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Frontiers in Immunology 2024Accumulating studies have indicated that the gut microbiota plays a pivotal role in the onset of autoimmune diseases by engaging in complex interactions with the host.... (Review)
Review
Accumulating studies have indicated that the gut microbiota plays a pivotal role in the onset of autoimmune diseases by engaging in complex interactions with the host. This review aims to provide a comprehensive overview of the existing literatures concerning the relationship between the gut microbiota and autoimmune diseases, shedding light on the complex interplay between the gut microbiota, the host and the immune system. Furthermore, we aim to summarize the impacts and potential mechanisms that underlie the interactions between the gut microbiota and the host in autoimmune diseases, primarily focusing on systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome, type 1 diabetes mellitus, ulcerative colitis and psoriasis. The present review will emphasize the clinical significance and potential applications of interventions based on the gut microbiota as innovative adjunctive therapies for autoimmune diseases.
Topics: Humans; Gastrointestinal Microbiome; Autoimmune Diseases; Animals; Dysbiosis; Autoimmunity
PubMed: 38765017
DOI: 10.3389/fimmu.2024.1365554 -
European Review For Medical and... Sep 2023Autoimmune diseases (ADs) are common conditions in which an individual's immune system reacts against its healthy cells. This condition is a common cause of morbidity... (Review)
Review
Autoimmune diseases (ADs) are common conditions in which an individual's immune system reacts against its healthy cells. This condition is a common cause of morbidity and mortality, with an estimated prevalence ranging from 5 per 100,000 to more than 500 per 100,000. According to the National Stem Cell Foundation (NSCF), ADs are prevalent in about 4% of the world's population, which creates a burden on society due to the high treatment cost. ADs show a clear gender bias with a higher prevalence among women, occurring at a rate of 2:1 female-to-male ratio. The etiology of ADs includes genetic and environmental factors. ADs are more likely to develop in genetically susceptible individuals. The higher concordance ratio between monozygotic twins compared to dizygotic twins or other siblings validates the role of genetic factors in the pathogenesis of many ADs. ADs diagnosis includes conventional immunoassay such as indirect immunofluorescence, complement fixation, passive agglutination, autoantibodies detection, and most recent advances, including multiplex platforms such as microspots, line-blot, addressable microbeads and barcoded nanoparticles that allow multiplex parallel testing of autoantibodies. ADs treatment includes biological and synthetic drugs that block many pathways and components of the immune system, including Janus kinase (JAK) inhibitors, non-receptor tyrosine-protein kinase (TYK2), and other cytokines. Generally, recent immune-modulatory drugs used in ADs treatment are non-disease specific with broad action and are associated with many side effects like infection and malignant diseases. Furthermore, gene therapy seeks to control the levels of proinflammatory cytokine molecules and lymphocyte infiltration through the delivery and expression of therapeutic genes. Recent genomic-wide association studies (GWAS) have allowed the identification of various genetic loci associated with disease susceptibility and have revealed candidate genes that can be used in targeted therapeutics. This review summarizes recent literature on the genetic factors associated with susceptibility to the 11 most common ADs, namely: Type 1 diabetes mellitus (T1DM), Multiple sclerosis (MS), Grave's disease, Sjögren's syndrome (SS), Celiac disease, Hashimoto's thyroiditis (HT), Anti-phospholipid syndrome (APS), Autoimmune hemolytic anemia, Rheumatoid arthritis (RA), Systemic lupus erythematosus (SLE), and Scleroderma (systemic sclerosis).
Topics: Female; Male; Humans; Genome-Wide Association Study; Sexism; Autoimmune Diseases; Sjogren's Syndrome; Lupus Erythematosus, Systemic; Autoantibodies; Scleroderma, Systemic
PubMed: 37782163
DOI: 10.26355/eurrev_202309_33772 -
European Journal of Obstetrics,... Dec 2023Rheumatic diseases, mainly affecting women, including rheumatoid arthritis, Sjogren's syndrome, systemic lupus erythematosus, etc., are chronic, inflammatory, autoimmune... (Review)
Review
BACKGROUND
Rheumatic diseases, mainly affecting women, including rheumatoid arthritis, Sjogren's syndrome, systemic lupus erythematosus, etc., are chronic, inflammatory, autoimmune disorders that may involve multiple organs or systems and are closely related to sexual health, which is an important aspect of human physical and mental health. Sjogren's syndrome (SS) is the second most common rheumatic illnesses after rheumatoid arthritis with a female predominance. At present, the research on sexual health of female SS patients is still scarce and difficult to summarize.
