Pathogenesis Of Rheumatic Diseases Research Articles

Clinical and pathogenetic significance of the phenomenon of functional heterogeneity of oxygen-dependent functions of neutrophils in ankylosing spondylitis

Neutrophils are able to exert a variety of effects on other cells of the immune system, which indicates their heterogeneity. In various rheumatic diseases, neutrophils are involved in the immunopathological process. The study of the phenomenon of functional heterogeneity of neutrophils associated with the pathogenesis of rheumatic diseases is a promising area of research in immunology and rheumatology. The purpose of the research: study of factors influencing oxygen-dependent neutrophil functions in ankylosing spondylitis (AS). A total of 82 patients with AS were examined. The functional activity of neutrophils was assessed according to the data of determining the indicators of oxygen-dependent functions by the chemiluminescence method. Functional neutrophil reserve (FNR) was assessed by activation coefficients (the ratio of chemiluminescence induced by suspension of heat-killed staphylococcus cells to spontaneous value). Statistical data processing was carried out using Statistica 10.0 program. An increase in oxygen-dependent neutrophil functions in AS was accompanied by an increase in disease activity. The greatest influence on the increase in the functional activity of cells was exerted by the age of patients, the stage of the disease and the level of circulating immune complexes. The process of stabilizing the metabolic activity of neutrophils was significantly influenced by the age of patients, ESR, ã-globulins, total cholesterol, and low-density lipoprotein cholesterol. Among the laboratory parameters, the majority of AS patients with moderate and high FNR had elevated levels of ESR, CRP, and IgM; there was a tendency to increase IgA in AS patients with high FNR. Statistical analyses showed an association between FNR and disease activity; there was no statistically significant dependence of FNR on the stage, course, and form of AS. The study of the metabolic activity of neutrophils during dynamic observation revealed a group of patients with stabilization of FNR parameters against the background of therapy with the achievement of a normal level of oxygen-dependent metabolism. Thus, in ankylosing spondylitis, the functional heterogeneity of neutrophils associated with disease activity was established according to the determination of oxygen-dependent metabolism.

Emerging Role and Mechanism of Mesenchymal Stem Cells-Derived Extracellular Vesicles in Rheumatic Disease.

Mesenchymal stem cells (MSCs) are pluripotent stem cells derived from mesoderm. Through cell-to-cell contact or paracrine effects, they carry out biological tasks like immunomodulatory, anti-inflammatory, regeneration, and repair. Extracellular vesicles (EVs) are the primary mechanism for the paracrine regulation of MSCs. They deliver proteins, nucleic acids, lipids, and other active compounds to various tissues and organs, thus facilitating intercellular communication. Rheumatic diseases may be treated using MSCs and MSC-derived EVs (MSC-EVs) due to their immunomodulatory capabilities, according to mounting data. Since MSC-EVs have low immunogenicity, high stability, and similar biological effects as to MSCs themselves, they are advantageous over cell therapy for potential therapeutic applications in rheumatoid arthritis, systemic erythematosus lupus, systemic sclerosis, Sjogren's syndrome, and other rheumatoid diseases. This review integrates recent advances in the characteristics, functions, and potential molecular mechanisms of MSC-EVs in rheumatic diseases and provides a new understanding of the pathogenesis of rheumatic diseases and MSC-EV-based treatment strategies.

