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ID PMID Title PublicationDate abstract
33197589 Does preoperative diagnosis impact patient outcomes following reverse total shoulder arthr 2021 Jun BACKGROUND: The indications for reverse total shoulder arthroplasty (rTSA) have expanded to include the treatment of a wide variety of shoulder pathologies, and there may be significant differences in patient outcomes based on preoperative diagnosis. METHODS: A systematic review of the orthopedic literature contained in the PubMed, Cochrane, and Embase databases was performed on November 14, 2019. Studies investigating rTSA indicated for 7 distinct preoperative diagnoses (massive rotator cuff tear [MCT] without glenohumeral osteoarthritis [GHOA], MCT with GHOA or cuff tear arthropathy, primary GHOA, inflammatory arthritis with MCT, failed shoulder arthroplasty, proximal humeral fracture [PHF], and sequelae following PHF) were included. The main outcomes of interest included functional outcomes (abduction, external rotation, and forward flexion) and patient-reported outcome measures (American Shoulder and Elbow Surgeons shoulder score and Constant-Murley score). Because of significant variation in measurement and reporting, data on internal rotation were not extracted. In addition, radiographic outcomes and complication rates were extracted and recorded for each of the included studies. RESULTS: In total, 47 studies, comprising 2280 patients, met the inclusion criteria. Significant improvements in functional outcomes and patient-reported outcome measures were found across the preoperative diagnostic groups. There were no significant differences between the diagnostic groups regarding improvement between preoperative and postoperative values for the outcomes of interest, with the exception that the inflammatory arthropathy group had significantly less improvement in the Constant-Murley score than the primary GHOA and revision arthroplasty groups. Although there were few differences in improvement between groups, there were significant differences regarding the level of postoperative functional performance, which was not as consistent in the context of trauma or revision operations (ie, complex PHF, fracture sequela, and revision arthroplasty groups). CONCLUSION: Reverse total shoulder arthroplasty can provide reliable improvement in clinical outcomes regardless of preoperative diagnosis, with few differences across diagnostic groups regarding preoperative to postoperative improvement. The groups with primary GHOA and MCTs with or without GHOA demonstrated the most reliable postoperative functional outcomes of the examined diagnostic groups. Postoperative outcomes were not as consistent in the context of trauma or revision operations, and these groups may benefit from a variety of modern advancements in rTSA, although further research into these modalities for these groups is needed. Finally, rTSA remains an important treatment option in the context of rheumatoid arthritis, with similar outcomes and complication rates compared with the 6 other operative indications.
35386986 Translational Analysis of Moderate to Severe Asthma GWAS Signals Into Candidate Causal Gen 2021 Asthma affects more than 300 million people globally and is both under diagnosed and under treated. The most recent and largest genome-wide association study investigating moderate to severe asthma to date was carried out in 2019 and identified 25 independent signals. However, as new and in-depth downstream databases become available, the translational analysis of these signals into target genes and pathways is timely. In this study, unique (U-BIOPRED) and publicly available datasets (HaploReg, Open Target Genetics and GTEx) were investigated for the 25 GWAS signals to identify 37 candidate causal genes. Additional traits associated with these signals were identified through PheWAS using the UK Biobank resource, with asthma and eosinophilic traits amongst the strongest associated. Gene expression omnibus dataset examination identified 13 candidate genes with altered expression profiles in the airways and blood of asthmatic subjects, including MUC5AC and STAT6. Gene expression analysis through publicly available datasets highlighted lung tissue cell specific expression, with both MUC5AC and SLC22A4 genes showing enriched expression in ciliated cells. Gene enrichment pathway and interaction analysis highlighted the dominance of the HLA-DQA1/A2/B1/B2 gene cluster across many immunological diseases including asthma, type I diabetes, and rheumatoid arthritis. Interaction and prediction analyses found IL33 and IL18R1 to be key co-localization partners for other genes, predicted that CD274 forms co-expression relationships with 13 other genes, including the HLA-DQA1/A2/B1/B2 gene cluster and that MUC5AC and IL37 are co-expressed. Drug interaction analysis revealed that 11 of the candidate genes have an interaction with available therapeutics. This study provides significant insight into these GWAS signals in the context of cell expression, function, and disease relationship with the view of informing future research and drug development efforts for moderate-severe asthma.