OBJECTIVES
The objective of our study was to systematically review the literature for the influence of maternal SS on sexual health, such as sexual function, sex hormones, fertility, and pregnancy outcomes.
METHODS
We performed a comprehensive literature search based on PubMed and Web of science databases from inception to 1 November 2022. Outcomes were divided into 4 categories: sex hormones, sexual function, fertility, and pregnancy and offspring outcomes.
RESULTS
A total of 756 potentially eligible papers were retrieved. After eliminating duplicate articles and reviewing the titles and abstracts to exclude records, we read the remaining 92 articles in full for further evaluation, and selected 42 studies. Results on sex hormones, sexual function, fertility and pregnancy and offspring outcomes were reported in 13, 12, 3 and 14 SS-related articles, respectively. The levels of some sex hormones in SS patients may have undergone changes. Female patients with SS have a high prevalence of sexual dysfunction compared with controls. Most studies suggested SS had an adverse impact on maternal and fetal outcomes following pregnancy. However, there is insufficient evidence that directly indicating the fertility of SS women is diminished.
CONCLUSIONS
In summary, certain aspects of sexual health (sexual function, sex hormones and pregnancy outcomes) are impaired in SS women. Screening for sexual health problems in SS female should become an integral part of medical clinical practice. Rheumatologists should be aware of this association and collaborate with gynecologists, obstetricians, psychologists, and other experts on this issue to determine appropriate therapeutic approaches.
Topics: Pregnancy; Humans; Female; Male; Sjogren's Syndrome; Sexual Health; Arthritis, Rheumatoid; Lupus Erythematosus, Systemic; Gonadal Steroid Hormones
PubMed: 37801781
DOI: 10.1016/j.ejogrb.2023.09.025 -
Scientific Reports Jul 2023Novel modalities, such as salivary ultrasonography (SGUS) and shear wave elastography (SWE), have previously been introduced to evaluate Sjögren's syndrome (SS)....
Novel modalities, such as salivary ultrasonography (SGUS) and shear wave elastography (SWE), have previously been introduced to evaluate Sjögren's syndrome (SS). However, in secondary SS (sSS), the diagnostic performance of SGUS and its relationship with clinicopathological characteristics have not yet been clearly defined. In this study, we aimed to investigate sSS in RA patients using SGUS and SWE and sought to determine its pathological correlations. Thirty-one RA patients who presented with sicca symptoms were included to be evaluated on SS, and were compared with 18 primary SS (pSS) patients. All subjects were assessed through SGUS, SWE, and conventional diagnostic approaches for SS, including minor salivary gland biopsy (MSGB). In SGUS evaluation, two separate scoring systems, suggested by Hocevar and OMERACT, were used. Among 31 RA patients with sicca symptoms, 19 (61.2%) were diagnosed as sSS. Similar to pSS, SGUS showed good diagnostic performance (sensitivity 68.4% and 78.9%, and specificity 91.7% and 75.0% for Hocever and OMERACT, respectively) in differentiating sSS from RA patients with simple sicca symptoms. The sSS and pSS patients exhibited significantly higher lymphoid infiltration areas in MSGB than RA patients without SS. Focus score and lymphoid infiltration areas correlated well with sonographic severity. Severity of fibrosis in MSGB showed better positive correlation with SWE than with SGUS. Similar to pSS, SGUS shows good diagnostic performance for sSS in RA patients. SWE reflects histopathologic chronicity of MSGB well in both pSS and sSS.
Topics: Humans; Sjogren's Syndrome; Salivary Glands; Ultrasonography; Salivary Glands, Minor
PubMed: 37443200
DOI: 10.1038/s41598-023-38469-z -
Arthritis Research & Therapy Aug 2023Iguratimod (IGU) reduces hypergammaglobulinemia and disease activity in pSS (primary Sjögren's syndrome) patients. However, the therapeutical mechanism of IGU for pSS...
BACKGROUND
Iguratimod (IGU) reduces hypergammaglobulinemia and disease activity in pSS (primary Sjögren's syndrome) patients. However, the therapeutical mechanism of IGU for pSS remains largely unknown. This study aimed to investigate the regulation of Tfh cell differentiation by IGU in pSS patients.
METHODS
We prospectively enrolled 13 pSS patients treated with IGU for 3 months and examined circulating T cell and B cell subsets by flow cytometry. We measured Tfh cell differentiation treated by IGU in pSS patients and healthy controls. Transcriptome analysis combined with molecular docking were employed to identify potential therapeutical targets of IGU, which were verified by Western blot and Tfh cell differentiation.
