Prevalence and contributing factors of metabolic syndrome in rheumatoid arthritis patients.

BACKGROUND: Promoting prevalence of metabolic syndrome (MetS) in Rheumatoid arthritis (RA) patients might occur secondary to RA therapy as well as sedentary life style. However, conflicting observations have been reported on the correlation between MetS and RA. This study aimed to determine the frequency of MetS and association of its components in RA. METHODS: In this study, 500 RA patients and 500 age- and gender-matched healthy controls were enrolled. MetS was fulfilled through the International Diabetes Federation (IDF) criteria. A multivariate regression model was used to control for variables independently associated with the risk of MetS in RA patients. RESULTS: The prevalence of MetS was 58.8% on IDF criteria in RA patients that was higher than controls (20.4%). Higher incidence of cardiovascular disease (CVD), the familial history of CVD, hypertension, type 2 diabetes mellitus (T2DM), smoking, dyslipidemia, and higher levels of body mass index (BMI), waist circumference (WC), total cholesterol level, fasting blood sugar (FBS), triglyceride (TG) level, low-density lipoprotein (LDL) level, while lower levels of high-density lipoprotein (HDL) were associated with an increased risk of MetS in RA patients. Multivariate regression analysis indicated that age, WC, dyslipidemia, LDL, and DAS28 were independent predictors of MetS in the RA patients. CONCLUSIONS: The prevalence of MetS is higher in RA patients. Our findings suggest an association between cardiovascular risk factors and the increased prevalence of MetS in RA patients.

Argonaute, Vault, and Ribosomal Proteins Targeted by Autoantibodies in Systemic Lupus Erythematosus.

OBJECTIVE: To expand, in an unbiased manner, our knowledge of autoantigens and autoantibodies in patients with systemic lupus erythematosus (SLE) and evaluate their associations with serological and clinical variables. METHODS: Human proteome arrays (> 21,000 proteins) were screened with serum from patients with SLE (n = 12) and healthy controls (n = 6) for IgG and IgA binding. Top hits were validated with 2 cohorts of patients with SLE (cohort 1, n = 49; cohort 2, n = 46) and other rheumatic diseases by ELISA. Clinical associations of the autoantibodies were tested. RESULTS: Ro60 was the top hit in the screen, and the 10 following proteins included 2 additional known SLE autoantigens plus 8 novel autoantigens involved in microRNA processing (Argonaute protein 1 [AGO1], AGO2, and AGO3), ribosomes (ribosomal protein lateral stalk subunit P2 and ovarian tumor deubiquitinase 5 [OTUD5]), RNA transport by the vault (major vault protein), and the immune proteasome (proteasome activator complex subunit 3). Patient serum contained IgG reactive with these proteins and IgA against the AGO proteins. Using the 95th percentile of healthy donor reactivity, 5-43% were positive for the novel antigens, with OTUD5 and AGO1 showing the highest percentages of positivity. Autoantibodies against AGO1 proteins were more prevalent in patients with oral ulcers in a statistically significant manner. IgG autoantibodies against AGO proteins were also seen in other rheumatic diseases. CONCLUSION: We discovered new autoantigens existing in cytosolic macromolecular protein assemblies containing RNA (except the proteasome) in cells. A more comprehensive list of autoantigens will allow for a better analysis of how proteins are targeted by the autoimmune response. Future research will also reveal whether specific autoantibodies have utility in the diagnosis or management of SLE.

Efferocytosis: a double-edged sword in microbial immunity.

Efferocytosis is characterized as the rapid and efficient process by which dying or dead cells are removed. This type of clearance is initiated via "find-me" signals, and then, carries on by "eat-me" and "don't-eat-me" ones. Efferocytosis has a critical role to play in tissue homeostasis and innate immunity. However, some evidence suggests it as a double-edged sword in microbial immunity. In other words, some pathogens have degraded efferocytosis by employing efferocytic mechanisms to bypass innate immune detection and promote infection, despite the function of this process for the control and clearance of pathogens. In this review, the efferocytosis mechanisms from the recognition of dying cells to phagocytic engulfment are initially presented, and then, its diverse roles in inflammation and immunity are highlighted. In this case, much focus is also laid on some bacterial, viral, and parasitic infections caused by Mycobacterium tuberculosis (M. tb), Mycobacterium marinum (M. marinum), Listeria monocytogenes (L. monocytogenes), Chlamydia pneumoniae (CP), Klebsiella pneumoniae (KP), Influenza A virus (IAV), human immunodeficiency virus (HIV), and Leishmania, respectively.

