Dietary acid load as well as dietary phytochemical index, and association with multiple sclerosis: results from a case-control study.

INTRODUCTION: Multiple sclerosis (MS) is a chronic inflammatory disease characterized by central nervous system (CNS) lesions. Although the etiology and pathogenesis of MS remains unclear, nutrition is among the environmental factors that may be involved in developing MS. Currently, no specific diet has been associated with MS. This study aimed to investigate the relationship between the dietary phytochemical index (DPI), dietary acid load (DAL), and the risk of developing MS. METHODS: This case‒control study was conducted on 174 patients with MS and 171 healthy individuals in Mashhad, Iran. Data were collected using a 160-item semiquantitative food frequency questionnaire (FFQ). The study investigated the association between DPI, DAL, and MS, considering anthropometric measures, dietary intake, smoking habits, and sex. DPI, potential renal acid load (PRAL), and net endogenous acid production (NEAP), as indicators of DAL, were calculated based on the FFQ. RESULTS: The study analyzed 345 participants, comprising 174 (50.4%) MS patients and 171 (49.6%) healthy individuals. The mean age of the participants was 32.45 ± 8.66 years. The DPI score was significantly lower among MS patients, while the NEAP and PRAL scores were significantly higher among MS patients compared to the healthy group. There was no relationship between NEAP (OR 1.001; 95% CI 0.959-1.044; P = 0.974) and PRAL (OR 1.019; 95% CI 0.979-1.061; P = 0.356) and MS incidence. CONCLUSIONS: The study found higher smoking and obesity rates in MS patients, with a reduced DPI score and increased DAL. Further studies are needed before recommending plant-based foods and dietary acid-base balance evaluation as therapeutic approach.

Patient-reported outcomes in HSCT for autoimmune diseases: Considerations on behalf of the EBMT ADWP, PAC, and Nurses Group.

Background: Over the last 3 decades, hematopoietic stem cell transplantation (HSCT) has been successfully used to treat severe and refractory autoimmune diseases (AIDs). A multidisciplinary appraisal of potential benefits and risks by disease and transplant specialists is essential to determine individual suitability for HSCT. Objective: Our aim was to observe that patient-reported outcomes (PROs) and health-related quality of life instruments can capture the unique patient perspective on disease burden and impact of treatment. Methods: Herein, we describe the basis and complexity of end points measuring patient-reported perceptions of efficacy and tolerability used in clinical practice and trials for patients with AIDs undergoing autologous HSCT. Results: PRO measures and patient-reported experience measures are key tools to evaluate the impact and extent of disease burden for patients affected by AIDs. For formal scientific assessment, it is essential that validated general instruments are used, whereas adaptations have resulted in disease-specific instruments that may help guide tailored interventions. An additional approach relates to qualitative evaluations, from carefully structured qualitative research to informal narratives, as patient stories. The patients' subjectively reported responses to HSCT may be influenced by their preprocedure expectations and investment in the HSCT journey. Conclusions: The complexity of AIDs advocates for individualized and multidisciplinary approach to positively affect the patient journey. PROs and health-related quality of life need to be collected using validated instruments in clinical practice and trials to enable robustness of data and to ensure the impact of the intervention is comprehensively assessed, addressing the main questions and needs of the involved stakeholders.

Cryptococcosis Associated With Biologic Therapy: A Narrative Review.

Cryptococcus is an opportunistic fungal pathogen that can cause disseminated infection with predominant central nervous system involvement in patients with compromised immunity. Biologics are increasingly used in the treatment of neoplasms and autoimmune/inflammatory conditions and the prevention of transplant rejection, which may affect human defense mechanisms against cryptococcosis. In this review, we comprehensively investigate the association between cryptococcosis and various biologics, highlighting their risks of infection, clinical manifestations, and clinical outcomes. Clinicians should remain vigilant for the risk of cryptococcosis in patients receiving biologics that affect the Th1/macrophage activation pathways, such as tumor necrosis factor α antagonists, Bruton tyrosine kinase inhibitors, fingolimod, JAK/STAT inhibitors (Janus kinase/signal transducer and activator of transcription), and monoclonal antibody against CD52. Other risk factors-such as age, underlying condition, and concurrent immunosuppressants, especially corticosteroids-should also be taken into account during risk stratification.