34869275 A Fluorescent Aptasensor Based on Assembled G-Quadruplex and Thioflavin T for the Detectio 2021 VEGF165, a regulator of angiogenesis, has been widely used as a serum biomarker for a number of human diseases, including cancer, rheumatoid arthritis, bronchial asthma, and diabetic eye disease. The rapid, accurate, and convenient detection of VEGF165 is a crucial step in effective healthcare monitoring, disease diagnosis, and prognosis assessment. In this study, a fluorescent aptasensor based on an assembled G-quadruplex and the signal molecule ThT was developed for VEGF165 detection. First, G-rich DNA fragments were assembled at both ends of the anti-VEGF165 aptamer, and the B-DNA form was converted into a G-quadruplex structure aptamer (G4-Apt). Then, ThT was introduced, and the G-quadruplex significantly enhanced the fluorescence intensity of the bound ThT. When VEGF165 was present, the higher affinity of the aptamer to the target protein allowed the G4-Apt/VEGF165 complex to form and release ThT, which emitted only weak fluorescence in the free state. Therefore, the aptasensor exhibited a good linear detection window from 1.56 to 25 nM VEGF165, with a limit of detection of 0.138 nM. In addition, the aptasensor was applied to detect VEGF165 in clinical serum samples, showing good accuracy, reproducibility, and stability. These results indicate that our developed fluorescent aptasensor can potentially be a reliable, convenient, and cost-effective approach for the sensitive, specific, and rapid detection of the VEGF165 biomarker.
34846249 A dyadic exploration of support in everyday life of persons with RA and their significant 2021 Nov 30 BACKGROUND: Support from significant others is important for participation in everyday life for persons with rheumatoid arthritis (RA). Meanwhile, significant others also experience limitations. AIMS: To explore how support is expressed by persons with RA and significant others, and how support relates to participation in everyday life of persons with RA. MATERIAL AND METHODS: Sixteen persons with RA and their significant others participated in individual semi-structured interviews. The material was analyzed using dyadic analysis. RESULTS: Persons with RA and significant others reported that RA and support had become natural parts of everyday life, especially emotional support. The reciprocal dynamics of support were also expressed as imperative. Also, support from people outside of the dyads and well-functioning communication facilitated everyday life. CONCLUSIONS: Significant others and the support they give are prominent factors and facilitators in everyday life of persons with RA. Concurrently, the support persons with RA provide is important, along with support from outside of the dyads. SIGNIFICANCE: The results indicate that the interaction between persons with RA and the social environment is central to gain insight into how support should be provided for optimal participation in everyday life. Significant others can preferably be more involved in the rehabilitation process.
34834246 Chronobiology and Chronotherapy in Inflammatory Joint Diseases. 2021 Nov 2 Circadian rhythm perturbations can impact the evolution of different conditions, including autoimmune diseases. This narrative review summarizes the current understanding of circadian biology in inflammatory joint diseases and discusses the potential application of chronotherapy. Proinflammatory cytokines are key players in the development and progression of rheumatoid arthritis (RA), regulating cell survival/apoptosis, differentiation, and proliferation. The production and secretion of inflammatory cytokines show a dependence on the human day-night cycle, resulting in changing cytokine plasma levels over 24 h. Moreover, beyond the circadian rhythm of cytokine secretion, disturbances in timekeeping mechanisms have been proposed in RA. Taking into consideration chronotherapy concepts, modified-release (MR) prednisone tablets have been introduced to counteract the negative effects of night-time peaks of proinflammatory cytokines. Low-dose MR prednisone seems to be able to improve the course of RA, reduce morning stiffness and morning serum levels of IL-6, and induce significant clinical benefits. Additionally, methotrexate (MTX) chronotherapy has been reported to be associated with a significant improvement in RA activity score. Similar effects have been described for polymyalgia rheumatica and gout, although the available literature is still limited. Growing knowledge of chronobiology applied to inflammatory joint diseases could stimulate the development of new drug strategies to treat patients in accordance with biological rhythms and minimize side effects.
