Mitochondrial transfer and implications for muscle function in idiopathic inflammatory myopathies.

Impairment in cellular bioenergetics as either the cause, consequence, or major contributor of tissue damage has drawn increasing scientific curiosity across aging and chronic health conditions, with mitochondrial dysfunction emerging as a central mechanism in the pathogenesis of a variety of inflammatory and degenerative disorders. Beyond bioenergetics, mitochondria play critical regulatory roles in programmed cell death of dysfunctional/defective cells as well as in metabolite synthesis and metabolic signalling. Further, extra-cellular exposure to fragmentation of injured mitochondria is associated with incitement of systemic and organ-based inflammation. Thus, mitochondrial function has recently drawn intense, spectral scientific interest as an integral component across maladies.In muscle, mitochondrial dysfunction is clinically associated with atrophy and diminished endurance. Direct myo-histopathological evidence characterising loss of mitochondrial integrity as a hallmark of muscle compromise was first noticed in inclusion body myositis (IBM). This was followed by the discovery of multiple deletions in mitochondrial DNA in sarcopenia, IBM, and other inflammatory myopathies, like dermatomyositis. Though fraught with bioethical considerations, the transplant technology of mitochondrial transfer is swiftly gaining prominence in cellular biology and muscle physiology to remediate mitochondrial diminution and dysfunction. Assembling seminal works and recent developments, this review ventures into the rapidly evolving landscape of mitochondrial transfer, focusing on its implications on muscle function, and offers an integrated perspective on the potential roles of mitochondrial transfer and its implications for preserving and restoring muscle health. Presented here is a consolidated viewpoint on mitochondrial transfer in idiopathic inflammatory myopathies.

Late-Onset Autoimmune Lymphoproliferative Syndrome in a Costa Rican Woman.

Autoimmune lymphoproliferative syndrome (ALPS) is a primary immune regulatory disorder (PIRD). This disease usually develops during childhood. However, atypically, some cases may have their onset in adulthood. We report the case of a 44-year-old woman with a history of autoimmune hemolytic anemia at 33 years old. The patient presented due to asthenia and a large, painful lymph node in the left axillary region for the last four months. Enlargement of the axillary and inguinal lymph nodes was found by mammography, breast, and abdominal ultrasounds. An excisional biopsy of the axillary lymph node conglomerate did not document immunophenotypical alterations of T or B lymphocytes but showed progressive transformation of germinal centers with reactive follicular hyperplasia. The lymph node cytometry did not show a malignant phenotype. The immunological work-up documented IgG and IgA hypergammaglobulinemia and slightly decreased IgM; the B cell immunophenotype documented a slight increase in CD21low B cells and decreased memory B cells. The blood count was normal. The T cell compartment evidenced 27% CD3+/αß+/γδ-/CD4-/CD8- of the total T CD3+ cells and 15% of the total lymphocytes. A pathogenic heterozygous variant in the FAS gene, exon 9, c.785T>A (p.Ile262Asn), was documented. This variant has not been previously described. This case highlights the importance of considering the diagnosis of ALPS even in adulthood. Genetic conditions such as incomplete penetrance or variable expressivity that depend on factors that are not entirely clear in ALPS, such as epigenetics and environmental factors, among others, could generate the onset of this disease in adulthood in a smaller number of patients.

The emerging role of Growth Differentiation Factor 15 as a potential disease biomarker in juvenile dermatomyositis.

OBJECTIVE: We aimed to investigate the potential of Growth Differentiation Factor 15 (GDF-15) as a novel biomarker for disease activity in Juvenile Dermatomyositis (JDM). METHODS: We recruited children with juvenile myositis including juvenile dermatomyositis (n = 77), polymyositis (n = 6), and healthy controls (n = 22). GDF-15 levels in plasma were measured using ELISA. Statistical analyses were performed using non-parametric tests. RESULTS: Levels of GDF-15 were significantly elevated in JDM compared with healthy controls (p< 0.001). GDF-15 levels exhibited strong positive correlations with disease activity scores, including the Disease Activity Score (DAS) total score, DAS skin score, DAS muscle score, and Childhood Myositis Assessment Scale (CMAS). Additionally, GDF-15 levels could differentiate between active disease and remission based on the Physician Global Assessment of muscle score. Positive correlations were observed between levels of GDF-15 and creatine kinase, neopterin, and nailfold end row loops, indicating the potential involvement of GDF-15 in muscle damage, immune activation, and vascular pathology. ROC curve analysis showed GDF-15 to be more effective in assessing disease activity in JDM than creatine kinase (AUC 0.77, p= 0.001 and AUC 0.6369, p= 0.0738, respectively). CONCLUSION: GDF-15 may serve as a valuable biomarker for assessing disease activity in JDM. It exhibits better sensitivity and specificity than creatine kinase, and the levels correlate with various disease activity scores and functional measures. GDF-15 may provide valuable information for treatment decision-making and monitoring disease progression in JDM.

The Emerging Role of Mitochondrial Dysfunction in the Pathogenesis of Idiopathic Inflammatory Myopathies.

