Search Results (12)

Background: Anti-MDA5 antibody-bearing (anti-MDA5⁺)-dermatomyositis (DM) or polymyositis (PM) is notorious for causing rapidly progressive interstitial lung disease (RPILD) and/or cancers with high mortality rate. However, anti-MDA5 antibodies (Abs) are also found in other connective tissue diseases and their link with RPILD, especially with regard to the mortality rate, are unknown. Methods: We retrospectively recruited 71 patients bearing anti-MDA5-Abs in serum, stratified them in terms of a presence or absence of RPILD, and evaluated their clinical features, laboratory findings, associated myositis antibodies, concurrent connective tissue disease (CTD) as well as newly developed malignancies. Results: In total, 39 (55%) patients presented with DM/PM, but 32 (45%) did not. In total, 22 of the former and 11 of the latter developed RPILD eventually, accounting for a total of 46% of all MDA-5 bearing patients. On the other hand, 15 of all 71 (21.1%) patients had cancers. Among the 32 patients who did not have DM/PM, 27 (38.0% of all 71) had other CTDs, indicating that only 5 (7.0% of 71) patients did not have CTDs. Senility (odds ratio (OR) = 1.816, p = 0.032), presence of anti-Ro-52 antibody (OR = 1.676, p = 0.018), elevated C-reactive protein (CRP, OR = 4.354, p < 0.001) and carcinoembryonic antigen (CEA, OR = 2.625, p = 0.005) posed risks for RPILD. High lactose dehydrogenase (LDH, p = 0.009), CRP (p = 0.001) and CEA (p = 0.001), ferritin (p ≤ 0.001) and low albumin (p ≤ 0.001) were significantly associated with mortality. Anti-SAE antibodies were negatively correlated with RPILD as analyzed by univariate (OR = 0.245, p = 0.017) and multivariate (OR = 0.058, p = 0.036) regressions, indicating that they may be a protective factor in relation to RPILD (OR = 0.543, p = 0.008) or fatality (OR = 0.707, p = 0.012), which was also demonstrated in subgroup analyses. Conclusions: In contrast to various risk factors for RPILD or mortality, anti-SAE antibodies might conversely be a protective factor in anti-MDA5⁺ patients. Full article

Background and Objective: The International Map of Axial Spondyloarthritis (IMAS) explores the physical, psychological, and social experiences of patients with axial spondyloarthritis (axSpA). This initiative is now being expanded to Taiwan as the Taiwanese Map of Axial Spondyloarthritis (TMAS). We aim to provide rheumatologists with insights into the perspectives of Taiwanese patients, enabling physicians to better understand the unmet needs of these patients and optimize their management. Materials and Methods: The TMAS is a cross-sectional study gathering data through an online survey of axSpA patients, promoted by the Ankylosing Spondylitis Caring Society of R.O.C. (ASCARES), conducted from July 2017 to March 2018 by Ipsos, and analyzed by the Health & Territory Research (HTR) group of the University of Seville. The questionnaire includes 99 questions that cover domains such as patient profile, diagnosis, habits/lifestyle, employment status, physical/psychological health status, social support, use of healthcare services, and treatments. Results: A total of 112 axSpA patients were included in this survey. The mean age was 38.6 years and 75.0% were male. The average diagnostic delay was 3 years, and 19.6% reported extra-articular manifestations. Out of the 49 respondents who reported HLA-B27 information, 35 were HLA-B27-positive. The disease burden was high, with a mean BASDAI score of 4.9 and 75.9% having a mild to moderate degree of spinal stiffness. Furthermore, they were socially and psychologically burdened, with 88.4% experiencing work-related issues and 25.9% suffering from anxiety. Conclusions: The TMAS sheds light on the overall perspective of axSpA patients in Taiwan. The TMAS shows shorter diagnostic delay compared to patients from the EMAS. However, high disease activity and significant psychological distress still trouble the patients, causing functional impairments and even leading to career failures. Understanding the perspective of axSpA patients can help rheumatologists adjust treatment strategies to their unmet needs and improve their disease outcomes. Full article