The prevalence and contributing risk factors of coronavirus disease 2019 infection in patients with metabolic syndrome.

BACKGROUND: Components of metabolic syndrome (MetS) was reported to contribute to severe and worse outcomes of coronavirus disease 2019 (COVID-19). Hereby, we evaluated the association of MetS and its components with susceptibility to COVID-19. METHODS: Here, 1000 subjects with MetS were recruited that were diagnosed via the International Diabetes Federation (IDF) criterion. Real-time PCR was exerted to detect SARS-CoV-2 in the nasopharyngeal swabs. RESULTS: Among the MetS patients, 206 (20.6%) cases were detected to have COVID-19. Smoking (OR = 5.04, 95%CI = 3.53-7.21, P < 0.0001) and CVD (OR = 1.62, 95%CI = 1.09-2.40, P = 0.015) were associated with increased chance of COVID-19 infection in the MetS patients. BMI was significantly higher (P = 0.0001) in MetS cases with COVID-19 than those without COVID-19. Obesity was associated with increased susceptibility to COVID-19 in MetS patients (OR = 2.00, 95%CI = 1.47-2.74, P < 0.0001). Total cholesterol, TG, LDL were significantly higher in the MetS cases with COVID-19 than those without COVID-19. Dyslipidemia was associated with increased chance of COVID-19 (OR = 1.50, 95%CI = 1.10-2.05, P = 0.0104). FBS level was significantly higher in the MetS cases with COVID-19. T2DM was associated with increased risk of COVID-19 in MetS patients (OR = 1.43, 95%CI = 1.01-2.00, P = 0.0384). Hypertension was associated with increased chance of COVID-19 in the MetS patients (OR = 1.44, 95%CI = 1.05-1.98, P = 0.0234). CONCLUSIONS: MetS and its components, like obesity, diabetes, dyslipidemia, cardiovascular complications were associated with increased chance of COVID-19 infection development and probably with aggravated symptoms in such patients.

Evidence of membranolytic targeting and intracellular citrullination in neutrophils isolated from patients with rheumatoid arthritis.

Anti-citrullinated protein autoantibodies (ACPA) are diagnostic for rheumatoid arthritis (RA). The antigens recognized by these autoantibodies are produced by protein arginine deiminases (PADs), particularly PAD4. However, it remains unknown why and how PAD4 causes this aberrant citrullination in RA. Here, we report that poly-perforin pores are present on freshly isolated neutrophils from RA patients, but not on healthy donor neutrophils. Neutrophils with perforin pores also contained intracellular citrullinated proteins in the region adjacent to the pores. This response was replicated in vitro by treating neutrophils with purified perforin, which generated intense dots of anti-perforin immunofluorescence, calcium influx, and intracellular citrullination. Extensive neutrophil killing in Felty's syndrome, an aggressive form of RA, correlated with particularly high ACPA, and PAD4 autoantibodies. In contrast, other forms of death, including NETosis, apoptosis, and pyroptosis, produced minimal citrullination. We conclude that neutrophil targeting by perforin leading to intracellular citrullination takes place in patients with RA.

Subcellular location of L1 retrotransposon-encoded ORF1p, reverse transcription products, and DNA sensors in lupus granulocytes.

BACKGROUND: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with an unpredictable course of recurrent exacerbations alternating with more stable disease. SLE is characterized by broad immune activation and autoantibodies against double-stranded DNA and numerous proteins that exist in cells as aggregates with nucleic acids, such as Ro60, MOV10, and the L1 retrotransposon-encoded ORF1p. RESULTS: Here we report that these 3 proteins are co-expressed and co-localized in a subset of SLE granulocytes and are concentrated in cytosolic dots that also contain DNA: RNA heteroduplexes and the DNA sensor ZBP1, but not cGAS. The DNA: RNA heteroduplexes vanished from the neutrophils when they were treated with a selective inhibitor of the L1 reverse transcriptase. We also report that ORF1p granules escape neutrophils during the extrusion of neutrophil extracellular traps (NETs) and, to a lesser degree, from neutrophils dying by pyroptosis, but not apoptosis. CONCLUSIONS: These results bring new insights into the composition of ORF1p granules in SLE neutrophils and may explain, in part, why proteins in these granules become targeted by autoantibodies in this disease.

