Set during the Annual Meeting of the International Society for Magnetic Resonance in Medicine (ISMRM), the \"Clinical Focus Meeting\" (CFM) aims to bridge the gap between innovative magnetic resonance imaging (MRI) scientific research and daily patient care. This initiative is dedicated to maximizing the impact of MRI technology on healthcare outcomes for patients. At the 2023 Annual Meeting, clinicians and scientists from across the globe were invited to discuss neuroinflammation from various angles (entitled \"Imaging the Fire in the Brain\"). Topics ranged from fundamental mechanisms and biomarkers of neuroinflammation to the role of different contrast mechanisms, including both proton and non-proton techniques, in brain tumors, autoimmune disorders, and pediatric neuroinflammatory diseases. Discussions also delved into how systemic inflammation can trigger neuroinflammation and the role of the gut-brain axis in causing brain inflammation. Neuroinflammation arises from various external and internal factors and serves as a vital mechanism to mitigate tissue damage and provide neuroprotection. Nonetheless, excessive neuroinflammatory responses can lead to significant tissue injury and subsequent neurological impairments. Prolonged neuroinflammation can result in cellular apoptosis and neurodegeneration, posing severe consequences. MRI can be used to visualize these consequences, by detecting blood-brain barrier damage, characterizing brain lesions, quantifying edema, and identifying specific metabolites. It also facilitates monitoring of chronic changes in both the brain and spinal cord over time, potentially leading to better patient outcomes. This paper represents a summary of the 2023 CFM, and is intended to guide the enthusiastic MR user to several key and novel sequences that MRI offers to image pathophysiologic processes underlying acute and chronic neuroinflammation. EVIDENCE LEVEL: 5 TECHNICAL EFFICACY: Stage 3.

UNASSIGNED: It remains unclear about the pathogenesis of intracranial aneurysms (IAs) in the setting of autoimmune disorders (ADs). However, the underlying systemic inflammatory characteristics of ADs may affect IAs through shared inflammatory pathways. Therefore, this study was conducted to explore the relationship between ADs and IAs and assess causal effects.
UNASSIGNED: In this study, 6 common ADs were included to explore their causal relationship with IAs. Besides, a bidirectional two-sample univariable Mendelian randomization (UVMR) analysis was performed. In addition, the primary analysis was performed by the inverse variance weighted (IVW) and Bayesian weighted Mendelian randomization (BWMR) method, and a series of sensitivity analyses were performed to assess the robustness of the results. Further, the data related to ADs and IAs were collected from open genome-wide association study studies (GWASs) and the Cerebrovascular Disease Knowledge Portal (CDKP) (including 11,084 cases and 311,458 controls), respectively. These analyses were conducted based on both the East Asian and European populations. Moreover, 6 ADs were subject to grouping according to connective tissue disease, inflammatory bowel disease, and thyroid disease. On that basis, a multivariate MR (MVMR1) analysis was further performed to explore the independent causal relationship between each AD and IAs, and an MVMR 2 analysis was conducted to investigate such potential confounders as smoking, alcohol consumption, and systolic blood pressure. Finally, these results were verified based on the data from another GWAS of IAs.
UNASSIGNED: The UVMR analysis results demonstrated that systemic lupus erythematosus (SLE) was associated with a high risk of IAs in the East Asian population (IVW OR, 1.06; 95%CI, 1.02-1.11; p = 0.0065, UVMR), which was supported by the results of BWMR (OR, 1.06; 95%CI, 1.02-1.11; p = 0.0067, BWMR), MVMR1 (OR, 1.06; 95%CI, 1.01-1.10; p = 0.015, MVMR1), MVMR2 (OR, 1.05; 95%CI, 1.00-1.11; p = 0.049, MVMR2), and sensitivity analyses. The results in the validation group also suggested a causal relationship between SLE and IAs (IVW OR, 1.04; 95% CI, 1.00-1.09; p = 0.046). The reverse MR analysis results did not reveal a causal relationship between IAs and ADs.
UNASSIGNED: In this MR study, SLE was validated to be a risk factor for IAs in the East Asian population. Therefore, the management of IAs in patients with SLE should be highlighted to avoid stroke events.