Background: Graft failure resulting from rejection or any other adverse event usually originates from an aberrant and/or exaggerated immune response and is often catastrophic in renal transplantation. So, it is essential to monitor patients’ immune status for detecting a rejection/graft failure early on. Methods: We monitored the sequence change of complementary determining region 3 (CDR3) in B-cell receptor (BCR) immunoglobulin heavy-chain (IGH) immune repertoire (iR) in 14 renal transplant patients using next-generation sequencing (NGS), correlating its diversity to various clinical events occurring after transplantation. BCR-IGH-CDR3 in peripheral blood mononuclear cells was sequenced along the post-transplantation course by NGS using the iRweb server. Results: Datasets covering VDJ regions of BCR-IGH-CDR3 indicated clonal diversity (D50) variations along the post-transplant course. Furthermore, principal component analysis showed the clustering of these sequence variations. A total of 544 shared sequences were identified before transplantation. D50 remained low in three patients receiving rituximab. Among them, one’s D50 resumed after 3 m, indicating graft tolerance. The D50 rapidly increased after grafting and decreased thereafter in four patients without rejection, decreased in two patients with T-cell-mediated rejection (TCMR) and exhibited a sharp down-sliding after 3 m in two patients receiving donations after cardiac death (DCD). In another two patients with TCMR, D50 was low just before individual episodes, but either became persistently low or returned to a plateau, depending on the failure or success of the immunosuppressive treatments. Shared CDR3 clonal expansions correlated to D50 changes. Agglomerative hierarchical clustering showed a commonly shared CDR3 sequence and at least two different clusters in five patients. Conclusions: Clonal diversity in BCR-IGH-CDR3 varied depending on clinical courses of 14 renal transplant patients, including B-cell suppression therapy, TCMR, DCD, and graft tolerance. Adverse events on renal graft failure might lead to different clustering of BCR iR. However, these preliminary data need further verification in further studies for the possible applications of iR changes as genetic expression biomarkers or laboratory parameters to detect renal graft failure/rejection earlier. Full article

Polymorphonuclear neutrophils (PMNs) are the most abundant white blood cells in the circulation. These cells act as the fast and powerful defenders against environmental pathogenic microbes to protect the body. In addition, these innate inflammatory cells can produce a number of cytokines/chemokines/growth factors for actively participating in the immune network and immune homeostasis. Many novel biological functions including mitogen-induced cell-mediated cytotoxicity (MICC) and antibody-dependent cell-mediated cytotoxicity (ADCC), exocytosis of microvesicles (ectosomes and exosomes), trogocytosis (plasma membrane exchange) and release of neutrophil extracellular traps (NETs) have been successively discovered. Furthermore, recent investigations unveiled that PMNs act as a double-edged sword to exhibit paradoxical activities on pro-inflammation/anti-inflammation, antibacteria/autoimmunity, pro-cancer/anticancer, antiviral infection/COVID-19-induced immunothrombotic dysregulation. The NETs released from PMNs are believed to play a pivotal role in these paradoxical activities, especially in the cytokine storm and immunothrombotic dysregulation in the recent SARS-CoV-2 pandemic. In this review, we would like to discuss in detail the molecular basis for these strange activities of PMNs. Full article

Rheumatoid arthritis (RA) is a typical autoimmune-mediated rheumatic disease presenting as a chronic synovitis in the joint. The chronic synovial inflammation is characterized by hyper-vascularity and extravasation of various immune-related cells to form lymphoid aggregates where an intimate cross-talk among innate and adaptive immune cells takes place. These interactions facilitate production of abundant proinflammatory cytokines, chemokines and growth factors for the proliferation/maturation/differentiation of B lymphocytes to become plasma cells. Finally, the autoantibodies against denatured immunoglobulin G (rheumatoid factors), EB virus nuclear antigens (EBNAs) and citrullinated protein (ACPAs) are produced to trigger the development of RA. Furthermore, it is documented that gene mutations, abnormal epigenetic regulation of peptidylarginine deiminase genes 2 and 4 (PADI2 and PADI4), and thereby the induced autoantibodies against PAD2 and PAD4 are implicated in ACPA production in RA patients. The aberrant expressions of non-coding RNAs (ncRNAs) including microRNAs (miRs) and long non-coding RNAs (lncRNAs) in the immune system undoubtedly derange the mRNA expressions of cytokines/chemokines/growth factors. In the present review, we will discuss in detail the expression of these ncRNAs and their target molecules participating in developing RA, and the potential biomarkers for the disease, its diagnosis, cardiovascular complications and therapeutic response. Finally, we propose some prospective investigations for unraveling the conundrums of rheumatoid pathogenesis. Full article

