Abnormalities In SLE Research Articles

Mitochondrial aberrations in systemic lupus erythematosus pathogenesis: Insights and therapeutic implications

AbstractSystemic lupus erythematosus (SLE), a chronic autoimmune disease, is marked by impaired immune tolerance and heightened activity in both innate and adaptive immune systems. Hallmarks of SLE include elevated type I interferons and autoantibody production, though the exact causes of SLE remain elusive despite advances in research techniques. Crucial to SLE research is understanding its pathogenesis and developing effective diagnostic and therapeutic methods. Recent studies have highlighted a significant link between mitochondrial abnormalities and SLE's development and progression. Mitochondrial dysfunction plays a key role in SLE pathogenesis through various mechanisms such as mitochondrial DNA mutations, oxidative stress, immune metabolic reprogramming, and cellular death. These factors collectively contribute to the loss of self‐tolerance, increased autoantibody production, and impaired clearance of immune complexes, leading to their deposition. This triggers sustained inflammatory responses and damages multiple organs. This review focuses on the diagnostic and therapeutic approaches related to mitochondrial abnormalities in SLE. Targeting mitochondrial pathways presents a promising strategy for treating SLE, potentially improving prognosis and quality of life for those affected. Future research should further investigate the role of mitochondria in the onset and progression of SLE, providing new avenues for understanding and managing this complex disease.

White matter microstructure alterations in systemic lupus erythematosus: A preliminary coordinate-based meta-analysis of diffusion tensor imaging studies.

Systemic lupus erythematosus is often accompanied with neuropsychiatric symptoms. Neuroimaging evidence indicated that microstructural white matter (WM) abnormalities play role in the neuropathological mechanism. Diffusion tensor imaging (DTI) studies allows the assessment of the microstructural integrity of WM tracts, but existing findings were inconsistent. This present study aimed to conduct a coordinate-based meta-analysis (CBMA) to identify statistical consensus of DTI studies in SLE. Relevant studies that reported the differences of fractional anisotropy (FA) between SLE patients and healthy controls (HC) were searched systematically. Only studies reported the results in Talairach or Montreal Neurological Institute (MNI) coordinates were included. The anisotropic effect size version of signed differential mapping (AES-SDM) was applied to detect WM alterations in SLE. Totally, five studies with seven datasets which included 126 patients and 161 HC were identified. The pooled meta-analysis demonstrated that SLE patients exhibited significant FA reduction in the left striatum and bilateral inferior network, mainly comprised the corpus callosum (CC), bilateral inferior fronto-occipital fasciculus (IFOF), bilateral anterior thalamic projections, bilateral superior longitudinal fasciculus (SLF), left inferior longitudinal fasciculus (ILF), and left insula. No region with higher FA was identified. Disorders of the immune system might lead to subtle WM microstructural alterations in SLE, which might be related with cognitive deficits or emotional distress symptoms. This provides a better understanding of the pathological mechanism of microstructural brain abnormalities in SLE.

Postactivated B cells in systemic lupus erythematosus: update on translational aspects and therapeutic considerations.

This review summarizes recent insights and current understanding of the role of postactivated B cells in SLE and related pathogenic and potential therapeutic implications. B cells are considered key players in SLE and experience from various B-cell-targeted therapies underlines their clinical relevance. In the last years, new insights have been obtained on B-cell abnormalities within the complex pathophysiology of SLE. These insights involve a revised understanding of BCR signaling, that has been reported to be hyperresponsive in the past, but newer studies suggest a postactivation functiotype in terms of reduced BCR and TLR signaling. Despite comprehensive efforts to delineate B-cell abnormalities on assessing large-scale genomic, epigenomic and proteomic data, understanding functional impairments of cellular interactions and subcellular functions remains crucial. A recently identified enhanced protein tyrosine phosphatase (PTP) activity was found in relation to diminished BCR responses in SLE. This finding together with reduced cytokine production upon TLR9 activation appears to mark postactivated lupus B cells. Other studies identified increased PTP activity in line with a gain-of-function mutation of phosphatase PTPN22, one of the strongest SLE risk alleles. Improved understanding of these B cell abnormalities in SLE holds promise to gain further insights in mechanisms of autoimmunity and pave the way for selective therapies targeting key principles of chronic autoimmunity. SLE B cells (similar as previously described for lupus T cells) are characterized by a postactivation (exhausted) functiotype mandating consideration for innovative therapies.