34765630 The Potential Effects of Dielectric Barrier Discharge Plasma on the Extraction Efficiency 2021 Radix paeoniae alba (RPA) is a kind of herbal medicine of traditional Chinese medicine (TCM) that is widely used for the treatment of liver diseases and rheumatoid arthritis in clinical practice. As a result of the low extraction efficiency of RPA by the conventional method, many patients are given high dosages. In this study, four exposure doses of dielectric barrier discharge (DBD) plasma (0, 60, 120, and 180 s) were applied to modify the extraction efficiency of paeoniflorin, benzoylpaeoniflorin, tannic acid, gallic acid, 2'-hydroxy-4'-methoxyacetophenone, and polysaccharide in RPA. Finally, the application of plasma for 180 s exhibited a 24.6% and 12.0% (p < 0.001) increase of tannic acid and polysaccharide contents, however, a 2.1% (p < 0.05) and 5.4% (p < 0.001) reduction of paeoniflorin and gallic acid composition, respectively, and no significant difference (p > 0.05) in results obtained from benzoylpaeoniflorin and 2'-hydroxy-4'-methoxyacetophenone contents. Our results of scanning electron microscopy (SEM), automatic specific surface area and pore analyzer, Fourier transform infrared spectroscopy (FTIR), X-ray photoelectron spectroscopy (XPS), and thermal gravimetric analysis (TGA) indicated that DBD plasma can etch the surface and undergo graft polymerization by reactive species thereby changing the water/oil holding capacity and eventually changing the extraction efficiency of bioactive compounds in RPA. Overall, our observations provide a scientific foundation for modifying the extraction efficiency of bioactive ingredients related to the pharmacological activities of RPA.
34584555 Linc8986 and linc0597 in plasma are novel biomarkers for systemic lupus erythematosus. 2021 Nov Despite increasing evidence that large intergenic non-coding RNAs (lincRNAs) are widely involved in human disease, the role of lincRNAs in the development of systemic lupus erythematosus (SLE) has remained largely elusive. The purpose of the present study was to investigate the expression of three lincRNAs (linc0597, linc8986 and linc7190) in the plasma of patients with SLE and their potential use as biomarkers for the diagnosis and treatment of SLE. Plasma samples were obtained from 54 patients with SLE, 24 patients with rheumatoid arthritis (RA), 24 patients with Sjogren's syndrome (SS) and 22 healthy controls. LincRNA expression levels were measured by reverse transcription-quantitative PCR. Compared with those in the healthy controls, the plasma levels of linc0597 and linc8986 were significantly increased in the patients with SLE (P<0.001), while the difference in the level of linc7190 was not significant (P=0.052). In addition, there was no significant difference in the levels of linc0597 and linc8986 among patients with RA, patients with SS and the healthy controls (P>0.05). Compared with patients with SLE without lupus nephritis (LN), the levels of linc0597 were significantly higher in patients with LN (P=0.044). For linc7190 and linc8986, there was no significant difference between patients with and without LN (P>0.05). Furthermore, complement component 3 (C3) levels were used to evaluate whether the expression of linc8986 and linc0597 is related to the activity of SLE. The results indicated that the levels of linc8986 and linc0597 were negatively correlated with the level of C3 (P<0.001 and P=0.004, respectively). Further analysis suggested that linc0597 and linc8986 were able to specifically identify patients with SLE and that a combination of linc0597 and linc8986 may improve the diagnostic accuracy. Therefore, the plasma levels of linc0597 and linc8986 may be suitable biomarkers for diagnosing SLE.
34563237 Contrast agents for photoacoustic imaging: a review of stem cell tracking. 2021 Sep 25 With the advent of stem cell therapy for spinal cord injuries, stroke, burns, macular degeneration, heart diseases, diabetes, rheumatoid arthritis and osteoarthritis; the need to track the survival, migration pathways, spatial destination and differentiation of transplanted stem cells in a clinical setting has gained increased relevance. Indeed, getting regulatory approval to use these therapies in the clinic depends on biodistribution studies. Although optoacoustic imaging (OAI) or photoacoustic imaging can detect functional information of cell activities in real-time, the selection and application of suitable contrast agents is essential to achieve optimal sensitivity and contrast for sensing at clinically relevant depths and can even provide information about molecular activity. This review explores OAI methodologies in conjunction with the specific application of exogenous contrast agents in comparison to other imaging modalities and describes the properties of exogenous contrast agents for quantitative and qualitative monitoring of stem cells. Specific characteristics such as biocompatibility, the absorption coefficient, and surface functionalization are compared and how the labelling efficiency translates to both short and long-term visualization of mesenchymal stem cells is explored. An overview of novel properties of recently developed optoacoustic contrast agents and their capability to detect disease and recovery progression in clinical settings is provided which includes newly developed exogenous contrast agents to monitor stem cells in real-time for multimodal sensing.