Polymorphonuclear neutrophils (PMNs) are traditionally regarded as professional phagocytic and acute inflammatory cells that engulf the microbial pathogens. However, accumulating data have suggested that PMNs are multi-potential cells exhibiting many important biological functions in addition to phagocytosis. These newly found novel activities of PMN include production of different kinds of cytokines/chemokines/growth factors, release of neutrophil extracellular traps (NET)/ectosomes/exosomes and trogocytosis (membrane exchange) with neighboring cells for modulating innate, and adaptive immune responses. Besides, PMNs exhibit potential heterogeneity and plasticity in involving antibody-dependent cellular cytotoxicity (ADCC), cancer immunity, autoimmunity, inflammatory rheumatic diseases, and cardiovascular diseases. Interestingly, PMNs may also play a role in ameliorating inflammatory reaction and wound healing by a subset of PMN myeloid-derived suppressor cells (PMN-MDSC). Furthermore, PMNs can interact with other non-immune cells including platelets, epithelial and endothelial cells to link hemostasis, mucosal inflammation, and atherogenesis. The release of low-density granulocytes (LDG) from bone marrow initiates systemic autoimmune reaction in systemic lupus erythematosus (SLE). In clinical application, identification of certain PMN phenotypes may become prognostic factors for severe traumatic patients. In the present review, we will discuss these newly discovered biological and pathobiological functions of the PMNs. Full article

Systemic lupus erythematosus (SLE) is a complex systemic autoimmune disease with heterogeneous clinical manifestations. A diverse innate and adaptive immune dysregulation is involved in the immunopathogenesis of SLE. The dysregulation of immune-related cells may derive from the intricate interactions among genetic, epigenetic, environmental, and immunological factors. Of these contributing factors, non-coding RNAs (ncRNAs), including microRNAs (miRNAs, miRs), and long non-coding RNAs (lncRNAs) play critical roles in the post-transcriptional mRNA expression of cytokines, chemokines, and growth factors, which are essential for immune modulation. In the present review, we emphasize the roles of ncRNA expression in the immune-related cells and cell-free plasma, urine, and tissues contributing to the immunopathogenesis and tissue damage in SLE. In addition, the circular RNAs (circRNA) and their post-translational regulation of protein synthesis in SLE are also briefly described. We wish these critical reviews would be useful in the search for biomarkers/biosignatures and novel therapeutic strategies for SLE patients in the future. Full article

IgG4-related disease (IgG4-RD) is a spectrum of complex fibroinflammatory disorder with protean manifestations mimicking malignant neoplasms, infectious or non-infectious inflammatory process. The histopathologic features of IgG4-RD include lymphoplasmacytic infiltration, storiform fibrosis and obliterative phlebitis together with increased in situ infiltration of IgG4 bearing-plasma cells which account for more than 40% of all IgG-producing B cells. IgG4-RD can also be diagnosed based on an elevated serum IgG4 level of more than 110 mg/dL (normal < 86.5 mg/mL in adult) in conjunction with protean clinical manifestations in various organs such as pancreato–hepatobiliary inflammation with/without salivary/lacrimal gland enlargement. In the present review, we briefly discuss the role of genetic predisposition, environmental factors and candidate autoantibodies in the pathogenesis of IgG4-RD. Then, we discuss in detail the immunological paradox of IgG4 antibody, the mechanism of modified Th2 response for IgG4 rather than IgE antibody production and the controversial issues in the allergic reactions of IgG4-RD. Finally, we extensively review the implications of different immune-related cells, cytokines/chemokines/growth factors and Toll-like as well as NOD-like receptors in the pathogenesis of tissue fibro-inflammatory reactions. Our proposals for the future investigations and prospective therapeutic strategies for IgG4-RD are shown in the last part. Full article

Systemic sclerosis (SSc) is a multi-system autoimmune disease with tissue fibrosis prominent in the skin and lung. In this review, we briefly describe the autoimmune features (mainly autoantibody production and cytokine profiles) and the potential pathogenic contributors including genetic/epigenetic predisposition, and environmental factors. We look in detail at the cellular and molecular bases underlying tissue-fibrosis which include trans-differentiation of fibroblasts (FBs) to myofibroblasts (MFBs). We also state comprehensively the pro-inflammatory and pro-fibrotic cytokines relevant to MFB trans-differentiation, vasculopathy-associated autoantibodies, and fibrosis-regulating microRNAs in SSc. It is conceivable that tissue fibrosis is mainly mediated by an excessive production of TGF-β, the master regulator, from the skewed Th2 cells, macrophages, fibroblasts, myofibroblasts, and keratinocytes. After binding with TGF-β receptors on MFB, the downstream Wnt/β-catenin triggers canonical Smad 2/3 and non-canonical Smad 4 signaling pathways to transcribe collagen genes. Subsequently, excessive collagen fiber synthesis and accumulation as well as tissue fibrosis ensue. In the later part of this review, we discuss limited data relevant to the role of long non-coding RNAs (lncRNAs) in tissue-fibrosis in SSc. It is expected that these lncRNAs may become the useful biomarkers and therapeutic targets for SSc in the future. The prospective investigations in the development of novel epigenetic modifiers are also suggested. Full article