Gut microbiota and rheumatic diseases: new insights into pathogenesis

Background: Rheumatic diseases are a group of disorders characterised by a loss of immune tolerance, which leads to chronic inflammation, degeneration or metabolic abnormalities in various organs or tissues. Despite the lack of clarity surrounding the causes of these diseases, both environmental and genetic factors play an important role. Recent research indicates that alterations in the composition of the gut microbiota, known as gut dysbiosis, may contribute to the development of a number of rheumatic diseases, including rheumatoid arthritis, systemic lupus, ankylosing spondylitis, systemic scleroderma and Sjögren's syndrome. The gut microbiota influences the balance between pro- and anti-inflammatory immune responses, which may have important implications for the pathogenesis of these diseases. Furthermore, studies have indicated that the composition of the gut microbiota may be associated with the response to therapies used to treat rheumatic diseases, thus opening up new avenues for the development of microbiota-targeted treatments for these conditions. Aim of the study: The objective of this review is to investigate the impact of the gut microbiota on the pathogenesis of rheumatic diseases and to evaluate potential therapies targeting the manipulation of the gut microbiota. Material and methods: The present study is based on literature available in scientific databases from 2019-2024, such as PubMed, Corchane Library and Google Scholar.Results and conclusions: A growing body of evidence suggests a potential link between the gut microbiota and rheumatic diseases. Patients often exhibit a reduced ratio of Firmicutes to Bacteroidetes and abnormal numbers of Bacteroides. Molecular mimicry and a potential association with short-chain fatty acids have also been observed. Further human studies are needed to more fully understand the role of the gut microbiota and potential therapeutic interventions.

The Genetic Landscape of Systemic Rheumatic Diseases: A Comprehensive Multigene-Panel Study Identifying Key Gene Polymorphisms.

Systemic rheumatic diseases, including conditions such as rheumatoid arthritis, Sjögren's syndrome, systemic sclerosis, and systemic lupus erythematosus, represent a complex array of autoimmune disorders characterized by chronic inflammation and diverse clinical manifestations. This study focuses on unraveling the genetic underpinnings of these diseases by examining polymorphisms in key genes related to their pathology. Utilizing a comprehensive genetic analysis, we have documented the involvement of these genetic variations in the pathogenesis of rheumatic diseases. Our study has identified several key polymorphisms with notable implications in rheumatic diseases. Polymorphism at chr11_112020916 within the IL-18 gene was prevalent across various conditions with a potential protective effect. Concurrently, the same IL18R1 gene polymorphism located at chr2_103010912, coding for the IL-18 receptor, was observed in most rheumatic conditions, reinforcing its potential protective role. Additionally, a further polymorphism in IL18R1 at chr2_103013408 seems to have a protective influence against the rheumatic diseases under investigation. In the context of emerging genes involved in rheumatic diseases, like PARK2, a significant polymorphism at chr6_161990516 was consistently identified across different conditions, exhibiting protective characteristics in these pathological contexts. The findings underscore the complexity of the genetic landscape in rheumatic autoimmune disorders and pave the way for a deeper understanding of their etiology and the possible development of more targeted and effective therapeutic strategies.

Hurdles in new drug development in rheumatic diseases

IntroductionRheumatic diseases are heterogenous conditions with multifactorial underlying physiologic pathogeneses. Despite recent progress in the identification and development of advanced therapies primarily focusing on disrupting the immunological abnormalities that cause these conditions, rheumatic disease management remains challenging in a notable proportion of patients, with many exhibiting uncontrolled or refractory disease activity. New and improved therapies are needed to respond to this treatment gap. However, there are important hurdles that can affect the expedited identification and assessment of new treatments. MethodsWe present a review of key hurdles in the development of antirheumatic agents, as well as possible solutions to these obstacles. ResultsWe highlight the challenges presented by incomplete understanding of the complexity of rheumatic disease pathophysiology and the resultant difficulties in the identification, development, and evaluation of new therapies. We further explore the diversity of the underlying disease processes leading to heterogeneity in patient response to treatment, necessitating the re-design of clinical trials of antirheumatic agents to detect efficacy signals and better inform clinical disease management. Finally, emergent strategies and methodologies with potential to improve upon these hurdles are presented. ConclusionNew and modified study designs and research tools that leverage ongoing advancements in the elucidation of rheumatic disease pathogenesis coupled with progress in methods to mine available data will be instrumental in overcoming current hurdles in antirheumatic drug development.

Cigarette smoking and risk of adult-onset Still disease: a propensity score matching analysis.

