Exploiting the neonatal crystallizable fragment receptor to treat kidney disease.

The neonatal Fc receptor (FcRn) was initially discovered as the receptor that allowed passive immunity in newborns by transporting maternal IgG through the placenta and enterocytes. Since its initial discovery, FcRn has been found to exist throughout all stages of life and in many different cell types. Beyond passive immunity, FcRn is necessary for intrinsic albumin and IgG recycling and is important for antigen processing and presentation. Given its multiple important roles, FcRn has been utilized in many disease treatments including a new class of agents that were developed to inhibit FcRn for treatment of a variety of autoimmune diseases. Certain cell populations within the kidney also express high levels of this receptor. Specifically, podocytes, proximal tubule epithelial cells, and vascular endothelial cells have been found to utilize FcRn. In this review, we summarize what is known about FcRn and its function within the kidney. We also discuss how FcRn has been used for therapeutic benefit, including how newer FcRn inhibiting agents are being used to treat autoimmune diseases. Lastly, we will discuss what renal diseases may respond to FcRn inhibitors and how further work studying FcRn within the kidney may lead to therapies for kidney diseases.

Position statement of the Brazilian society of Rheumatology on mesna use as a preventive therapy for bladder disease in patients with systemic autoimmune diseases and systemic vasculitis under cyclophosphamide treatment.

OBJECTIVE: To review current literature to support the use of mesna as a preventive therapy for hemorrhagic cystitis and bladder cancer in patients with systemic autoimmune diseases and systemic vasculitis treated with cyclophosphamide. MATERIALS AND METHODS: The search for articles was conducted systematically through MEDLINE, LILACS, Cochrane Library, and Embase databases. Only articles in English were selected. For available records, titles and abstracts were selected independently by two investigators. RESULTS: Eighteen studies were selected for analysis. The known adverse effects of cyclophosphamide were hematological toxicity, infections, gonadal toxicity, teratogenicity, increased risk for malignancy and hemorrhagic cystitis. Long-term toxicity was highly dependent on cyclophosphamide cumulative dose. The risk of bladder cancer is especially higher in long-term exposure and with cumulative doses above 36 g. The risk remains high for years after drug discontinuation. Hemorrhagic cystitis is highly correlated with cumulative dose and its incidence ranges between 12 and 41%, but it seems to be lower with new regimens with reduced cyclophosphamide dose. No randomized controlled trials were found to analyze the use of mesna in systemic autoimmune rheumatic diseases and systemic vasculitis. Retrospective studies yielded conflicting results. Uncontrolled prospective studies with positive results were considered at high risk of bias. No evidence was found to support the use of mesna during the treatment with cyclophosphamide for autoimmune diseases or systemic vasculitis to prevent hemorrhagic cystitis and bladder cancer. In the scenarios of high cumulative cyclophosphamide dose (i.e., > 30 g), patients with restricted fluid intake, neurogenic bladder, therapy with oral anticoagulants, and chronic kidney disease, mesna could be considered. CONCLUSION: The current evidence was found to be insufficient to support the routine use of mesna for the prophylaxis of hemorrhagic cystitis and bladder cancer in patients being treated for systemic autoimmune diseases and systemic vasculitis with cyclophosphamide. The use may be considered for selected cases.

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.

Discovery of the Clinical Candidate IDOR-1117-2520: A Potent and Selective Antagonist of CCR6 for Autoimmune Diseases.

Migration of immune cells to sites of inflammation is a critical step in the body's response to infections but also during autoimmune flares. Chemokine receptors, members of the GPCR receptors, are instrumental in directing specific cell types to their target organs. Herein, we describe a highly potent small molecule antagonist of the chemokine receptor CCR6, which came out of fine-tuned structural elaborations from a proprietary HTS hit. Three main issues in the parent chemical series-cytotoxicity, phototoxicity, and hERG, were successfully solved. Biological characterization demonstrated that compound 45 (IDOR-1117-2520) is a selective and insurmountable antagonist of CCR6. In vivo proof-of-mechanism studies in a mouse lung inflammation model using a representative compound from the chemical class of 45 confirmed that the targeted CCR6+ cells were efficiently inhibited from migrating into the bronchoalveoli. Finally, ADMET and physicochemical properties were well balanced and the preclinical package warranted progress in the clinic.

Promising Role of Alkaloids in the Prevention and Treatment of Thyroid Cancer and Autoimmune Thyroid Disease: A Comprehensive Review of the Current Evidence.

Thyroid cancer (TC) and thyroid autoimmune disorders (AITD) are among the most common diseases in the general population, with higher incidence in women. Chronic inflammation and autoimmunity play a pivotal role in carcinogenesis. Some studies, indeed, have pointed out the presence of AITD as a risk factor for TC, although this issue remains controversial. Prevention of autoimmune disease and cancer is the ultimate goal for clinicians and scientists, but it is not always feasible. Thus, new treatments, that overcome the current barriers to prevention and treatment of TC and AITD are needed. Alkaloids are secondary plant metabolites endowed with several biological activities including anticancer and immunomodulatory properties. In this perspective, alkaloids may represent a promising source of prophylactic and therapeutic agents for TC and AITD. This review encompasses the current published literature on alkaloids effects on TC and AITD, with a specific focus on the pathways involved in TC and AITD development and progression.