Controversies regarding transplantation of mesenchymal stem cells.

Mesenchymal stem cells (MSCs) have tantalized regenerative medicine with their therapeutic potential, yet a cloud of controversies looms over their clinical transplantation. This comprehensive review navigates the intricate landscape of MSC controversies, drawing upon 15 years of clinical experience and research. We delve into the fundamental properties of MSCs, exploring their unique immunomodulatory capabilities and surface markers. The heart of our inquiry lies in the controversial applications of MSC transplantation, including the perennial debate between autologous and allogeneic sources, concerns about efficacy, and lingering safety apprehensions. Moreover, we unravel the enigmatic mechanisms surrounding MSC transplantation, such as homing, integration, and the delicate balance between differentiation and paracrine effects. We also assess the current status of clinical trials and the ever-evolving regulatory landscape. As we peer into the future, we examine emerging trends, envisioning personalized medicine and innovative delivery methods. Our review provides a balanced and informed perspective on the controversies, offering readers a clear understanding of the complexities, challenges, and potential solutions in MSC transplantation.

Acquired ductopenia: an insight into imaging findings.

Hepatic ductopenia is a pathologic diagnosis characterized by a decrease in the number of intrahepatic bile ducts as a consequence of various underlying etiologies. Some etiologies, such as primary sclerosing cholangitis, primary biliary cholangitis, and ischemic cholangitis, often have distinctive imaging findings. In contrast, other causes such as chronic rejection following liver transplantation, drug-induced biliary injury, infection, malignancy such as lymphoma, and graft-versus-host disease may only have ancillary or non-specific imaging findings. Thus, diagnosing ductopenia in conditions with nonspecific imaging findings requires a multidimensional approach, including clinical evaluation, serological testing, imaging, and liver histology to identify the underlying cause. These etiologies lead to impaired bile flow, resulting in cholestasis, liver dysfunction, and, ultimately, cirrhosis and liver failure if the underlying cause remains untreated or undetected. In the majority of instances, individuals diagnosed with ductopenia exhibit a positive response to treatment addressing the root cause or cessation of the causative agent. This article focuses on acquired causes of ductopenia, its clinical manifestation, histopathology, imaging diagnosis, and management.

Coexistence of myasthenia gravis and lichen planus: A case report and systematic review of related case reports from 1971 to 2024.

Key Clinical Message: The co-occurrence of myasthenia gravis (MG) and lichen planus (LP) is a rare phenomenon, with only 13 cases reported in the English literature between 1971 and 2024. Patients with MG or LP, regardless of the thymoma status, require close monitoring for other autoimmune diseases. Abstract: Myasthenia gravis (MG) is an uncommon autoimmune disease, resulting in fatigable muscle weakness in the ocular, bulbar, and respiratory muscles, as well as muscles of the extremities. Lichen planus (LP) is an autoimmune mucocutaneous disease, presenting with pruritic and violaceous plaques on the skin and mucosal surfaces. So far, MG and LP co-occurrence is only reported in anecdotal individuals. This study reports a patient with MG and LP and systematically reviews the English literature on this rare co-occurrence from 1971 to 2024, indicating only 13 cases with similar conditions. A 67-year-old man presented with ocular and progressive bulbar symptoms, a year after being diagnosed with generalized LP. Laboratory evaluations were normal except for the high anti-AchR-Ab titer and a positive ANA titer. Neurologic examinations revealed asymmetric bilateral ptosis, weakness and fatigability in proximal muscles, and a severe reduction in the gag reflex. He was diagnosed with late-onset, seropositive MG. The treatment included pyridostigmine (60 mg, three times daily), intravenous immunoglobulin (25 g daily for 5 days), and oral prednisolone. There was no evidence of thymoma in the chest x-ray and CT scan without contrast. However, a CT scan with contrast was not performed due to the patient's unstable condition. A common autoimmune mechanism may underlie the unclear pathophysiology of MG and LP co-occurrence, with or without thymoma. Patients with MG, LP, or thymoma require close monitoring and assessment for other possible autoimmune diseases.