Abnormal B Cell Development in Systemic Lupus Erythematosus: What the Genetics Tell Us.

Although the immunologic abnormalities in SLE are complex, numerous, and not fully understood, B cells have a central role in the development of the disease, from driving immune complex production to secretion of proinflammatory cytokines. Since SLE is an archetypal complex disease, the genetic association data reflect that complexity, with many variants, affecting several areas of the immune system 13, 14. The advent of GWAS has identified many potential abnormal pathways relevant to the breaking of self tolerance in SLE (summarized in Table 1). The data emphasize the central role of B cells, with a significant proportion of identified genes affecting B cell function and epigenetic annotation reinforcing this 13, 14, 65, 66. GWAS have also helped to explain clinical variability between individuals—it is easy to see how each patient is likely to have a different combination of risk variants resulting in a pattern of immune dysfunction unique to that individual. We can already see how variants in TLR genes can help predict disease and serologic markers, or how variants in the gene for Lyn can protect against hematologic involvement 36, 49. Traditionally, B cell–targeted therapy has mostly been focused on depletion of numbers (e.g., through targeting CD20‐mediated depletion through rituximab), but with our growing understanding, less crude approaches are being investigated. For example, Aiolos depletion therapy with the CC‐220 molecule results in down‐regulation of genes mediating B cell differentiation, reduces proliferation, and inhibits antibody secretion in B cells from SLE patients 69. Emerging therapy such as epratuzumab (a monoclonal antibody to CD22) has been shown to block B cell differentiation and activation directly through selective inhibition of BLIMP‐1 (encoded by PRDM1), demonstrating how data from GWAS can inform future drug therapy 70. Although the results from GWAS confirm the complexity of SLE pathogenesis and show that different intrinsic B cell abnormalities are likely to drive disease in each individual case, the principles underlying the loss of central tolerance (deficient BCR signaling) and peripheral tolerance (dysregulated T cell–B cell interaction) are universal. Genetic information helps us to personalize therapy, whereby relevant molecules can be targeted through understanding the exact pathways involved in an individual's disease.

Pilot study reveals placental abnormalities in SLE

Pilot study reveals placental abnormalities in SLE

The role of ultrasound in assessing musculoskeletal symptoms of systemic lupus erythematosus: a systematic literature review.

Musculoskeletal symptoms are common in SLE and are associated with significant morbidity. However, assessing their nature can be challenging, with implications for treatment decisions and measuring response. US has been shown to be valid and reliable for the assessment of other inflammatory arthritides, but data in SLE are more limited. The objectives of this systematic literature review were to determine the characteristics of musculoskeletal US abnormalities in SLE and to evaluate the metric properties of US in the detection and quantification of musculoskeletal symptoms. We systematically searched the literature using the PubMed, Embase and Cochrane Library databases for studies using musculoskeletal US for assessing SLE. Studies were assessed for quality using the Quality Assessment of Diagnostic Accuracy Studies tool and for their metric qualities, including reliability and validity. Nine studies were identified. Most studies investigated construct validity. Rates of abnormality were highly variable: synovitis and tenosynovitis were reported in 25-94% and 28-65% of patients, respectively; power Doppler and erosions were reported in 10-82% and 2-41% of patients, respectively. There was poor to moderate association between US abnormalities and disease activity indices and immunological findings. There was moderate to high risk of bias and there were concerns about applicability in most studies. US has potential value in the assessment of musculoskeletal symptoms in SLE. However, there is methodological variation between studies that may account for lack of consensus on US abnormalities. Studies that address these problems are required before US can used as an outcome measure in SLE.

