic JIA patients and in a corresponding mouse model, plasma G-CSF levels were increased. In the mouse model, we demonstrated that G-CSF is responsible for the observed neutrophilia and extramedullary myelopoiesis and the induction of immature neutrophils and myeloid-derived suppressor-like cells. Administration of a G-CSFR antagonizing antibody blocked the maturation and differentiation of neutrophils in CFA-immunized mice. In IFNγ-KO mice, treatment was associated with almost complete inhibition of arthritis due to reduced neutrophilia and osteoclast formation. Disease symptoms were ameliorated, but slight increases in interleukin-6 (IL-6), tumor necrosis factor, and IL-17 were detected upon G-CSFR inhibition in the IFNγ-KO mice, and were associated with mild increases in weight loss, tail damage, and immature red blood cells. CONCLUSION: We describe the role of G-CSF in a mouse model of systemic JIA and suggest an important role for G-CSF-induced myelopoiesis and neutrophilia in regulating the development of arthritis.

Asunto(s)

Artritis Juvenil , Factor Estimulante de Colonias de Granulocitos , Mielopoyesis , Animales , Artritis Juvenil/inmunología , Modelos Animales de Enfermedad , Factor Estimulante de Colonias de Granulocitos/inmunología , Interferón gamma/genética , Ratones , Ratones Endogámicos BALB C , Neutrófilos/metabolismo

RESUMEN

BACKGROUND: An association of different autoimmune diseases is suspected. In juvenile idiopathic arthritis (JIA), only few and partially conflicting data on the co-existence of other autoimmune disorders are available. The prevalence of autoantibodies in patients with JIA in Germany is not known. METHODS: Samples from 499 patients (median age at time of blood collection 11 years, median disease duration 4.4 years) in the prospective, multicenter inception cohort of children newly diagnosed with JIA (ICON-JIA) were analysed for the presence of anti-thyroid antibodies, celiac disease-specific antibodies (anti-tTG IgA, anti-tTG IgG), and connective tissue disease-associated antibodies (CTD-screen). RESULTS: A total of 76 (15.2%) patients had either clinically diagnosed autoimmune comorbidity or elevated autoantibodies. Of 21 patients with clinical autoimmune comorbidity, only 8 were also serologically positive at the time of testing, while 55 patients had autoantibodies without clinical diagnosis. Thus, 63 patients (12.6%) had at least one elevated autoantibody. Antibodies against thyroglobulin were found in 3% and against thyreoperoxidase in 4% of the samples. TSH receptor antibodies could not be detected in any of the 499 patients. Tissue transglutaminase antibodies were elevated in 0.4% of the patients. A positive screen for CTD-specific antinuclear antibodies was found in 7%, but only rarely specific antibodies (anti-dsDNA 1.4%, anti-SS-A and -SS-B 0.2% each, anti-CENP-B 0.4%) were confirmed. CONCLUSIONS: In our study, a specific correlation between JIA and other autoimmune phenomena could not be confirmed. The lack of well-matched control groups makes interpretation challenging. Further data need to corroborate the suspected increased risk of developing other autoimmune phenomena in JIA patients.

Asunto(s)

Artritis Juvenil/sangre , Artritis Juvenil/inmunología , Autoanticuerpos/sangre , Adolescente , Niño , Femenino , Alemania , Humanos , Estudios Longitudinales , Masculino , Prevalencia , Estudios Prospectivos

RESUMEN

OBJECTIVE: Antinuclear antibody (ANA)-positive juvenile idiopathic arthritis (JIA) is characterized by synovial B cell hyperactivity, but the precise role of CD4+ T cells in promoting local B cell activation is unknown. This study was undertaken to determine the phenotype and function of synovial CD4+ T cells that promote aberrant B cell activation in JIA. METHODS: Flow cytometry was performed to compare the phenotype and cytokine patterns of PD-1high CD4+ T cells in the synovial fluid (SF) of patients with JIA and T follicular helper cells in the tonsils of control individuals. TCRVB next-generation sequencing was used to analyze T cell subsets for signs of clonal expansion. The functional impact of these T cell subsets on B cells was examined in cocultures in vitro. RESULTS: Multidimensional flow cytometry revealed the expansion of interleukin-21 (IL-21) and interferon-γ (IFNγ)-coexpressing PD-1high CXCR5-HLA-DR+CD4+ T cells that accumulate in the joints of ANA-positive JIA patients. These T cells exhibited signs of clonal expansion with restricted T cell receptor clonotypes. The phenotype resembled peripheral T helper (Tph) cells with an extrafollicular chemokine receptor pattern and high T-bet and B lymphocyte-induced maturation protein 1 expression, but low B cell lymphoma 6 expression. SF Tph cells, by provision of IL-21 and IFNy, skewed B cell differentiation toward a CD21low/- CD11c+ phenotype in vitro. Additionally, SF Tph cell frequencies correlated with the appearance of SF CD21low/- CD11c+CD27-IgM- double-negative (DN) B cells in situ. CONCLUSION: Clonally expanded CD4+ Tph cells accumulate in the joints of ANA-positive JIA patients and, in particular, promote CD21low/- CD11c+ DN B cell differentiation. The expansion of Tph cells and DN B cells might reflect the autoimmune response in the joints of ANA-positive JIA patients.

Asunto(s)

Anticuerpos Antinucleares , Artritis Juvenil/inmunología , Linfocitos B/inmunología , Linfocitos T CD4-Positivos/inmunología , Articulaciones/citología , Receptor de Muerte Celular Programada 1/inmunología , Receptores CXCR5/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Diferenciación Celular , Humanos , Activación de Linfocitos

RESUMEN

Systemic JIA (SJIA) is distinguished from other forms of JIA by the prevalence of the severe, life-threatening complications macrophage activation syndrome (SJIA-MAS) and lung disease (SJIA-LD). Alternative therapeutics are urgently needed, as disease pathogenesis diverges from what is observed in SJIA, and currently available biologics are insufficient. SJIA-MAS, defined by a cytokine storm and dysregulated proliferation of T-lymphocytes, and SJIA-LD which presents with lymphocytic interstitial inflammation and pulmonary alveolar proteinosis, are both thought to be driven by IFNs, in particular the type II IFN-γ. Involvement of IFNs and a possible crosstalk of type I IFNs with existing biologics indicate a distinct role for the JAK-STAT signalling pathway in the pathogenesis of SJIA-MAS and SJIA-LD. Here, we review this role of JAK-STATs and IFNs in SJIA complications and discuss how new insights of ongoing research are shaping future therapeutic advances in the form of JAK inhibitors and antibodies targeting IFNs.

Asunto(s)

Quinasas Janus/metabolismo , Factores de Transcripción STAT/metabolismo , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Neutralizantes/uso terapéutico , Artritis Juvenil/tratamiento farmacológico , Artritis Juvenil/inmunología , Humanos , Interferones/fisiología , Inhibidores de las Cinasas Janus/uso terapéutico , Síndrome de Activación Macrofágica/tratamiento farmacológico , Transducción de Señal