Immunometabolism Dysfunction in the Pathophysiology and Treatment of Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial hyperplasia and joint damage. Systemic complications and progressive disability are burdens that lead to a significant socio-economic costs in patients with RA. Current RA biomarkers used in predicting, diagnosing, and monitoring the treatment of the disease have not been very successful. Moreover, only 60% of patients show a satisfactory response to current biological and conventional therapies. Studies on immunometabolism have suggested that dysregulated enzymes, transcription factors, metabolites, and metabolic pathways could be considered potential therapeutic targets for the treatment of RA. Factors such as the high concentration of various intermediate molecules arising from metabolism, hypoxia, lack of nutrients, and other metabolic alterations affect local immune responses and preserve a state of chronic inflammation in synovial tissues. Fortunately, in vitro and in vivo studies have shown that targeting specific metabolic pathways is associated with a decreased level of inflammation. Specifically, targeting metabolic intermediates, such as succinate or lactate, has shown promising clinical outcomes in RA treatment. These findings open an avenue for the identification of novel biomarkers for diagnosis, prognosis, and determining the success of various treatments in RA patients, as well as the discovery of new therapeutic targets.

MicroRNAs and Efferocytosis: Implications for Diagnosis and Therapy.

About 10-100 billion cells are generated in the human body in a day, and accordingly, 10- 100 billion cells predominantly die for maintaining homeostasis. Dead cells generated by apoptosis are also rapidly engulfed by macrophages (Mθs) to be degraded. In case of the inefficient engulfment of apoptotic cells (ACs) via Mθs, they experience secondary necrosis and thus release intracellular materials, which display damage-associated molecular patterns (DAMPs) and result in diseases. Over the last decades, researchers have also reflected on the significant contribution of microRNAs (miRNAs) to autoimmune diseases through the regulation of Mθs functions. Moreover, miRNAs have shown intricate involvement with completely adjusting basic Mθs functions, such as phagocytosis, inflammation, efferocytosis, tumor promotion, and tissue repair. In this review, the mechanism of efferocytosis containing "Find-Me", "Eat-Me", and "Digest-Me" signals is summarized and the biogenesis of miRNAs is briefly described. Finally, the role of miRNAs in efferocytosis is discussed. It is concluded that miRNAs represent promising treatments and diagnostic targets in impaired phagocytic clearance, which leads to different diseases.

Role of CCL2/CCR2 axis in the immunopathogenesis of rheumatoid arthritis: Latest evidence and therapeutic approaches.

Evidence suggests that uncontrolled immune system responses and their components play a significant role in developing rheumatoid arthritis (RA), which is considered an autoimmune disease (AD). Among immune system mediators, cytokines and chemokines are involved in numerous physiological and pathological processes. CCL2 or monocyte chemoattractant protein-1 (MCP-1) is known as a CC chemokine that can induce the locomotion and recruitment of monocytes and macrophages to the site of injury. When CCL2 binds to its receptors, the most important of which is CCR2, various signaling pathways are triggered, eventually leading to various immunological events such as inflammation. This chemokine also participates in several events involved in RA pathogenesis, such as osteoclastogenesis, migration of effector T cells to the RA synovium tissue, and angiogenesis. In this review article, the role of the CCL2/CCR2 axis in RA pathogenesis and the immunotherapy opportunities based on CCL2/CCR2 axis targeting has been discussed based on existing investigations.

CD47 Functionalization of Nanoparticles as a Poly(ethylene glycol) Alternative: A Novel Approach to Improve Drug Delivery.

Bio-degradable nanoparticles (NPs) have several utilizations as drug delivery vehicles due to their acceptable bio-availability, lower toxicity, potency for encapsulation and controlled release. Moreover, the interaction of the NPs with the macrophages of the reticuloendothelial system (RES) may decrease NPs efficacy for medical purposes. The surface of NPs is conventionally neutralized with the molecules such as poly(ethylene glycol) (PEG), as one of the most widely applied stealth polymers, in order to restrict the NPs clearance through the RES system. In fact, these molecules exhibit resistance to RES clearance and protein adsorption. It is unfortunate that modifying the PEG has some shortcomings, like problems in the synthesis as well as correlation to the immune reaction. The CD47 receptor has been well known as a 'don't-eat-me' molecule on the self-- cells' surface. Therefore, the receptor will inhibit phagocytosis via binding to its ligand that is known as the signal regulatory protein α (SIRP-α). Moreover, the CD47 receptor, as one of the biomimetic substances, or its derivative peptides, have been used recently on the surface of nanoparticles to inhibit phagocytosis and increase the NPs retention time in the blood circulation. Therefore, this review study examined the CD47 receptor and its role in the immune system as well as the use of the CD47 receptor in coating NPs to increase their retention time in the blood circulation.