Environmental factors play an important role in the pathogenesis of rheumatic diseases. Smoking is thought to be a risk factor for autoimmune rheumatic diseases. The purpose of the present study was to assess the association between smoking and adult-onset Still disease (AOSD) and the effect of smoking on outcomes of this disease. In this case-control study, patients with AOSD who met the Yamaguchi criteria, were older than 16 years at the disease onset and were in follow-up for at least 12 months were consecutively enrolled in the study. The outcome of AOSD was assessed by acquiring remission on treatment, remission off treatment, time to remission and rate of flare. The smoking status of participants was defined by direct or phone interviews. Individuals who had smoked daily for at least 6 months were defined as a smoker. We performed propensity score matching analyses by using four parameters, including age, sex, educational status and marital status. Propensity score matching resulted in 72 patients with AOSD and 216 matched controls. The number of ever smokers in the AOSD and control groups were 11 (15.3%) and 25 (11.6%) respectively. There was no significant increase in the risk of AOSD in multivariate analysis after adjustment for age, sex, marital status and educational level. There were no significant differences in the outcomes of AOSD between ever and never smokers. Smoking probably is not a risk factor for AOSD and did not affect the response to treatment.

CircIFNGR2 regulating ankylosing spondylitis-associated inflammation through macrophage polarization

Macrophages activation is crucial in pathogenesis of rheumatic diseases like ankylosing spondylitis (AS). Circular RNAs (circRNAs)-induced macrophage-associated inflammation participates in many autoimmune diseases but remains elusive in AS. Here, we verified increased expression of circIFNGR2 in peripheral blood mononuclear cells from patients with AS and its expression levels were correlated with the AS severity. Invitro assays revealed that circIFNGR2 enhances macrophage proliferation, and regulates M1/M2 macrophage polarization and NF-κB/Akt pathways. We identified that circIFNGR2 promoted the expression of iNOS/TNFα and M1 polarization, and restrained M2 polarization by sponging miR-939. Additionally, the RNA-binding protein, eIF4A3, was found to enhance the production of circIFNGR2. Interestingly, miR-939 attenuated joint damage in collagen-induced arthritis mice, whereas circIFNGR2 reversed this effect. Our findings highlight the pro-inflammatory roles of eIF4A3-induced circIFNGR2 in AS by modulating macrophage-associated inflammation through miR-939.

Integrated Immune Cell-Cell Communication Networks Underpinning Rheumatoid Arthritis Pathogenesis

Rheumatoid Arthritis (RA) is a chronic, systemic auto-inflammatory disease that targets peripheral joints causing bone erosion, worsened mobility, and lower quality of life. RA is a complex autoimmune disease that develops through the combined actions of many cell types. In particular, monocytes, fibroblasts, and T cells play critical roles within the arthritic joint driving disease pathogenesis. These cells communicate with each other via ligand-receptor interactions orchestrating inflammatory responses ultimately leading to joint destruction. However, it remains unclear how the combined efforts of these different cells form an integrated network of immune responses which ultimately lead to disease development. Therefore, we hypothesized that an integrated communication network between the different immune cells found within RA joints functions to promote inflammation and drive RA disease pathogenesis. I utilized predictive assessment of cell-cell communication networks through single-cell RNA-sequencing to determine how immune cell interactions differ between autoimmune and non-autoimmune joint destruction. These studies identified a novel cell-cell communication network in which monocytes, fibroblasts and T cells cooperate to promote cell-cell interactions, immune activation, and induction of pro-inflammatory gene networks. Together, these results identify numerous potential therapeutic targets for the intervention of RA disease.

Restoring Balance: Immune Tolerance in Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a systemic musculoskeletal disease where immune dysregulation and subsequent autoimmunity induce significant synovial joint inflammation and damage, causing pain and disability. RA disease onset is promoted through multifaceted interactions between genetic and environmental risk factors. However, the mechanisms of disease onset are not completely understood and disease-specific treatments are yet to be developed. Current RA treatments include nonspecific disease-modifying antirheumatic drugs (DMARDs) that suppress destructive immune responses and prevent damage. However, DMARDs are not curative, and relapses are common, necessitating lifelong therapy in most patients. Additionally, DMARD-induced systemic immunosuppression increases the risk of serious infections and malignancies. Herein, we review the current understanding of RA disease pathogenesis, with a focus on T and B cell immune tolerance breakdown, and discuss the development of antigen-specific RA therapeutics that aim to restore a state of immune tolerance, with the potential for disease prevention and reduction of treatment-associated adverse effects.