Systemic lupus erythematosus 2014.

Systemic lupus erythematosus 2014.

Ultrasound evaluation of hand, wrist and foot joint synovitis in systemic lupus erythematosus

To assess the prevalence and severity of inflammatory abnormalities of the hand, wrist and foot joints in SLE patients by US and to correlate them with clinical, laboratory and disease activity score parameters. Sixty-two consecutive SLE patients were enrolled in the present study and underwent clinical evaluation, laboratory tests and bilateral high-resolution US of the hand, wrist and foot joints. Joint effusion (JE), synovial hypertrophy (SH) and local pathological vascularization [power Doppler (PD)] were evaluated according to both a dichotomous score and a semi-quantitative (0-3) grading system. In addition, a global US score was calculated by summing the values given to each elementary lesion for every single joint and every joint group. US findings were correlated with physical examination, serological parameters (CRP, ANA, anti-dsDNA, ENA, aPL, C3 and C4 serum levels) and disease activity indexes (SLEDAI-2K, ECLAM). US detected inflammatory joint abnormalities in 54/62 patients (87.1%); 72.6% presented involvement of the MTP joints, 46.7% the MCP joints, 19.3% the PIP joints and 53% the wrists. A total of 1984 joints were examined highlighting JE in 19.1% of cases, SH in 6.9% and positive PD in 1.1%. The global US inflammatory score had a mean value of 10.9 (s.d. 15.2). No correlations were found between US findings and SLE disease activity parameters. US demonstrated a high prevalence of inflammatory joint abnormalities in SLE that were also present in asymptomatic patients. Interestingly, the foot joints were the most frequently involved. US is a valuable tool for detecting subclinical synovitis in SLE.

MicroRNA-mediated modulations in hyperactive plasmacytoid dendritic cells in systemic lupus erythematosus (P4072)

Abstract Systemic lupus erythematosus (SLE) patients are typically presented by their increased serum type I interferon (IFN) activities. Plasmacytoid dendritic cells (pDCs), the most potent type I IFN-producing cells, are found to be hyperactive in SLE. Using the New Zealand Black/White F1 lupus mouse model, we sought for the regulatory mechanism of IFN production by pDCs in SLE. Mice with lupus symptoms such as high titers of serum anti-nuclear antibodies and persistent proteinuria were compared with the pre-symptomatic ones. Upon toll-like receptor (TLR) 7 and TLR9 stimulations, the up-regulations of co-stimulatory markers CD40, CD86 and MHC class II were significantly heightened in bone-marrow-derived pDCs from the symptomatic mice. Furthermore, the expression profiles of over 700 microRNA (miRNAs) in pDCs upon TLR7 activation were analyzed by low-density arrays. Among those, miRNA-155 was the most highly induced and its induction was consistently higher in pDCs from the symptomatic mice. It was previously found in human studies that miRNA-155 regulates type I IFN production by pDCs and itself inversely regulated by the autocrine/paracrine IFN dynamics. Current investigations pursue on the correlation between up-regulated miRNA-155 induction and aberrant pDC functions in SLE using miRNA mimics and inhibitors. Together, our study should reveal miRNA-mediated modulations in pDC abnormalities in SLE.

Underexpression of mitochondrial-DNA encoded ATP synthesis-related genes and DNA repair genes in systemic lupus erythematosus.