RESULTS
Tfh, plasmablast, and plasma cells were suppressed by IGU treatment at 1 and 3 months. Tfh cell differentiation and function were significant inhibited by IGU in pSS patients and healthy controls in vitro. Pyruvate dehydrogenase kinase 1 (PDK1) was identified as a target of IGU during Tfh cell differentiation, and the downstream Akt phosphorylation was attenuated by IGU. Moreover, the activity of mTORC1 and phosphorylation of STAT3 were suppressed by IGU, with downregulation of BCL6 and upregulation of PRDM1. Finally, Akt activator restored IGU-suppressed Tfh cell differentiation.
CONCLUSIONS
IGU suppresses Tfh cell differentiation in pSS patients through interacting with PDK1 and suppressing Akt-mTOR-STAT3 signaling.
Topics: Humans; Proto-Oncogene Proteins c-akt; Molecular Docking Simulation; Sjogren's Syndrome; TOR Serine-Threonine Kinases; Cell Differentiation; STAT3 Transcription Factor
PubMed: 37608388
DOI: 10.1186/s13075-023-03109-4 -
PloS One 2024Previous observational studies have reported an association between Sjögren's syndrome (SS) and an increased risk of Parkinson's Disease (PD). However, the causal... (Observational Study)
Observational Study
BACKGROUND
Previous observational studies have reported an association between Sjögren's syndrome (SS) and an increased risk of Parkinson's Disease (PD). However, the causal relationship between these conditions remains unclear. The objective of this study was to investigate the causal impact of SS on the risk of developing PD, utilizing the Mendelian randomization (MR) approach.
METHODS
We conducted a bidirectional MR analysis using publicly available genome-wide association studies (GWAS) data. The primary analysis utilized the inverse-variance weighted (IVW) method. Complementary methods, such as MR-Egger regression, weighted mode, weighted median, and MR-pleiotropy residual sum and outlier (MR-PRESSO), were utilized to identify and correct for the presence of horizontal pleiotropy.
RESULTS
The IVW MR analysis revealed no significant association between SS and PD (IVW: OR = 1.00, 95% CI = 0.94-1.07, P = 0.95). Likewise, the reverse MR analysis did not identify any significant causal relationship between PD and SS (IVW: OR = 0.98, 95% CI = 0.85-1.12, P = 0.73). The results from MR-Egger regression, weighted median, and weighted mode approaches were consistent with the IVW method. Sensitivity analyses suggested that horizontal pleiotropy is unlikely to introduce bias to the causal estimates.
CONCLUSION
This study does not provide evidence to support the assertion that SS has a conclusive impact on the risk of PD, which contradicts numerous existing observational reports. Further investigation is necessary to determine the possible mechanisms behind the associations observed in these observational studies.
Topics: Humans; Sjogren's Syndrome; Genome-Wide Association Study; Mendelian Randomization Analysis; Parkinson Disease
PubMed: 38568911
DOI: 10.1371/journal.pone.0298778 -
Annals of the Rheumatic Diseases Jan 2024Extracting immunological and clinical heterogeneity across autoimmune rheumatic diseases (AIRDs) is essential towards personalised medicine.
OBJECTIVE
Extracting immunological and clinical heterogeneity across autoimmune rheumatic diseases (AIRDs) is essential towards personalised medicine.
METHODS
We conducted large-scale and cohort-wide immunophenotyping of 46 peripheral immune cells using Human Immunology Protocol of comprehensive 8-colour flow cytometric analysis. Dataset consisted of >1000 Japanese patients of 11 AIRDs with deep clinical information registered at the FLOW study, including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). In-depth clinical and immunological characterisation was conducted for the identified RA patient clusters, including associations of inborn human genetics represented by Polygenic Risk Score (PRS).
RESULTS
Multimodal clustering of immunophenotypes deciphered underlying disease-cell type network in immune cell, disease and patient cluster resolutions. This provided immune cell type specificity shared or distinct across AIRDs, such as close immunological network between mixed connective tissue disease and SLE. Individual patient-level clustering dissected patients with AIRD into several clusters with different immunological features. Of these, RA-like or SLE-like clusters were exclusively dominant, showing immunological differentiation between RA and SLE across AIRDs. In-depth clinical analysis of RA revealed that such patient clusters differentially defined clinical heterogeneity in disease activity and treatment responses, such as treatment resistance in patients with RA with SLE-like immunophenotypes. PRS based on RA case-control and within-case stratified genome-wide association studies were associated with clinical and immunological characteristics. This pointed immune cell type implicated in disease biology such as dendritic cells for RA-interstitial lung disease.