34341562 Autoinflammation and autoimmunity across rheumatic and musculoskeletal diseases. 2021 Oct Most rheumatic and musculoskeletal diseases (RMDs) can be placed along a spectrum of disorders, with autoinflammatory diseases (including monogenic systemic autoinflammatory diseases) and autoimmune diseases (such as systemic lupus erythematosus and antiphospholipid syndrome) representing the two ends of this spectrum. However, although most autoinflammatory diseases are characterized by the activation of innate immunity and inflammasomes and classical autoimmunity typically involves adaptive immune responses, there is some overlap in the features of autoimmunity and autoinflammation in RMDs. Indeed, some 'mixed-pattern' diseases such as spondyloarthritis and some forms of rheumatoid arthritis can also be delineated. A better understanding of the pathogenic pathways of autoinflammation and autoimmunity in RMDs, as well as the preferential cytokine patterns observed in these diseases, could help us to design targeted treatment strategies.
34176247 Drug-related cancers: Analyses of head and neck cases reported in the literature. 2021 Apr BACKGROUND: Recent advances have attributed carcinogenic potential to pharmacotherapy. Cancers of the head and neck region are no exception. OBJECTIVES: This descriptive investigation aimed to identify studies reporting on drugs that have contributed to cancer development in the head and neck region. MATERIAL AND METHODS: Online databases were searched for relevant articles and their data were summarized, including age, gender, main drug classification and name, additional drugs, primary disorders, drug-related cancers, and the site of each drug-related cancer. RESULTS: The mean age of the patients included in this analysis was 52.9 years. However, drug-related head and neck cancers (DR HNCs) were most prevalent in persons over 60 years of age. Overall, these cancers were more prevalent in females than in males (1.33/1). The HNC-related drugs could mainly be categorized into 3 groups, namely, immunomodulatory/immunosuppressive, chemotherapeutic and chemoprotective drugs, while the most frequently used additional drugs across the studies were corticosteroids. The 5 most prevalent primary conditions for which the patients had received pharmacotherapy were organ transplantations, lymphoproliferative disorders (LPD), rheumatoid arthritis (RA), Epstein-Barr virus (EBV) infection, and bone sarcoma. The most prevalent HNCs were squamous cell carcinoma (SCCs), thyroid cancers (including papillary and follicular thyroid carcinomas), LPD, and mucoepidermoid/acinic cell carcinomas, which occurred mostly in the oral cavity, neck, salivary glands, pharynx/larynx, and head/face. CONCLUSIONS: This study was the first of its kind to analyze and discuss the aforementioned findings regarding the head and neck region in depth. Clinicians should familiarize themselves with DR HNC cases to effectively screen suspected patients.
34008986 Characterization of Citrullination Sites in Neutrophils and Mast Cells Activated by Ionomy 2021 Jun 4 Citrullination is an important post-translational modification implicated in many diseases including rheumatoid arthritis (RA), Alzheimer's disease, and cancer. Neutrophil and mast cells have different expression profiles for protein-arginine deiminases (PADs), and ionomycin-induced activation makes them an ideal cellular model to study proteins susceptible to citrullination. We performed high-resolution mass spectrometry and stringent data filtration to identify citrullination sites in neutrophil and mast cells treated with and without ionomycin. We identified a total of 833 validated citrullination sites on 395 proteins. Several of these citrullinated proteins are important components of pathways involved in innate immune responses. Using this benchmark primary sequence data set, we developed machine learning models to predict citrullination in neutrophil and mast cell proteins. We show that our models predict citrullination likelihood with 0.735 and 0.766 AUCs (area under the receiver operating characteristic curves), respectively, on independent validation sets. In summary, this study provides the largest number of validated citrullination sites in neutrophil and mast cell proteins. The use of our novel motif analysis approach to predict citrullination sites will facilitate the discovery of novel protein substrates of protein-arginine deiminases (PADs), which may be key to understanding immunopathologies of various diseases.