Systemic lupus erythematosus (SLE) is a prototype of systemic autoimmune disease involving almost every organ. Polygenic predisposition and complicated epigenetic regulations are the upstream factors to elicit its development. Mitochondrial dysfunction-provoked oxidative stress may also play a crucial role in it. Classical epigenetic regulations of gene expression may include DNA methylation/acetylation and histone modification. Recent investigations have revealed that intracellular and extracellular (exosomal) noncoding RNAs (ncRNAs), including microRNAs (miRs), and long noncoding RNAs (lncRNAs), are the key molecules for post-transcriptional regulation of messenger (m)RNA expression. Oxidative and nitrosative stresses originating from mitochondrial dysfunctions could become the pathological biosignatures for increased cell apoptosis/necrosis, nonhyperglycemic metabolic syndrome, multiple neoantigen formation, and immune dysregulation in patients with SLE. Recently, many authors noted that the cross-talk between oxidative stress and ncRNAs can trigger and perpetuate autoimmune reactions in patients with SLE. Intracellular interactions between miR and lncRNAs as well as extracellular exosomal ncRNA communication to and fro between remote cells/tissues via plasma or other body fluids also occur in the body. The urinary exosomal ncRNAs can now represent biosignatures for lupus nephritis. Herein, we’ll briefly review and discuss the cross-talk between excessive oxidative/nitrosative stress induced by mitochondrial dysfunction in tissues/cells and ncRNAs, as well as the prospect of antioxidant therapy in patients with SLE. Full article

Systemic lupus erythematosus (SLE) is an archetype of systemic autoimmune disease, characterized by the presence of diverse autoantibodies and chronic inflammation. There are multiple factors involved in lupus pathogenesis, including genetic/epigenetic predisposition, sexual hormone imbalance, environmental stimulants, mental/psychological stresses, and undefined events. Recently, many authors noted that “inflammaging”, consisting of immunosenescence and inflammation, is a common feature in aging people and patients with SLE. It is conceivable that chronic oxidative stresses originating from mitochondrial dysfunction, defective bioenergetics, abnormal immunometabolism, and premature telomere erosion may accelerate immune cell senescence in patients with SLE. The mitochondrial dysfunctions in SLE have been extensively investigated in recent years. The molecular basis of normoglycemic metabolic syndrome has been found to be relevant to the production of advanced glycosylated and nitrosative end products. Besides, immunosenescence, autoimmunity, endothelial cell damage, and decreased tissue regeneration could be the results of premature telomere erosion in patients with SLE. Herein, the molecular and cellular bases of inflammaging and cardiovascular complications in SLE patients will be extensively reviewed from the aspects of mitochondrial dysfunctions, abnormal bioenergetics/immunometabolism, and telomere/telomerase disequilibrium. Full article

The role of mitochondrial DNA (mtDNA) alterations in the pathophysiology of systemic lupus erythematosus (SLE) remains unclear. We investigated sequence variations in the D310 region and copy number change of mtDNA in 85 SLE patients and 45 normal subjects. Leukocyte DNA and RNA were extracted from leukocytes of the peripheral venous blood. The D310 sequence variations and copy number of mtDNA, and mRNA expression levels of mtDNA-encoded genes in leukocytes were determined by quantitative real-time polymerase chain reaction (Q-PCR) and PCR-based direct sequencing, respectively. We found that leukocyte mtDNA in SLE patients exhibited higher frequency of D310 heteroplasmy (69.4% vs. 48.9%, p = 0.022) and more D310 variants (2.2 vs. 1.7, p = 0.014) than those found in controls. Among normal controls and patients with low, medium or high SLE disease activity index (SLEDAI), an ever-increasing frequency of D310 heteroplasmy was observed (p = 0.021). Leukocyte mtDNA copy number tended to be low in patients of high SLEDAI group (p = 0.068), especially in those harboring mtDNA with D310 heteroplasmy (p = 0.020). Moreover, the mtDNA copy number was positively correlated with the mRNA level of mtDNA-encoded ND1 (NADH dehydrogenase subunit 1) (p = 0.041) and ATPase 6 (ATP synthase subunit 6) (p = 0.030) genes. Patients with more D310 variants were more susceptible to lupus nephritis (p = 0.035). Taken together, our findings suggest that decrease in the mtDNA copy number and increase in D310 heteroplasmy of mtDNA are related to the development and progression of SLE, and that the patients harboring more D310 variants of mtDNA are more susceptible to lupus nephritis. Full article