IntroductionSystemic lupus erythematosus (SLE) is a prototypical autoimmune disease characterized by various systemic symptoms and multiple organ damage. We clarify biological and functional abnormalities in SLE by comparing the gene expression profiles of SLE patients with those of healthy individuals.MethodsGene expression profiles from the peripheral blood of 21 SLE patients and 45 healthy individuals were obtained using a DNA microarray. Gene ontology analysis and network pathway analysis were performed on the genes differentially expressed between SLE and healthy individuals.ResultsA total of 2,329 upregulated genes and 1,884 downregulated genes were differentially expressed. Gene ontology analysis revealed that the upregulated genes were classified as response to biotic stimulus genes, which mainly includes genes related to immune response. Abnormalities in other categories such as cell motility and regulation of apoptosis were also revealed. Downregulated genes were mainly sorted into two gene categories, sensory perception and response to radiation/light. The sensory perception genes included ATPase/ATPase domain-containing genes, myosin-related genes, and two excision repair cross-complementing genes, which are involved in DNA repair. Other genes in this group - including three crystallin genes, genes encoding the receptor protein for melanocyte-stimulating hormone, and six mitochondrial-DNA encoded genes, which are involved in ATP synthesis - were also categorized as response to radiation genes. Using network pathway analysis, IL-6, transforming growth factor beta 1, TNF, and hepatocyte nuclear factor 4α were found to play central roles in the networks of sensory perception-related molecules.ConclusionsFunctional abnormalities in ATP synthesis and DNA repair are implicated in peripheral blood cells from SLE patients.

Colour Doppler ultrasound of the ocular circulation in patients with systemic lupus erythematosus identifies altered microcirculatory haemodynamics

We assessed whether quantitative analysis of Doppler flow velocity waveforms is able to identify subclinical microvascular abnormalities in SLE and whether eigenvector analysis can detect changes not detectable using the resistive index (RI). Fifty-four SLE patients with no conventional cardiovascular risk factors, major organ involvement or retinopathy were compared to 32 controls. Flow velocity waveforms were obtained from the ophthalmic artery (OA), central retinal artery (CRA) and common carotid artery (CA). The waveforms were analysed using eigenvector decomposition and compared between groups at each arterial site. The RI was also determined. The RI was comparable between groups. In the OA and CRA, there were significant differences in the lower frequency sinusoidal components (P < 0.05 for each component). No differences were apparent in the CA between groups. Eigenvector analysis of Doppler flow waveforms, recorded in proximity of the terminal vascular bed, identified altered ocular microvascular haemodynamics in SLE. Altered waveform structure could not be identified by changes in RI, the traditional measure of downstream vascular resistance. This analytical approach to waveform analysis is more sensitive in detecting preclinical microvascular abnormalities in SLE. It may hold potential as a useful tool for assessing disease activity, response to treatment, and predicting future vascular complications.

Atrial Ejection Force in Systemic Autoimmune Diseases

Systemic autoimmune disorders may affect several organs, including the heart. We analyzed two-dimensional and pulsed Doppler echocardiograms of patients (n = 37) with systemic lupus erythematosus (SLE, n = 24) or rheumatoid arthritis (RA, n = 13) to determine whether atrial ejection force (AEF) could represent a suitable parameter for detecting left ventricular filling abnormalities in SLE and RA. In both patient subgroups, AEF was significantly higher than in healthy controls (n = 40) matched for gender and age (14.0 ± 5.4 vs. 11.0 ± 3.5 kdyn, p < 0.01). Because conventional echocardiographic parameters of left ventricular function failed to detect such a difference, AEF might serve as an additional sensitive parameter for detecting left ventricular diastolic filling abnormalities early in the course of a systemic autoimmune disease.

Skeletal Muscle Immune Deposits in Systemic Lupus Erythematosus: Correlation with histologic changes, autoantibodies, and clinical involvement

Skeletal muscle biopsy and autopsy samples of 132 SLE patients were studied by immunofluorescence and light microscopic techniques. Immune deposits were compared to histologic abnormalities and clinical and serologic findings. Immune deposits with a mainly granular pattern were observed at different locations in 49 patients (37%). They correlated significantly (p<0.001) with inflammatory myopathy, demonstrated in 33 (25%), with noninflammatory myopathy which occurred in 38 (29%) vasculitis, observed in 13 (10%), and with noninflammatory vasculopathy which was noted in 10 patients (8%). The correlation of muscle immune deposits with anti-DNA antibodies was significant at p=0.016. Anti-Sm and anti-U1 RNP antibodies were associated significantly with the intensity of immune deposits. Furthermore, a correlation of immune deposits with increased creatine phosphokinase and myopathic electromyogram, but not with evidence of clinical involvement, was shown. A key pathogenetic role of immune deposits in the development of skeletal muscle histologic abnormalities in SLE was demonstrated.