Identification of lipid-modifying drug targets for autoimmune diseases: insights from drug target mendelian randomization.

BACKGROUNDS: A growing body of evidence has highlighted the interactions of lipids metabolism and immune regulation. Nevertheless, there is still a lack of evidence regarding the causality between lipids and autoimmune diseases (ADs), as well as their possibility as drug targets for ADs. OBJECTIVES: This study was conducted to comprehensively understand the casual associations between lipid traits and ADs, and evaluate the therapeutic possibility of lipid-lowering drug targets on ADs. METHODS: Genetic variants for lipid traits and variants encoding targets of various lipid-lowering drugs were derived from Global Lipid Genetics Consortium (GLGC) and verified in Drug Bank. Summary data of ADs were obtained from MRC Integrative Epidemiology Unit (MER-IEU) database and FinnGen consortium, respectively. The causal inferences between lipid traits/genetic agents of lipid-lowering targets and ADs were evaluated by Mendelian randomization (MR), summary data-based MR (SMR), and multivariable MR (MVMR) analyses. Enrichment analysis and protein interaction network were employed to reveal the functional characteristics and biological relevance of potential therapeutic lipid-lowering targets. RESULTS: There was no evidence of causal effects regarding 5 lipid traits and 9 lipid-lowering drug targets on ADs. Genetically proxied 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) inhibition was associated with a reduced risk of rheumatoid arthritis (RA) in both discovery (OR [odds ratio] = 0.45, 95%CI: 0.32, 0.63, P = 6.79 × 10- 06) and replicate datasets (OR = 0.37, 95%CI: 0.23, 0.61, P = 7.81 × 10- 05). SMR analyses supported that genetically proxied HMGCR inhibition had causal effects on RA in whole blood (OR = 0.48, 95%CI: 0.29, 0.82, P = 6.86 × 10- 03) and skeletal muscle sites (OR = 0.75, 95%CI: 0.56, 0.99, P = 4.48 × 10- 02). After controlling for blood pressure, body mass index (BMI), smoking and drinking alchohol, HMGCR suppression showed a direct causal effect on a lower risk of RA (OR = 0.33, 95%CI: 0.40, 0.96, P = 0.042). CONCLUSIONS: Our study reveals causal links of genetically proxied HMGCR inhibition (lipid-lowering drug targets) and HMGCR expression inhibition with a decreased risk of RA, suggesting that HMGCR may serve as candidate drug targets for the treatment and prevention of RA.

Overview of Structural and Functional Insights of SLFN12 Associated With Different Diseases.

Schlafen12 is a member of the Schlafen gene family where Slfns have been linked to many functions such as anti-proliferation and cell differentiation, viral replication inhibition, migration of cancer cells and invasion prevention, and sensitivity to DNA-damaging medicines. Researchers are interested in studying the biochemical mechanisms that control thymocyte development to extract and describe gene expression and transcriptionally elevated by the process of positive selection that led to the discovery of this novel gene family. This review aims to give adequate knowledge about human SLFN12 by reviewing the most notable papers from five reliable databases regarding SLFN12 milestones and alterations in SLFN12 expression in various disease discoveries from 1997 to the present. In conclusion, SLFN12 seems to be linked with autoimmune diseases such as multiple sclerosis. Furthermore, SLFN12 levels could modify the effects of radiation and chemotherapy.

DNA methylation in human diseases.