33854514 Emerging Therapeutics for Immune Tolerance: Tolerogenic Vaccines, T cell Therapy, and IL-2 2021 Autoimmune diseases affect roughly 5-10% of the total population, with women affected more than men. The standard treatment for autoimmune or autoinflammatory diseases had long been immunosuppressive agents until the advent of immunomodulatory biologic drugs, which aimed at blocking inflammatory mediators, including proinflammatory cytokines. At the frontier of these biologic drugs are TNF-α blockers. These therapies inhibit the proinflammatory action of TNF-α in common autoimmune diseases such as rheumatoid arthritis, psoriasis, ulcerative colitis, and Crohn's disease. TNF-α blockade quickly became the "standard of care" for these autoimmune diseases due to their effectiveness in controlling disease and decreasing patient's adverse risk profiles compared to broad-spectrum immunosuppressive agents. However, anti-TNF-α therapies have limitations, including known adverse safety risk, loss of therapeutic efficacy due to drug resistance, and lack of efficacy in numerous autoimmune diseases, including multiple sclerosis. The next wave of truly transformative therapeutics should aspire to provide a cure by selectively suppressing pathogenic autoantigen-specific immune responses while leaving the rest of the immune system intact to control infectious diseases and malignancies. In this review, we will focus on three main areas of active research in immune tolerance. First, tolerogenic vaccines aiming at robust, lasting autoantigen-specific immune tolerance. Second, T cell therapies using Tregs (either polyclonal, antigen-specific, or genetically engineered to express chimeric antigen receptors) to establish active dominant immune tolerance or T cells (engineered to express chimeric antigen receptors) to delete pathogenic immune cells. Third, IL-2 therapies aiming at expanding immunosuppressive regulatory T cells in vivo.
33732266 The Immunomodulatory Effect and Clinical Efficacy of Daratumumab in a Patient With Cold Ag 2021 Daratumumab is a monoclonal antibody directed against the transmembrane glycoprotein CD38 expressed on plasma cells and lymphoplasmocytes, with a proven efficacy in multiple myeloma. Here we show its clinical efficacy in a patient with cold agglutinin disease (CAD) relapsed after multiple lines of therapy. CAD is caused by cold reactive autoantibodies that induce complement mediated hemolysis and peripheral circulatory symptoms. The disease is also characterized by the presence of monoclonal IgM gammopathy and of a lymphoid bone marrow infiltration that benefits from B-cell targeting therapies (i.e., rituximab) but also from plasma cell directed therapies, such as proteasome inhibitors. In the patient described, we also show that daratumumab therapy influenced the dynamics of several immunoregulatory cytokine levels (IL-6, IL-10, IL-17, IFN-γ, TNF-α, TGF-β) indicating an immunomodulatory effect of the drug beyond plasma cell depletion. In addition, we provide a literature review on the use of daratumumab in autoimmune conditions, including multi-treated and refractory patients with autoimmune hemolytic anemia (both CAD and warm forms), Evans syndrome (association of autoimmune hemolytic anemia and immune thrombocytopenia) and non-hematologic autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis.
33515791 Hydroxychloroquine in systemic and autoimmune diseases: Where are we now? 2021 May Hydroxychloroquine (HCQ), one of the oldest drugs used in rheumatology, came recently into attention as one of the potential therapies tested for the severe acute respiratory syndrome coronavirus-2 disease treatment. Used initially as an antimalarial, then translated to rheumatic diseases, HCQ has been used in a wide range of pathologies, including infectious diseases, immune disorders, diabetes, dyslipidemia, or neoplasia. Regarding systemic diseases, HCQ is the mainstay treatment for systemic lupus erythematosus (SLE), where, according to last European guidelines, it is proposed to all SLE patients unless contraindicated or with side effects. HCQ proved positive impact in SLE on robust outcomes, such as accrual damage, disease activity and survival, but also pleiomorphic effects, including decrease in the need for glucocorticoids, reduction in the risk of neonatal lupus, lower fasting glucose and protection against diabetes, thrombotic risk, dyslipidemia, infections, etc. Moreover, HCQ can be used during pregnancy and breast-feeding. Besides SLE, the role for HCQ in the anti-phospholipid syndrome and Sjögren's disease is still under debate. On the contrary, recent advances showed only limited interest for rheumatoid arthritis, especially due the lack of structural damage prevention. There are still no strong data to sustain the HCQ use in other systemic diseases. In this review, we summarised the utility and efficacy of HCQ in different clinical conditions relevant for rheumatology practice.