Numerous studies establish a significant correlation between autoimmune disorders (AIDs) and prostate cancer (PCa). Our Mendelian randomization (MR) analysis investigates the potential connection between rheumatoid arthritis (RA) and PCa, aiming to confirm causal links between systemic lupus erythematosus (SLE), hyperthyroidism, and PCa. Summary statistics from genome-wide association studies provided data on PCa and three AIDs. MR analysis, using IVW as the main approach, assessed causal relationships, validated by sensitivity analysis. IVW revealed a correlation between genetically anticipated RA and PCa, notably in Europeans (OR = 1.03; 95% CI 1.01-1.04, p = 2*10-5). Evidence supported a lower PCa risk in individuals with SLE (OR = 0.94; 95% CI 0.91-0.97, p = 2*10-4) and hyperthyroidism (OR = 0.02; 95% CI 0.001-0.2, p = 2*10-3). Weighted mode and median confirmed these findings. No pleiotropic effects were observed, and MR heterogeneity tests indicated dataset homogeneity. Our study establishes a causal link between RA, SLE, hyperthyroidism, and PCa.

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Spleen tyrosine kinase (Syk) is an intracellular tyrosine kinase involved in the signal transduction in immune cells mainly. Its aberrant regulation is associated with diversified allergic disorders, autoimmune diseases and B cell malignancies. Therefore, inhibition of Syk is considered a reasonable approach to treat autoimmune/inflammatory diseases and B cell malignancies. Here we described the preclinical characterization of sovleplenib, a novel, highly potent and selective, oral Syk inhibitor, in several rodent autoimmune disease models. Sovleplenib potently inhibited Syk activity in a recombinant enzymatic assay and Syk-dependent cellular functions in various immune cell lines and human whole blood in vitro. Furthermore, sovleplenib, by oral administration, demonstrated strong in vivo efficacies in murine models of immune thrombocytopenia (ITP), autoimmune hemolytic anemia (AIHA), and chronic graft-versus-host disease (cGVHD), and a rat model of collagen induced arthritis (CIA) respectively, in a dose-dependent manner. Collectively, these results clearly supported sovleplenib as a therapeutic agent in the treatment of autoimmune diseases. Sovleplenib is being globally developed for ITP (Phase III, NCT05029635, Phase Ib/II, NCT03951623), wAIHA (Phase II/III, NCT05535933) and B-cell lymphoma (Phase I, NCT02857998, NCT03779113). SIGNIFICANCE STATEMENT: Syk is a key mediator of signaling pathways downstream of a wide array of receptors important for immune functions, including the B cell receptor, immunoglobulin receptors bearing Fc receptors. Inhibition of Syk could provide a novel therapeutic approach for autoimmune diseases and hematologic malignancies. The manuscript describes the preclinical pharmacology characterization of sovleplenib, a novel Syk inhibitor, in enzymatic and cellular assays in vitro and several murine autoimmune disease models in vivo.

Uric acid (UA) is an important natural antioxidant and strong peroxynitrite scavenger, but little is known about central nervous system (CNS) levels of UA in patients with anti-N-methyl-d-aspartate receptor encephalitis (NMDARE).
Cerebrospinal fluid (CSF) and serum levels of UA were determined in 72 patients with anti-NMDARE and 111 controls with non-inflammatory neurological diseases (NINDs). Serum UA levels were also evaluated in 132 healthy controls (HCs). CSF neuron-specific enolase (NSE) and blood-brain barrier (BBB) index were evaluated in patients with anti-NMDARE. The association of CSF UA levels with anti-NMDARE and its clinical parameters were evaluated in the patients.
CSF UA levels were lower in patients with anti-NMDARE than in patients with NINDs, especially in patients with severe impairments (modified Rankin Scale [mRS] scores >3 vs. ≤ 3, p = 0.006). Furthermore, serum UA levels in patients with anti-NMDARE were significantly lower than in patients with NINDs and HCs. CSF UA levels were significantly associated with mRS scores, and serum UA levels in patients with anti-NMDARE. Furthermore, CSF/serum UA ratio was significantly associated with BBB index.
CSF UA levels associated with disease severity and serum UA levels in patients with anti-NMDARE. And CSF/serum UA ratio correlated with BBB index, indicating that CSF and serum UA levels change similarly with BBB permeability in anti-NMDARE patients.