Subsets of Autoantibodies to Extractable Nuclear Antigens (ENA) as Assayed by ELISA Correlate with Specific Clinical Abnormalities in SLE

A clinicopathological study of antinuclear antibodies was performed in 43 patients with SLE. Autoantibodies to double-stranded DNA, measured by RIA, were found in 56% of subjects and were associated with the presence of mesangioproliferative glomerulonephritis, Raynaud's phenomenon and cryoglobulinaemia. Antibodies to extractable nuclear antigens (ENA), when assayed by ELISA, were found in 81% of subjects and were associated with photosensitivity and thrombocytopaenia. Antibodies to RNA-ase-resistant ENA were found in 42% and were associated with cryoglobulinaemia and sclerodactyly, while antibodies to RNA-ase sensitive ENA which had a 49% prevalence were associated with haemolysis and neutropaenia. RNP antibodies (detected by immunodiffusion in 40%) were also associated with photosensitivity. RNP antibody positive and negative sera differed from each other by virtue of their relationship with other autoantibodies, and because RNP-positive sera had significantly higher ENA antibody titres and affinities than did RNP-negative sera. We therefore concluded that various combinations of antinuclear antibodies may predispose to the development of specific clinicopathological lesions in SLE.

Cardiovascular Manifestations in Systemic Lupus Erythematosus : SYMPOSIUM ON SECONDARY MYOCARDIAL DISEASE : 44th Scientific Session of the Japanise Circulation Society

Cardiovascular manifestations in 48 patients with systemic lupus erythematosus were investigated by means of echocardiography and other non-invasive cardiac function tests. During the mean follow-up period of 17 months, 94 per cent of the patients showed abnormalities in the cardiac function tests. Pericardial effusion, a most frequent abnormality, was noted in 53 per cent of the patients at the active phese and in 12 per cent at the inactive phase. In the normotensive patients, echocardiographic values and ratio of pre-ejection period to left ventricular ejection time (PEP/LVET) changed toward normal range with change from the active phase to the inactive, and remained unchanged after a long-term corticosteroid therapy. In the hypertensives, on the other hand, these values changed toward more abnormal range after a long-term corticosteroid therapy. It was suggested that hypertension accerelates the cardiac lesions initiated by the autoimmune process. The patients who had manifested pericardial effusion showed more marked cardiac abnormalities than those without effusion at the both active and inactive phases, suggesting that some cardiac muscle involvement (lupus carditis) underlied behind the pericarditis. The patients who manifested Raynaud's phenomenon showed the significantly greater right ventricular dimension at the active phase than in those without this sign. As a mechanism for this result, the association of Raynaud's phenomenon and pulmonary vascular involvement was considered. Hence, the present study suggests 3 major mechanisms for the cardiac abnormalities in SLE: 1) lupus carditis, 2) pulmonary vascular involvement, and 3) systemic hypertension. The effects of corticosteroid therapy on these factors were discussed. A comparison between SLE and other allied diseases due to the auto-immune mechanism revealed that overlap syndrome is characterized by high incidence of increased right ventricular dimension and pulmonary hypertension.

Significance of persisting serologic abnormalities in SLE.

The significance of abnormal serum anti-DNA and complement levels persisting in SLE patients on treatment has been explored. Instances when serologic abnormalities returned to normal were followed by a significantly longer mean duration of remission. When anti-DNA persisted at abnormal levels, a more severe exacerbation was likely to follow, although this result was not the case for persisting hypocomplementemia. These data did not result from two variants of SLE, one mild and one severe, because druation of remission correlated directly with dosage of steroid. Randomly discovered abnormalities in anti-DNA and complement levels were of limited predictive value, because they frequently persisted for over 1 year before exacerbations occurred. Hypocomplementemia resolved spontaneously without recognizable exacerbation in nearly half the observed instances.