33505480 Efficacy and safety of mycophenolate mofetil in the treatment of rheumatic disease-related 2021 Mycophenolate mofetil (MMF) is an antimetabolite with a potent inhibitory effect on proliferation of T and B lymphocytes used since the early 1990s for the prevention of acute allograft rejection after organ transplant. MMF is also widely used for the treatment of a variety of rheumatic diseases (RDs) and their pulmonary involvement. Interstitial lung disease (ILD) is a heterogeneous group of progressive fibrotic diseases of the lung, which is often secondary to RD and represents a major cause of morbidity and mortality. MMF is considered the main alternative to cyclophosphamide as a first-line agent to treat RD-related ILD or as possible maintenance therapy after cyclophosphamide, with a lower rate of side-effects. However, as for other immunosuppressive agents, the use of MMF in RD-ILD is supported by poor scientific evidence. In this narrative review, we describe the available data and recent advances on the effectiveness and safety of MMF for the treatment of ILD related to RD, including rheumatoid arthritis, systemic sclerosis, primary Sjögren syndrome, systemic lupus erythematosus, idiopathic inflammatory myopathies, undifferentiated connective tissue disease, interstitial pneumonia with autoimmune features and antineutrophil cytoplasmic antibody-associated vasculitis.
33428504 Formulation and stability study of hydroxychloroquine sulfate oral suspensions. 2021 Mar Hydroxychloroquine is an antimalarial drug indicated in the treatment of acute attacks of malaria due to Plasmodium vivax, P. malariae, P. ovale, and susceptible strains of P. falciparum. It is also used for the treatment of rheumatoid arthritis, discoid and systemic lupus erythematosus, and more recently proposed in COVID-19 therapy. Hydroxychloroquine is only available in tablets which are not easy to administer for pediatric and geriatric patients, and patients unable to swallow such as patients found in intensive care units. The aim of this work was to develop and optimize a ready to use liquid hydroxychloroquine formulation and to carry out the corresponding chemical and microbiological stability studies. The formulation was evaluated for ease of preparation, physical properties, and palatability. Its stability was performed at ambient temperature and under refrigeration. After 6 months of stability testing, the results showed no pH change, no drug loss, no microbial development, and no visual change. The formulation, employing excipients in a range that EMA has recommended, showed chemical and microbiological stability for at least 6 months even in the worst storage conditions.
33352085 Invasive Fusariosis in Nonneutropenic Patients, Spain, 2000-2015. 2021 Jan Invasive fusariosis (IF) is associated with severe neutropenia in patients with concurrent hematologic conditions. We conducted a retrospective observational study to characterize the epidemiology of IF in 18 Spanish hospitals during 2000-2015. In that time, the frequency of IF in nonneutropenic patients increased from 0.08 cases per 100,000 admissions in 2000-2009 to 0.22 cases per 100,000 admissions in 2010-2015. Nonneutropenic IF patients often had nonhematologic conditions, such as chronic cardiac or lung disease, rheumatoid arthritis, history of solid organ transplantation, or localized fusariosis. The 90-day death rate among nonneutropenic patients (28.6%) and patients with resolved neutropenia (38.1%) was similar. However, the death rate among patients with persistent neutropenia (91.3%) was significantly higher. We used a multivariate Cox regression analysis to characterize risk factors for death: persistent neutropenia was the only risk factor for death, regardless of antifungal therapy.