Can potential mechanisms involved in the likely concurrence of diminished ovarian reserve (DOR) and miscarriage be identified using genetic data?
Concurrence between ovarian reserve and spontaneous miscarriage was observed, and may be attributed to shared genetic risk loci enriched in antigen processing and presentation and autoimmune disease pathways.
Previous studies have shown that lower serum anti-Müllerian hormone (AMH) levels are associated with increased risk of embryo aneuploidy and spontaneous miscarriage, although findings have not been consistent across all studies. A recent meta-analysis suggested that the association between DOR and miscarriage may not be causal, but rather a result of shared underlying causes such as clinical conditions or past exposure. Motivated by this hypothesis, we conducted the present analysis to explore the concurrence between DOR and miscarriage, and to investigate potential mechanisms using genetic data.
Three data sources were used in the study: the clinical IVF data were retrospectively collected from an academically affiliated Reproductive Medicine Center (17 786 cycles included); the epidemiological data from the UK Biobank (UKB), which is a large-scale, population-based, prospective cohort study (35 316 white women included), were analyzed; and individual-level genotype data from the UKB were extracted for further analysis.
There were three modules of analysis. First, clinical IVF data were used to test the association between ovarian reserve biomarkers and the subsequent early spontaneous miscarriage risk. Second, the UKB data were used to test the association of spontaneous miscarriage history and early menopause. Third, individual-level genotype data from the UKB were analyzed to identify specific pleiotropic genes which affect the development of miscarriage and menopause.
In the analysis of clinical IVF data, the risk of early spontaneous miscarriage was 1.57 times higher in the group with AMH < 1.1 ng/ml group (P < 0.001), 1.62 times for antral follicular count <5 (P < 0.001), and 1.39 times for FSH ≥10 mIU/ml (P < 0.001) in comparison with normal ovarian reserve groups. In the analysis of UKB data, participants with a history of three or more miscarriages had a one-third higher risk of experiencing early menopause (odds ratio: 1.30, 95% CI 1.13-1.49, P < 0.001), compared with participants without spontaneous miscarriage history. We identified 158 shared genetic risk loci that affect both miscarriage and menopause, which enrichment analysis showed were involved in antigen processing and presentation and autoimmune disease pathways.
The analyses of the UKB data were restricted to participants of European ancestry, as 94.6% of the cohort were of white ethnicity. Further studies are needed in non-white populations. Additionally, maternal age at the time of spontaneous miscarriage was not available in the UKB cohort, therefore we adjusted for age at baseline assessment in the models instead. It is known that miscarriage rate in IVF is higher compared to natural conception, highlighting a need for caution when generalizing our findings from the IVF cohort to the general population.
Our findings have implications for IVF clinicians in terms of patient counseling on the prognosis of IVF treatment, as well as for genetic counseling regarding miscarriage. Our results highlight the importance of further research on the shared genetic architecture and common pathophysiological basis of DOR and miscarriage, which may lead to new therapeutic opportunities.
This work was supported by the Hunan Youth Science and Technology Innovation Talent Project (2020RC3060), the International Postdoctoral Exchange Fellowship Program (Talent-Introduction Program, YJ20220220), the fellowship of China Postdoctoral Science Foundation (2022M723564), and the Natural Science Foundation of Hunan Province, China (2023JJ41016). This work has been accepted for poster presentation at the 39th Annual Meeting of ESHRE, Copenhagen, Denmark, 25-28 June 2023 (Poster number: P-477). The authors declare no conflict of interest.
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Tyrosine-protein kinase BLK, also known as B-cell lymphocyte kinase (BLK), is a non-receptor tyrosine kinase that is primarily expressed in B-cells. BLK plays a key role in B-cell signaling, particularly in B-cell development and maturation. The increased expression of BLK has been linked to various complex diseases, including autoimmune disorders, and specific malignancies of B cells, such as lymphomas and leukemias. Due to its significant involvement in B-cell signaling, BLK has emerged as a promising target for drug development, offering the potential for developing novel therapeutics to combat these diseases. Small molecule inhibitors of BLK hold great potential for therapeutic intervention; however, discovering potent and selective inhibitors remains challenging. Within this context, natural compounds hold significant potential as a valuable resource for discovering novel inhibitors of BLK. In the current study, a structure-based virtual screening of the IMPPAT 2 library was employed to identify promising candidates with potential as inhibitors of BLK. The control molecule for this study was the known BLK inhibitor, Dasatinib. After a multi-step filtering process, two molecules (Withanolide I and Mexogenin) demonstrated potential against BLK based on their superior binding affinity, ligand efficiency, and specific interaction. Interaction analysis of these compounds revealed several significant interactions with the active site residues of BLK. Both proposed molecules remained bound to the binding pocket of BLK, as indicated by the molecular dynamics (MD) simulation study. Taken together, these findings provide valuable insights for guiding future research endeavors and translational efforts in developing therapeutics for different complex diseases, such as autoimmune disorders, lymphomas, and leukemias.Communicated by Ramaswamy H. Sarma.