CONCLUSION
Cohort-wide and cross-disease immunophenotyping elucidate clinically heterogeneous patient subtypes existing within single disease in immune cell type-specific manner.
Topics: Humans; Immunophenotyping; Genome-Wide Association Study; Autoimmune Diseases; Arthritis, Rheumatoid; Lupus Erythematosus, Systemic; Rheumatic Diseases
PubMed: 37903543
DOI: 10.1136/ard-2023-224537 -
Frontiers in Immunology 2023The longitudinal responses towards multiple doses of COVID-19 mRNA vaccines in patients with systemic autoimmune diseases remain incompletely understood. While...
INTRODUCTION
The longitudinal responses towards multiple doses of COVID-19 mRNA vaccines in patients with systemic autoimmune diseases remain incompletely understood. While observational studies suggested the safety of COVID-19 mRNA vaccines in rheumatic disease patients, laboratory evidence is lacking.
METHODS
Here we evaluated seroreactivity, clinical manifestions, and multiple disease biomarkers after 2 or 3 doses of COVID-19 mRNA vaccines in a cohort of patients with rheumatic diseases.
RESULTS
Most patients generated high SARS-CoV-2 spike-specific neutralizing antibodies comparable to those in healthy controls after 2 doses of mRNA vaccines. The antibody level declined over time but recovered after the third dose of the vaccine. Patients with systemic lupus erythematosus (SLE) or psoriatic arthritis (PsA) remained without significant flares post-vaccination. The changes in anti-dsDNA antibody concentration and expression of type I interferon (IFN) signature genes were highly variable but did not show consistent or significant increases. Frequency of double negative 2 (DN2) B cells remained largely stable.
DISCUSSION
Our data provide experimental evidences indicating the efficacy and safety of repeated COVID-19 mRNA vaccination in rheumatic disease patients.
Topics: Humans; Antibodies, Viral; Arthritis, Psoriatic; COVID-19; Immunity; mRNA Vaccines; Rheumatic Diseases; RNA, Messenger; SARS-CoV-2; Vaccination; 2019-nCoV Vaccine mRNA-1273; COVID-19 Vaccines
PubMed: 37583697
DOI: 10.3389/fimmu.2023.1224702 -
Investigative Ophthalmology & Visual... Aug 2023We investigated the therapeutic effect of recombinant thymosin β4 (rTβ4) on rabbit autoimmune dacryoadenitis, an animal model of SS dry eye, and explore its mechanisms.
PURPOSE
We investigated the therapeutic effect of recombinant thymosin β4 (rTβ4) on rabbit autoimmune dacryoadenitis, an animal model of SS dry eye, and explore its mechanisms.
METHODS
Rabbits were treated topically with rTβ4 or PBS solution after disease onset for 28 days, and clinical scores were determined by assessing tear secretion, break-up time, fluorescein, hematoxylin and eosin staining, and periodic acid-Schiff. The expression of inflammatory mediators in the lacrimal glands were measured by real-time PCR. The expression of T helper 17 (Th17) cell-related transcription factors and cytokines were detected by real-time PCR and Western blotting. The molecular mechanism underlying the effects of rTβ4 on Th17 cell responses was investigated by Western blotting.
RESULTS
Topical administration of rTβ4 after disease onset efficiently ameliorated the ocular surface inflammation and relieved the clinical symptoms. Further analysis revealed that rTβ4 treatment significantly inhibited the expression of Th17-related genes (RORC, IL-17A, IL-17F, IL-1R1, IL-23R, and granulocyte-macrophage colony-stimulating factor) and IL-17 protein in lacrimal glands, and meanwhile decreased the inflammatory mediators expression. Mechanistically, we demonstrated that rTβ4 repressed the phosphorylation of signal transducer and activator of transcription 3 (STAT3) both in vivo and in vitro. Activation of the STAT3 signal pathway by Colivelin partly reversed the suppressive effects of rTβ4 on IL-17 expression in vitro.
CONCLUSIONS
rTβ4 could alleviate ongoing autoimmune dacryoadenitis in rabbits, probably by suppressing Th17 response via partly affecting the STAT3 pathway. These data may provide a new insight into the therapeutic effect and mechanism of rTβ4 in dry eye associated with Sjögren's syndrome.
Topics: Animals; Rabbits; Interleukin-17; Tears; Th17 Cells; Dacryocystitis; Dry Eye Syndromes; Disease Models, Animal
PubMed: 37531112
DOI: 10.1167/iovs.64.11.3