Increasing evidence points towards mitochondria as crucial players in the initiation and progression of auto-immune and degenerative disorders, to which impaired cell metabolism is but a facet of the subjacent etiopathogenesis. This review aims to introduce the reader to essential concepts of mitochondrial abnormalities in idiopathic inflammatory myopathy (IIM), underscoring inclusion-body myositis and dermatomyositis. Far surpassing the initial simplistic view of being responsible for energy generation, mitochondria have gathered attention regarding their role in inflammatory processes, being able to fuel autoimmunity, as shown by the presence of anti-mitochondrial antibodies (AMAs) in up to 10% of IIM patients. As cellular respiration takes place, mitochondrial metabolites might help to shape the pro-inflammatory milieu in affected muscle, beyond generating reactive oxygen species, which are well-recognized inducers of damage-associated molecular patterns. A series of mitochondrial components might facilitate the sterile activation of pro-inflammatory cells and the production of several cytokines responsible for enhancing auto-immune responses. Marked variation in the mitochondrial genome has also been reported in IIM patients. As such, we summarize key historical and recent advances linking aberrations and instabilities of mitochondrial DNA to impaired muscle function. Besides discussing mitochondrial dysfunction as an essential part of IIM development, we also highlight possible associations between presence of AMAs and a particular phenotype of IIM, with its own characteristic clinical and radiological pattern. Finally, we present promising treatment approaches targeting mitochondria, while briefly discussing experimental models for gaining deeper insight into the disease process, and ultimately leading to novel drug development.

Glucose and leukocyte esterase levels are possible biomarkers for bacterial septic arthritis.

OBJECTIVE: The objective of the study was to determine the added value of synovial fluid (SF) glucose levels and other biochemical parameters as possible biomarkers of bacterial septic arthritis (SA). MATERIALS AND METHODS: We prospectively examined adult patients with SA. As a control group, adults with uninfected joints were enrolled. SF samples were obtained, and microbiological analyses were made. SF glucose levels, pH, and leukocyte esterase were measured using a glucometer and colorimetric test strips. Blood samples were collected from both groups to determine glucose levels. RESULTS: We included eight subjects with knee ligaments lesions, six with meniscus lesions, and five with osteoarthritis as the control group, as well as 20 patients with SA. SF culture was positive in 60%. SF glucose levels from patients were lower than the controls (p = 0.0018) with the lowest concentration in patients with a positive culture (p = 0.0004). Blood and SF glucose concentration from the positive culture patients were compared (p < 0.0001). Leukocyte esterase presented the highest values in patients with a positive culture (p < 0.0001) and a more acidic pH was found compared to the control group (p < 0.0001). CONCLUSION: These biochemical parameters might be a quick and inexpensive added value for distinguishing between infective and non-infective joint disease.

OBJETIVO: Evaluar el valor añadido de los niveles de glucosa en el líquido sinovial (LS) y otros parámetros bioquímicos en el diagnostico de artritis séptica (AS). MATERIAL Y MÉTODOS: Análisis prospectivo de pacientes adultos con AS. Pacientes con articulaciones no infectadas fueron incluidos como grupo control. Se tomaron muestras de LS y sangre para la realización de análisis microbiológicos y bioquímicos en los pacientes y controles. RESULTADOS: Incluimos 8 sujetos con lesión ligamentosa de rodilla, 6 con lesiones meniscales y 5 con osteoartritis como grupo control, así como 20 pacientes con AS. El cultivo de LS fue positivo en 60%. Los niveles de glucosa en LS de pacientes con AS fueron más bajos que los controles (P = 0.0018) con la concentración más baja en pacientes con cultivo positivo (p = 0.0004). La relación de glucosa en sangre y LS de pacientes con cultivo positivo se vio afectada (p < 0.0001). La esterasa leucocitaria presentó valores más altos en pacientes con cultivo positivo (p < 0.0001); se encontró un pH más ácido en comparación con el grupo control (p < 0.0001). CONCLUSIÓN: Estos parámetros bioquímicos podrían ser un valor agregado útil, rápido y económico para distinguir entre enfermedad articular infecciosa y no infecciosa.

Systemic and Local Cytokines Profile Determine Severity and Prognosis in Human Septic Arthritis.

BACKGROUND: Septic arthritis (SA) is a medical emergency. The most common etiological agents are bacteria, which activate the local immune response coordinated by cytokines; however, little is known about the cytokine profile in human SA. AIM: To determine the association of local and systemic cytokine profiles with the severity and prognosis of patients with SA. METHODS: Patients with clinical and laboratory diagnosed SA were enrolled as well as a control group. Serum and synovial fluid (SF) samples were obtained for determining cytokines and glucose levels; SF samples were used for histological analysis. Osteochondral damage and general health status and quality of life (SF-36) were evaluated during recruitment day. WOMAC osteoarthritis index score and SF-36 questionnaire were used a year after recruitment day as a follow up. RESULTS: A systemic and local proinflammatory cytokine profile was found in patients compared to the control group (p <0.05). IL-6 was 28 and 525 times higher than controls in sera and SF, respectively (p <0.0001). Systemic IL-6 correlated negatively with general mental health score (p = 0.0184) and was associated with a higher osteoarthritis index after one year follow-up in the patients (p = 0.0352). HMGB1 in SF was found higher in patients with SA (p <0.0001), and it was associated with osteochondral damage (p = 0.0042). TNF-α in SF correlated negatively with SF-36 questionnaire one year after patients' recruitment in role limitation score (p = 0.0318), body pain score (p = 0.0315), and general mental health score (p = 0.0197). CONCLUSION: Serum and SF cytokine signatures are associated with disease severity and prognosis in patients with SA.