Effects of intestinal microbes on rheumatic diseases: A bibliometric analysis.

Rheumatic diseases (RD) are a group of multi-system inflammatory autoimmune diseases whose causes are still under study. In the past few decades, researchers have found traces of the association between rheumatic diseases and intestinal microbiota, which can partially explain the pathogenesis of rheumatic diseases. We aimed to describe the research trend and main divisions on how gut flora interreacts with rheumatic diseases, and discussed about the possible clinical applications. We analyzed bibliometric data from the Web of Science core collection (dated 15th May 2022). Biblioshiny R language software packages (bibliometrix) were used to obtain the annual publication and citations, core sources according to Bradford's law, and country collaboration map. We designed and verified the keyword co-occurrence network and strategic diagram with the help of VOSviewer and CiteSpace, subdivided the research topic into several themes and identified research dimensions. The tables of most local cited documents and core sources were processed manually. Furthermore, the Altmetric Attention Score and the annual Altmetric Top 100 were applied to analyze the annual publication and citation. From a total of 541 documents, we found that the overall trend of annual publication and citation is increasing. The major research method is to compare the intestinal microbial composition of patients with certain rheumatic disease and that of the control group to determine microbial alterations related to the disease's occurrence and development. According to Bradford's law, the core sources are Arthritis and Rheumatology, Annals of the Rheumatic Diseases, Current Opinion in Rheumatology, Nutrients, Rheumatology, and Journal of Rheumatology. Since 1976, 101 countries or regions have participated in studies of rheumatology and intestinal microbes. The United States ranks at the top and has the broadest academic association with other countries. Five themes were identified, including the pivotal role of inflammation caused by intestinal bacteria in the rheumatic pathogenesis, the close relationship between rheumatic diseases and inflammatory bowel disease, immunoregulation mechanism as a mediator of the interaction between rheumatic diseases and gut flora, dysbiosis and decreased diversity in intestine of patients with rheumatic diseases, and the influence of oral flora on rheumatic diseases. Additionally, four research dimensions were identified, including pathology, treatment, disease, and experiments. Studies on rheumatic diseases and the intestinal microbiota are growing. Attention should be paid to the mechanism of their interaction, such as the microbe-immune-RD crosstalk. Hopefully, the research achievements can be applied to diseases' prevention, diagnosis, and treatment, and our work can contribute to the readers' future research.

The Yin-Yang Pharmacomicrobiomics on Treatment Response in Inflammatory Arthritides: A Narrative Review.

(1) Background: Gut microbiota (GM) is the set of microorganisms inhabiting the gastroenteric tract that seems to have a role in the pathogenesis of rheumatic diseases. Recently, many authors proved that GM may influence pharmacodynamics and pharmacokinetics of several drugs with complex interactions that are studied by the growing field of pharmacomicrobiomics. The aim of this review is to highlight current evidence on pharmacomicrobiomics applied to the main treatments of Rheumatoid Arthritis and Spondyloarthritis in order to maximize therapeutic success, in the framework of Personalized Medicine. (2) Methods: We performed a narrative review concerning pharmacomicrobiomics in inflammatory arthritides. We evaluated the influence of gut microbiota on treatment response of conventional Disease Modifying Anti-Rheumatic drugs (cDMARDs) (Methotrexate and Leflunomide) and biological Disease Modifying Anti-Rheumatic drugs (bDMARDs) (Tumor necrosis factor inhibitors, Interleukin-17 inhibitors, Interleukin 12/23 inhibitors, Abatacept, Janus Kinase inhibitors and Rituximab). (3) Results: We found a great amount of studies concerning Methotrexate and Tumor Necrosis Inhibitors (TNFi). Conversely, fewer data were available about Interleukin-17 inhibitors (IL-17i) and Interleukin 12/23 inhibitors (IL-12/23i), while none was identified for Janus Kinase Inhibitors (JAKi), Tocilizumab, Abatacept and Rituximab. We observed that microbiota and drugs are influenced in a mutual and reciprocal way. Indeed, microbiota seems to influence therapeutic response and efficacy, whereas in the other hand, drugs may restore healthy microbiota. (4) Conclusions: Future improvement in pharmacomicrobiomics could help to detect an effective biomarker able to guide treatment choice and optimize management of inflammatory arthritides.