Aberrant epigenetic modifications, particularly DNA methylation, play a critical role in the pathogenesis and progression of human diseases. The current review aims to reveal the role of aberrant DNA methylation in the pathogenesis and progression of diseases and to discuss the original data obtained from international research laboratories on this topic. In the review, we mainly summarize the studies exploring the role of aberrant DNA methylation as diagnostic and prognostic biomarkers in a broad range of human diseases, including monogenic epigenetics, autoimmunity, metabolic disorders, hematologic neoplasms, and solid tumors. The last section provides a general overview of the possibility of the DNA methylation machinery from the perspective of pharmaceutic approaches. In conclusion, the study of DNA methylation machinery is a phenomenal intersection that each of its ways can reveal the mysteries of various diseases, introduce new diagnostic and prognostic biomarkers, and propose a new patient-tailored therapeutic approach for diseases.

Bevacizumab-induced immune thrombocytopenia in an ovarian cancer patient with mixed connective tissue disease: case report and literature review.

Drug-induced immune thrombocytopenia is an adverse reaction marked by accelerated destruction of blood platelets. In cancer therapy, thrombocytopenia has many other causes including bone marrow suppression induced by chemotherapeutic agents, infection, and progression of cancer; drug-induced thrombocytopenia can easily be misdiagnosed or overlooked. Here, we present a case of an ovarian cancer patient with a history of mixed connective tissue disease who underwent surgery followed by treatment with paclitaxel, cisplatin, and bevacizumab. The patient developed acute isolated thrombocytopenia after the sixth cycle. Serum antiplatelet antibody testing revealed antibodies against glycoprotein IIb. After we analyzed the whole therapeutic process of this patient, drug-induced immune thrombocytopenia was assumed, and bevacizumab was conjectured as the most probable drug. Thrombocytopenia was ultimately successfully managed using recombinant human thrombopoietin, prednisone, and recombinant human interleukin-11. We provide a summary of existing literature on immune thrombocytopenia induced by bevacizumab and discuss related mechanisms and triggers for drug-induced immune thrombocytopenia. The present case underscores the potential of bevacizumab to induce immune-mediated thrombocytopenia, emphasizing the need for heightened vigilance towards autoimmune diseases or an autoimmune-activated state as plausible triggers for rare drug-induced immune thrombocytopenia in cancer therapy.

A systematic review and meta-analysis of observational studies and uncontrolled trials reporting on the use of checkpoint blockers in patients with cancer and pre-existing autoimmune disease.

BACKGROUND: Cancer patients with autoimmune disease have been excluded from randomized trials of immune checkpoint blockers (ICBs). We conducted a systematic review of observational studies and uncontrolled trials including cancer patients with pre-existing autoimmune disease who received ICBs. METHODS: We searched 5 electronic databases through November 2023. Study selection, data collection, and quality assessment were performed independently by 2 investigators. We performed a meta-analysis to pool incidence of immune-related adverse events (irAEs), including de novo events and flares of existing autoimmune disease, hospitalizations due to irAEs, as well as deaths. RESULTS: A total of 95 studies were included (23,897 patients with cancer and preexisting autoimmune disease). The most common cancer evaluated was lung cancer (30.7 %) followed by skin cancer (15.7 %). Patients with autoimmune disease were more likely to report irAEs compared to patients without autoimmune disease (relative risk 1.3, 95 % CI 1.0 to 1.6). The pooled occurrence rate of any irAEs (flares or de novo) was 61 % (95 % CI 54 % to 68 %); that of flares was 36 % (95 % CI 30 % to 43 %), and that of de novo irAEs was 23 % (95 % CI 16 % to 30 %). Flares were mild (grade <3) in half of cases and more commonly reported in patients with psoriasis/psoriatic arthritis (39 %), inflammatory bowel disease (37 %), and rheumatoid arthritis (36 %). 32 % of the patients with irAEs required hospitalization and treatment of irAEs included corticosteroids in 72 % of the cases. The irAEs mortality rate was 0.07 %. There were no statistically significant differences in cancer response to ICBs between patients with and without autoimmune disease. CONCLUSIONS: Although more patients with pre-existing autoimmune disease had irAEs, these were mild and managed with corticosteroids in most cases, with no impact on cancer response. These results suggest that ICBs can be used in these patients, but careful monitoring is required, as over a third of the patients will experience a flare of their autoimmune disease and/or require hospitalization. These findings provide a crucial foundation for oncologists to refine their monitoring and management strategies, ensuring that the benefits of ICB therapy are maximized while minimizing its risks.