33235388 Novel human immunomodulatory T cell receptors and their double-edged potential in autoimmu 2021 Apr In the last decade, approaches based on T cells and their immunomodulatory receptors have emerged as a solid improvement in treatments for various types of cancer. However, the roles of these molecules in the therapeutic context of autoimmune and cardiovascular diseases are still relatively unexplored. Here, we review the best known and most commonly used immunomodulatory T cell receptors in clinical practice (PD-1 and CTLA-4), along with the rest of the receptors with known functions in animal models, which have great potential as modulators in human pathologies in the medium term. Among these other receptors is the receptor CD69, which has recently been described to be expressed in mouse and human T cells in autoimmune and cardiovascular diseases and cancer. However, inhibition of these receptors individually or in combination by drugs or monoclonal antibodies generates a loss of immunological tolerance and can trigger multiple autoimmune disorders in different organs and immune-related adverse effects. In the coming decades, knowledge on the functions of different immunomodulatory receptors will be pivotal for the development of new and better therapies with less harmful side effects. In this review, we discuss the roles of these receptors in the control of immunity from a perspective focused on therapeutic potential in not only cancer but also autoimmune diseases, such as systemic lupus erythematosus, autoimmune diabetes and rheumatoid arthritis, and cardiovascular diseases, such as atherosclerosis, acute myocardial infarction, and myocarditis.
33130388 Computational engineering the binding affinity of Adalimumab monoclonal antibody for desig 2021 Jan Amongst the anti-TNF-α therapy for rheumatoid arthritis and other autoimmune diseases, Adalimumab mAb is one of the best candidates. However, several risk factors are found to be associated with higher doses. Improvement of the binding properties will therefore significantly increase its therapeutic efficacy, reduce the dosage requirements, and ultimately the associated toxicity and treatment cost. Here, we proposed a systematic in silico approach of finding newer mAb variants with improved binding properties. Using various bioinformatics tools, we have identified the significant amino acid residues on Adalimumab mAb. Next, we searched for the suitability of the other residues for mutating the significant residues and from the combinations of suitable mutations, variants were designed. To find the most significant ones, binding properties of the variants were compared with the wild type Adalimumab mAb using molecular docking scrutiny and molecular dynamics simulation. Finally, structural properties between the variant and wild type were analyzed. We have identified the six most significant residues on Adalimumab mAb involved in the antigen-antibody interactions. Using the suitable mutations replacing each of these residues, we have modeled 143 variants. From several docking analyses, we have found five significant variants and after molecular dynamics simulation, one most significant variant with improved binding affinity was identified whose structural properties are similar to the wild type Adalimumab mAb. Designed variant from this study, may provide newer insights on the structure-based affinity improvements of monoclonal antibodies and likewise modifications of the Fc region will also improve the therapeutic effector functions of antibodies too.
35002722 Latent Transforming Growth Factor-β Binding Protein-2 Regulates Lung Fibroblast-to-Myofib 2021 Despite past extensive studies, the mechanisms underlying pulmonary fibrosis (PF) still remain poorly understood. The aberrantly activated lung myofibroblasts, predominantly emerging through fibroblast-to-myofibroblast differentiation, are considered to be the key cells in PF, resulting in excessive accumulation of extracellular matrix (ECM). Latent transforming growth factor-β (TGFβ) binding protein-2 (LTBP2) has been suggested as playing a critical role in modulating the structural integrity of the ECM. However, its function in PF remains unclear. Here, we demonstrated that lungs originating from different types of patients with PF, including idiopathic PF and rheumatoid arthritis-associated interstitial lung disease, and from mice following bleomycin (BLM)-induced PF were characterized by increased LTBP2 expression in activated lung fibroblasts/myofibroblasts. Moreover, serum LTBP2 was also elevated in patients with COVID-19-related PF. LTBP2 silencing by lentiviral shRNA transfection protected against BLM-induced PF and suppressed fibroblast-to-myofibroblast differentiation in vivo and in vitro. More importantly, LTBP2 overexpression was able to induce differentiation of lung fibroblasts to myofibroblasts in vitro, even in the absence of TGFβ1. By further mechanistic analysis, we demonstrated that LTBP2 silencing prevented fibroblast-to-myofibroblast differentiation and subsequent PF by suppressing the phosphorylation and nuclear translocation of NF-κB signaling. LTBP2 overexpression-induced fibroblast-to-myofibroblast differentiation depended on the activation of NF-κB signaling in vitro. Therefore, our data indicate that intervention to silence LTBP2 may represent a promising therapy for PF.