Neutrophils in the Pathogenesis of Rheumatic Diseases.

Rheumatic diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), are a group of auto-inflammatory disorders associated with substantial morbidity and mortality. One unifying feature of these diseases is the presence of abnormal neutrophils exhibiting dysregulated neutrophil extracellular trap (NET) release, reactive oxygen species (ROS) production, degranulation, and pro-inflammatory cytokines secretion. Moreover, the release of autoantigens associated with NETs promotes the generation of autoantibodies and a breakdown of self-tolerance, thereby perpetuating inflammation and tissue injury in these patients. In recent years, targeted therapies directed at neutrophilic effector functions have shown promising results in the management of rheumatic diseases. In this review, we will highlight the emerging roles of neutrophils in the onset and progression of rheumatic diseases, and further discuss current and future therapeutic approaches targeting the pathogenic functions of neutrophils, which can modulate inflammation and hence improve patients' survival and quality of life.

Gene regulatory network study of rheumatoid arthritis in single-cell chromatin landscapes of peripheral blood mononuclear cells.

Assays for transposase-accessible chromatin with single-cell sequencing (scATAC-seq) contribute to the progress in epigenetic studies. The purpose of our project was to discover the transcription factors (TFs) that were involved in the pathogenesis of rheumatoid arthritis (RA) at a single-cell resolution using epigenetic technology. Peripheral blood mononuclear cells of seven RA patients and seven natural controls were extracted nuclei suspensions for library construction. Subsequently, scATAC-seq was performed to generate a high-resolution map of active regulatory DNA for bioinformatics analysis. We obtained 22 accessible chromatin patterns. Then, 10 key TFs were involved in RA pathogenesis by regulating the activity of mitogen-activated protein kinase. Consequently, two genes (PTPRC and SPAG9) regulated by 10 key TFs were found, which may be associated with RA disease pathogenesis, and these TFs were obviously enriched in RA patients (P < .05, fold change value > 1.2). With further quantitative polymerase chain reaction validation on PTPRC and SPAG9 in monocytes, we found differential expression of these two genes, which were regulated by eight TFs [ZNF384, HNF1B, DMRTA2, MEF2A, NFE2L1, CREB3L4 (var. 2), FOSL2::JUNB (var. 2), and MEF2B], showing highly accessible binding sites in RA patients. These findings demonstrate the value of using scATAC-seq to reveal transcriptional regulatory variation in RA-derived peripheral blood mononuclear cells, providing insights into therapy from an epigenetic perspective.

Endoplasmic Reticulum Stress, Oxidative Stress, and Rheumatic Diseases.

Background: The endoplasmic reticulum (ER) is a multi-functional organelle responsible for cellular homeostasis, protein synthesis, folding and secretion. It has been increasingly recognized that the loss of ER homeostasis plays a central role in the development of autoimmune inflammatory disorders, such as rheumatic diseases. Purpose/Main contents: Here, we review current knowledge of the contribution of ER stress to the pathogenesis of rheumatic diseases, with a focus on rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). We also review the interplay between protein folding and formation of reactive oxygen species (ROS), where ER stress induces oxidative stress (OS), which further aggravates the accumulation of misfolded proteins and oxidation, in a vicious cycle. Intervention studies targeting ER stress and oxidative stress in the context of rheumatic diseases are also reviewed. Conclusions: Loss of ER homeostasis is a significant factor in the pathogeneses of RA and SLE. Targeting ER stress, unfolded protein response (UPR) pathways and oxidative stress in these diseases both in vitro and in animal models have shown promising results and deserve further investigation.