Interferon Epsilon: Properties and Functions.

Interferon epsilon (IFN-ε) belongs to the type I IFN group and exhibits various biological properties. IFN-ε exhibits different regulation mechanisms and expression via other type I IFNs. Its hormonal regulation suggests that this INF can have different functions and pathways from other type I IFNs. Although IFN-ε exhibits lower antiproliferative, anti-tumor, and antiviral activities compared to IFN-α, it has been identified to contribute to mucosal immunity, combat bacterial infections, and aid in the prevention of specific sexually transmitted diseases, such as HIV, Zika virus, etc. IFN-α and IFN-ß with their well-established properties have been a research hotspot for many years; nevertheless, IFN-ε, whose unique roles are only now beginning to emerge, may be an intriguing subject for future study. This review focuses on the known activity of IFN-ε in certain cancers, pregnancy, autoimmune diseases, bacterial infections, and viruses. The aim of this paper is to enhance the understanding of the potential efficacy of IFN-ε treatment in the future.

Sudden Sensorineural Hearing Loss in Patients Aged from 15 to 40 Years.

Objectives: The purpose of this study was to investigate the hearing characteristics and causes of sudden sensorineural hearing loss (SSNHL) in patients aged from 15 to 40 years, focusing on audiological outcomes one year after the diagnosis. Methods: The medical records of individuals with SSNHL who were referred to our tertiary-level audiologic center were reviewed. All patients had undergone comprehensive diagnostic evaluations, including high-resolution 3D-FLAIR delayed magnetic resonance imaging (MRI), cone beam computed tomography (CBCT), and screening for coagulation, infectious, and autoimmune diseases. Results: Overall, 56 patients (mean age 28.1 ± 7.6 years) were included in the study. The hearing threshold in the affected ear improved significantly from 56.0 ± 18.0 dB at the diagnosis to 46.9 ± 22.3 dB after one year (p = 0.02). The degree of hearing loss, audiometric configurations, hearing improvements, and adherence to hearing treatments showed considerable variability among patients. Aural fullness, tinnitus, and hyperacusis were the predominant symptoms associated with SSNHL, and their prevalence decreased significantly over time. The diagnostic protocol led to the identification of the specific cause of SSNHL in 75% (42/56) of patients. The known etiology was found to be otological (39.3%), infectious (21.4%), autoimmune (7.1%), vascular (5.4%), or neoplastic (1.8%). In particular, Menière's disease (n = 12), isolated cochlear endolymphatic hydrops (n = 6), HSV-1 (n = 5), and EBV (n = 4) infections were the most frequent causes of SSNHL. Conclusions: The identification of the specific etiology of SSNHL may facilitate a more personalized approach to management and treatment.

Efficacy of substances containing 3 types of active ingredients-saponins, flavones, and alkaloids in regulation of cytokines in autoimmune diseases a systematic review and Meta-analysis based on animal studies.