UNASSIGNED: Case reports suggest that SARS-CoV-2 infection could lead to immune dysregulation and trigger autoimmunity while COVID-19 vaccination is effective against severe COVID-19 outcomes. We aim to examine the association between COVID-19 and development of autoimmune diseases (ADs), and the potential protective effect of COVID-19 vaccination on such an association.
UNASSIGNED: A retrospective cohort study was conducted in Hong Kong between 1 April 2020 and 15 November 2022. COVID-19 was confirmed by positive polymerase chain reaction or rapid antigen test. Cox proportional hazard regression with inverse probability of treatment weighting was applied to estimate the risk of incident ADs following COVID-19. COVID-19 vaccinated population was compared against COVID-19 unvaccinated population to examine the protective effect of COVID-19 vaccination on new ADs.
UNASSIGNED: The study included 1,028,721 COVID-19 and 3,168,467 non-COVID individuals. Compared with non-COVID controls, patients with COVID-19 presented an increased risk of developing pernicious anaemia [adjusted Hazard Ratio (aHR): 1.72; 95% Confidence Interval (CI): 1.12-2.64]; spondyloarthritis [aHR: 1.32 (95% CI: 1.03-1.69)]; rheumatoid arthritis [aHR: 1.29 (95% CI: 1.09-1.54)]; other autoimmune arthritis [aHR: 1.43 (95% CI: 1.33-1.54)]; psoriasis [aHR: 1.42 (95% CI: 1.13-1.78)]; pemphigoid [aHR: 2.39 (95% CI: 1.83-3.11)]; Graves\' disease [aHR: 1.30 (95% CI: 1.10-1.54)]; anti-phospholipid antibody syndrome [aHR: 2.12 (95% CI: 1.47-3.05)]; immune mediated thrombocytopenia [aHR: 2.1 (95% CI: 1.82-2.43)]; multiple sclerosis [aHR: 2.66 (95% CI: 1.17-6.05)]; vasculitis [aHR: 1.46 (95% CI: 1.04-2.04)]. Among COVID-19 patients, completion of two doses of COVID-19 vaccine shows a decreased risk of pemphigoid, Graves\' disease, anti-phospholipid antibody syndrome, immune-mediated thrombocytopenia, systemic lupus erythematosus and other autoimmune arthritis.
UNASSIGNED: Our findings suggested that COVID-19 is associated with an increased risk of developing various ADs and the risk could be attenuated by COVID-19 vaccination. Future studies investigating pathology and mechanisms would be valuable to interpreting our findings.
UNASSIGNED: Supported by RGC Collaborative Research Fund (C7154-20GF).

Systemic lupus erythematosus (SLE) is an autoimmune disorder in which excessive CD4+ T-cell activation and imbalanced effector T-cell differentiation play critical roles. Recent studies have implied a potential association between posttranscriptional N6-methyladenosine (m6A) modification and CD4+ T-cell-mediated humoral immunity. However, how this biological process contributes to lupus is not well understood. In this work, we investigated the role of the m6A methyltransferase like 3 (METTL3) in CD4+ T-cell activation, differentiation, and SLE pathogenesis both in vitro and in vivo.
The expression of METTL3 was knocked down and METTL3 enzyme activity was inhibited using siRNA and catalytic inhibitor, respectively. In vivo evaluation of METTL3 inhibition on CD4+ T-cell activation, effector T-cell differentiation, and SLE pathogenesis was achieved using a sheep red blood cell (SRBC)-immunized mouse model and a chronic graft versus host disease (cGVHD) mouse model. RNA-seq was performed to identify pathways and gene signatures targeted by METTL3. m6A RNA-immunoprecipitation qPCR was applied to confirm the m6A modification of METTL3 targets.
METTL3 was defective in the CD4+ T cells of SLE patients. METTL3 expression varied following CD4+ T-cell activation and effector T-cell differentiation in vitro. Pharmacological inhibition of METTL3 promoted the activation of CD4+ T cells and influenced the differentiation of effector T cells, predominantly Treg cells, in vivo. Moreover, METTL3 inhibition increased antibody production and aggravated the lupus-like phenotype in cGVHD mice. Further investigation revealed that catalytic inhibition of METTL3 reduced Foxp3 expression by enhancing Foxp3 mRNA decay in a m6A-dependent manner, hence suppressing Treg cell differentiation.
In summary, our findings demonstrated that METTL3 was required for stabilizing Foxp3 mRNA via m6A modification to maintain the Treg differentiation program. METTL3 inhibition contributed to the pathogenesis of SLE by participating in the activation of CD4+ T cells and imbalance of effector T-cell differentiation, which could serve as a potential target for therapeutic intervention in SLE.