Pathogenesis and Treatment of T-Large Granular Lymphocytic Leukemia (T-LGLL) in the Setting of Rheumatic Disease.

A complex relationship exists between rheumatic diseases and cancer. This delicate balance between chronic inflammation and malignant cell transformation in hematologic neoplasms has been observed, but is not well defined. Large Granular Lymphocyte (LGL) leukemia is at the intersection of a clonal lymphoproliferative disease, chronic inflammation, and autoimmunity. The association between rheumatoid arthritis (RA) and the spectrum of Felty’s Syndrome is well-known. Other rheumatic disorders have been reported including systemic lupus erythematosus (SLE), Sjogren’s Syndrome (SS), vasculitis, Behcet’s Disease (BD) and systemic sclerosis. The association between T-LGLL and rheumatic disease pathogenesis has been hypothesized, but has not yet been fully understood. Components of a shared pathogenesis includes chronic antigen stimulation, JAK-STAT pathway activation and overlap of various cytokines. We will summarize current knowledge on the molecular understanding between T-LGLL and rheumatic disease. There are many potential areas of research to help meet this need and lead to development of targeted therapeutic options.

The Role of IgG4 in Autoimmunity and Rheumatic Diseases

The distinguishing of the IgG4-related disease (IgG4-RD) from among other rheumatic diseases has brought attention to the IgG4 subclass of immunoglobulins. It is the least numerous subclass among immunoglobulins G. In general, IgG4 is considered to be non-inflammatory and tolerance inducing, due to its unique structure. However, in IgG4-RD this antibody plays a pathogenic role in activation of the fibrinogenesis and of the inflammatory process; there are also suggestions that it may be a marker of an abnormal inflammatory response. The importance of IgG4 for the pathogenesis of allergic diseases, with a vital role of its ratio to immunoglobulin E (IgE/IgG4 ratio), has been known for years. The role of IgG4 in the course and pathogenesis of rheumatic diseases is still being researched and is not yet fully understood. Increased IgG4 levels have been revealed in rheumatoid arthritis, although no clear link between this phenomenon and disease activity has been demonstrated. There are articles on the potential importance of IgG4 concentration (of both elevated and decreased serum levels) in Sjogren’s syndrome. Additionally, anti-nuclear IgG4 antibody significant titers have been detected in SLE patients, and it has been suggested that the effect of these antibodies on complement consumption and the production of proinflammatory cytokines may play a role in inhibiting the progression of SLE. IgG4 plays a role in autoimmune diseases other than rheumatic diseases, such as pemphigus, bullous pemphigoid, idiopathic membranous glomerulonephritis, or myasthenia gravis, but also in helmints infections. Research shows the importance of IgG4 in malignancy of neoplasms. Melanoma cells are known to stimulate IgG4 production through a modified Th2-based inflammatory response. The role of this immunoglobulin in cholangiocarcinoma is also considered as possible. The aim of this review article is to discuss the current knowledge of IgG4 not only from the perspective of the IgG4-RD but also from a point of view of other autoimmune diseases with particular emphasis on rheumatic diseases.

Single Cell RNA Sequencing in Autoimmune Inflammatory Rheumatic Diseases: Current Applications, Challenges and a Step Toward Precision Medicine.