OBJECTIVE: To investigate the efficacy of substances containing 3 types of active ingredients-saponins, flavones, and alkaloids on experimental animals with autoimmune diseases (AIDs). METHODS: The protocol for this systematic review and Meta-analysis was prospectively registered with PROSPERO (CRD42023395741). Searches were conducted in the China National Knowledge Infrastructure, Wanfang, Chinese Science and Technology Journals, China Biomedical, PubMed, Cochrane Library, and Embase databases to screen for animal studies investigating the therapeutic effects of saponins, flavones, or alkaloids on autoimmune diseases; consequently, corresponding data extraction tables were prepared. Systematic Review Centre for Laboratory Animal Experimentation was used to assess the risk of methodological bias in the included literature. RevMan 5.4 was used for the Meta-analysis on the 8 serum cytokines. RESULTS: A total of 31 studies were included, all of which were randomized controlled studies. Meta-analysis indicated that substances rich in saponins, flavones, and alkaloids reduced serum levels of interleukin (IL)-1ß [standardized mean difference (SMD) = -1.94, 95% confidence interval (CI) (-2.99, -0.90), P = 0.0003], IL-6 [SMD = -1.65, 95% CI (-2.33, -0.97,) P < 0.000 01], IL-17 [SMD = -2.41, 95% CI (-3.61, -1.20), P < 0.0001], tumor necrosis factor (TNF)-α [SMD = -1.84, 95% CI (-2.61, -1.06), P < 0.0001], and interferon (IFN)-γ [SMD = -1.54, 95% CI (-2.43, -0.65), P = 0.0007], but increased serum levels of IL-4 [SMD = 1.30, 95% CI (0.15, 2.44), P = 0.03) and IL-10 [SMD = 2.05, 95% CI (1.39, 2.70), P < 0.000 01) in animal models. However, no significant regulatory effect of these three active components was observed on serum levels of IL-2 [SMD = -0.63, 95% CI (-1.82, 0.57), P = 0.30]. CONCLUTIONS: Substances containing saponins, flavones, and alkaloids regulated the changes of immune-related cytokines, it may be a novel dietary substance to relieve and control autoimmune diseases in the future.

Selective CAR T cell-mediated B cell depletion suppresses IFN signature in SLE.

Applying advanced molecular profiling together with highly specific targeted therapies offers the possibility to better dissect the mechanisms underlying immune-mediated inflammatory diseases such as systemic lupus erythematosus (SLE) in humans. Here we apply a combination of single-cell RNA-Seq and T/B cell repertoire analysis to perform an in-depth characterization of molecular changes in the immune-signature upon CD19 CAR T cell-mediated depletion of B cells in patients with SLE. The resulting data sets not only confirm a selective CAR T cell-mediated reset of the B cell response but simultaneously reveal consequent changes in the transcriptional signature of monocyte and T cell subsets that respond with a profound reduction in type I IFN signaling. Our current data, thus, provide evidence for a causal relationship between the B cell response and the increased IFN signature observed in SLE and additionally demonstrate the usefulness of combining targeted therapies and analytic approaches to decipher molecular mechanisms of immune-mediated inflammatory diseases in humans.

Vitamin D and viral infections: Infectious diseases, autoimmune diseases, and cancers.

Viruses can cause many human diseases. Three types of human diseases caused by viruses are discussed in this chapter: infectious diseases, autoimmune diseases, and cancers. The infectious diseases included in this chapter include three respiratory tract diseases: influenza, COVID-19, and respiratory syncytial virus. In addition, the mosquito-borne dengue virus diseases are discussed. Vitamin D can reduce risk, severity, and mortality of the respiratory tract diseases and possibly for dengue virus. Many autoimmune diseases are initiated by the body's reaction to a viral infection. The protective role of vitamin D in Epstein-Barr virus-related diseases such as multiple sclerosis is discussed. There are a few cancers linked to viral infections. Such cancers include cervical cancer, head and neck cancers, Hodgkin's and non-Hodgkin's lymphoma, and liver cancer. Vitamin D plays an important role in reducing risk of cancer incidence and mortality, although not as strongly for viral-linked cancers as for other types of cancer.

Small molecule drug discovery targeting the JAK-STAT pathway.