Single cell RNA sequencing (scRNA-seq) represents a new large scale and high throughput technique allowing analysis of the whole transcriptome at the resolution of an individual cell. It has emerged as an imperative method in life science research, uncovering complex cellular networks and providing indices that will eventually lead to the development of more targeted and personalized therapies. The importance of scRNA-seq has been particularly highlighted through the analysis of complex biological systems, in which cellular heterogeneity is a key aspect, such as the immune system. Autoimmune inflammatory rheumatic diseases represent a group of disorders, associated with a dysregulated immune system and high patient heterogeneity in both pathophysiological and clinical aspects. This complicates the complete understanding of underlying pathological mechanisms, associated with limited therapeutic options available and their long-term inefficiency and even toxicity. There is an unmet need to investigate, in depth, the cellular and molecular mechanisms driving the pathogenesis of rheumatic diseases and drug resistance, identify novel therapeutic targets, as well as make a step forward in using stratified and informed therapeutic decisions, which could now be achieved with the use of single cell approaches. This review summarizes the current use of scRNA-seq in studying different rheumatic diseases, based on recent findings from published in vitro, in vivo, and clinical studies, as well as discusses the potential implementation of scRNA-seq in the development of precision medicine in rheumatology.

Single-Cell Sequencing in Rheumatic Diseases: New Insights from the Perspective of the Cell Type.

Rheumatic diseases are a group of highly heterogeneous autoimmune and inflammatory disorders involving multiple systems. Dysfunction of immune and non-immune cells participates in the complex pathogenesis of rheumatic diseases. Therefore, studies on the abnormal activation of cell subtypes provided a specific basis for understanding the pathogenesis of rheumatic diseases, which promoted the accuracy of disease diagnosis and the effectiveness of various treatments. However, there was still a far way to achieve individualized precision medicine as the result of heterogeneity among cell subtypes. To obtain the biological information of cell subtypes, single-cell sequencing, a cutting-edge technology, is used for analyzing their genomes, transcriptomes, epigenetics, and proteomics. Novel results identified multiple cell subtypes in tissues of patients with rheumatic diseases by single-cell sequencing. Consequently, we provide an overview of recent applications of single-cell sequencing in rheumatic disease and cross-tissue to understand the cell subtypes and functions.

Rheumatology and functional genome analysis in East Asia

AbstractRheumatic diseases differ in severity and outcome across ethnic groups. Although genetic predisposition is an important factor influencing the development of rheumatic diseases, genomic data to date have been accumulated mainly in Europeans. However, East Asia has become an influential center for genetic studies worldwide, and there is also a growing need for a functional genome database for East Asians. Expression quantitative trait locus data for immune cell subsets can be extremely useful in interpreting the function of disease‐associated genetic polymorphisms. The development of a functional genome database for East Asians is expected to make a significant contribution to the understanding and stratification of the pathogenesis of rheumatic diseases in this population in the future.

Identification of Novel, Immunogenic HLA-DR-Presented Prevotella copri Peptides in Patients With Rheumatoid Arthritis.

We previously identified HLA-DR-presented epitopes from a 27-kd protein of Prevotella copri (Pc) obtained from peripheral blood mononuclear cells (PBMCs) from 1 rheumatoid arthritis (RA) patient. Herein, we sought to identify other HLA-DR-presented Pc peptides and source proteins in PBMCs from additional patients to better understand Pc immune responses and RA disease pathogenesis. Using tandem mass spectrometry, we searched for HLA-DR-presented Pc peptides in PBMCs from RA and Lyme arthritis (LA) patients. The identified peptides and source proteins were tested for reactivity in RA patients, those with other arthritides, and the general population. These results were assessed for correlation with clinical findings. Including Pc-p27, we identified 5 HLA-DR-presented Pc peptides, each derived from a different Pc protein, in 3 of 4 RA patients, but none in 2 LA patients. When tested in our RA cohort, 14 of 19 patients (74%) had T cell responses, and 47 of 89 patients (53%) had IgG or IgA responses to ≥1 of the 5 Pc peptides or proteins, most commonly IgA reactivity with Pc-p27. Additionally, 74% of RA patients with IgA antibodies to ≥1 Pc protein had anti-citrullinated protein antibodies (ACPAs) compared with 49% of patients who lacked IgA Pc antibody responses (P = 0.05), and IgA Pc antibody levels correlated with ACPA values. The majority of the RA patients had Pc immune responses. The correlation of IgA Pc antibody responses, particularly to Pc-p27, with ACPA supports the hypothesis that specific microbial antigens in the mucosa have a role in shaping or amplifying immune responses in RA joints.