The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway functions as a central hub for transmitting signals from more than 50 cytokines, playing a pivotal role in maintaining hematopoiesis, immune balance, and tissue homeostasis. Dysregulation of this pathway has been implicated in various diseases, including immunodeficiency, autoimmune conditions, hematological disorders, and certain cancers. Proteins within this pathway have emerged as effective therapeutic targets for managing these conditions, with various approaches developed to modulate key nodes in the signaling process, spanning from receptor engagement to transcription factor activation. Following the success of JAK inhibitors such as tofacitinib for RA treatment and ruxolitinib for managing primary myelofibrosis, the pharmaceutical industry has obtained approvals for over 10 small molecule drugs targeting the JAK-STAT pathway and many more are at various stages of clinical trials. In this review, we consolidate key strategies employed in drug discovery efforts targeting this pathway, with the aim of contributing to the collective understanding of small molecule interventions in the context of JAK-STAT signaling. We aspire that our endeavors will contribute to advancing the development of innovative and efficacious treatments for a range of diseases linked to this pathway dysregulation.

Autoimmune diseases and the risk of bladder cancer: A Mendelian randomization analysis.

OBJECTIVE: To investigate the association between autoimmune diseases (AIDs) and bladder cancer (BC) at the genetic level using Mendelian randomization (MR). METHODS: Single nucleotide polymorphisms (SNPs) associated with the seven AIDs were extracted from the IEU GWAS database, and the SNPs were quality-controlled using strict screening criteria. The association between AIDs and BC risk was assessed by inverse-variance weighted (IVW), MR-Egger regression and Weighted median method. The heterogeneity of SNPs was evaluated by Cochran Q test. MR-Egger intercept test and MR-PRESSO global test were used to test the horizontal pleiotropy of SNPs. Both sides with potential causal associations were validated using the validation set. RESULTS: Our result showed that genetically predicted RA was significantly associated with an increased risk of BC (IVW OR = 1.214, 95 % CI = 1.062-1.388, P = 0.005). MS nominally increased the risk of BC (IVW OR = 1.095, 95 % CI = 1.005-1.193, P = 0.037), consistent with the results of the MR analysis of the BC validation cohort. However SLE, T1D, UC, CD, and MG were not causally associated with BC risk (P > 0.05). The sensitivity analyses showed that there was no heterogeneity or horizontal pleiotropy in our findings. CONCLUSION: This study provides evidence of a causal relationship between AIDs and BC risk at the genetic level, confirming a causal relationship between RA and MS in increasing the risk of BC.

Cross-species single-cell analysis uncovers the immunopathological mechanisms associated with IgA nephropathy progression.

IgA nephropathy (IgAN) represents the main cause of renal failure, while the precise pathogenetic mechanisms have not been fully determined. Herein, we conducted a cross-species single-cell survey on human IgAN and mouse and rat IgAN models to explore the pathogenic programs. Cross-species single-cell RNA sequencing (scRNA-Seq) revealed that the IgAN mesangial cells (MCs) expressed high levels of inflammatory signatures CXCL12, CCL2, CSF1, and IL-34 and specifically interacted with IgAN macrophages via the CXCL12/CXCR4, CSF1/IL-34/CSF1 receptor, and integrin subunit alpha X/integrin subunit alpha M/complement C3 (C3) axes. IgAN macrophages expressed high levels of CXCR4, PDGFB, triggering receptor expressed on myeloid cells 2, TNF, and C3, and the trajectory analysis suggested that these cells derived from the differentiation of infiltrating blood monocytes. Additionally, protein profiling of 21 progression and 28 nonprogression IgAN samples revealed that proteins CXCL12, C3, mannose receptor C-type 1, and CD163 were negatively correlated with estimated glomerular filtration rate (eGFR) value and poor prognosis (30% eGFR as composite end point). Last, a functional experiment revealed that specific blockade of the Cxcl12/Cxcr4 pathway substantially attenuated the glomerulus and tubule inflammatory injury, fibrosis, and renal function decline in the mouse IgAN model. This study provides insights into IgAN progression and may aid in the refinement of IgAN diagnosis and the optimization of treatment strategies.