Subconjunctival injection of rapamycin-loaded polymeric microparticles for effective suppression of noninfectious uveitis in rats.

Noninfective uveitis is a major cause of vision impairment, and corticosteroid medication is a mainstay clinical strategy that causes severe side effects. Rapamycin (RAPA), a potent immunomodulator, is a promising treatment for noninfective uveitis. However, because high and frequent dosages are required, it is a great challenge to implement its clinical translation for noninfective uveitis therapy owing to its serious toxicity. In the present study, we engineered an injectable microparticulate drug delivery system based on biodegradable block polymers (i.e., polycaprolactone-poly (ethylene glycol)-polycaprolactone, PCEC) for efficient ocular delivery of RAPA via a subconjunctival injection route and investigated its therapeutic efficacy in an experimental autoimmune uveitis (EAU) rat model. RAPA-PCEC microparticles were fabricated using the emulsion-evaporation method and thoroughly characterized using scanning electron microscopy, fourier transform infrared spectroscopy, X-ray diffraction, and differential scanning calorimetry. The formed microparticles exhibited slow in vitro degradation over 28 days, and provided both in vitro and in vivo sustained release of RAPA over 4 weeks. Additionally, a single subconjunctival injection of PCEC microparticles resulted in high ocular tolerance. More importantly, subconjunctival injection of RAPA-PCEC microparticles significantly attenuated the clinical signs of EAU in a dose-dependent manner by reducing inflammatory cell infiltration (i.e., CD45+ cells and Th17 cells) and inhibiting microglial activation. Overall, this injectable microparticulate system may be promising vehicle for intraocular delivery of RAPA for the treatment of noninfective uveitis.

Hospitalization and mortality in Asian autoimmune bullous dermatosis patients: A 17-year retrospective study.

Limited data exist on the factors associated with hospitalization and mortality in Asian inpatients with autoimmune bullous dermatoses (AIBDs). This study aimed to elucidate the risk factors affecting hospitalization and mortality rates in Asian patients with AIBDs. A retrospective analysis of patients with AIBDs treated at Siriraj Hospital during a 17-year period was performed using the International Classification of Diseases 10th revision codes. The characteristics of inpatients and outpatients were compared, and mortality rates and associated factors were identified. The study included 360 AIBD patients (180 inpatients, 180 outpatients). Inpatients were significantly younger than outpatients. The identified risk factors for hospitalization were malignancy (odds ratio [OR] 2.83, 95% confidence interval [CI] 1.13-8.04; p = 0.034), moderate to severe disease (OR 2.52, 95% CI 1.49-4.34; p < 0.001), systemic corticosteroid use ≥15 mg/day (OR 2.27, 95% CI 1.21-4.41; p = 0.013) and oral cyclophosphamide treatment (OR 9.88, 95% CI 3.82-33.7; p < 0.001). Kaplan-Meier analysis revealed mortality rates of 26%, 36% and 39% for inpatients with pemphigus at 1, 3 and 5 years, respectively. For inpatients with pemphigoid, the corresponding rates were 28%, 38% and 47%. Infections, particularly pneumonia, were the predominant cause of death in both conditions. This study confirmed that both Asian ethnicity and healthcare disparities may be correlated with adverse outcomes in patients with AIBDs. Pemphigus mortality rates were substantially greater in Asian patients than in Caucasian patients. Continuous monitoring of factors contributing to hospitalization and mortality is imperative to improve treatment outcomes.

Delivery technologies for therapeutic targeting of fibronectin in autoimmunity and fibrosis applications.

Fibronectin (FN) is a critical component of the extracellular matrix (ECM) contributing to various physiological processes, including tissue repair and immune response regulation. FN regulates various cellular functions such as adhesion, proliferation, migration, differentiation, and cytokine release. Alterations in FN expression, deposition, and molecular structure can profoundly impact its interaction with other ECM proteins, growth factors, cells, and associated signaling pathways, thus influencing the progress of diseases such as fibrosis and autoimmune disorders. Therefore, developing therapeutics that directly target FN or its interaction with cells and other ECM components can be an intriguing approach to address autoimmune and fibrosis pathogenesis.

Beneficial mechanisms of dimethyl fumarate in autoimmune uveitis: insights from single-cell RNA sequencing.

BACKGROUND: Dimethyl fumarate (DMF) is a fumaric acid ester that exhibits immunoregulatory and anti-inflammatory properties. However, the function of DMF in autoimmune uveitis (AU) is incompletely understood, and studies comprehensively exploring the impact of DMF on immune cells are still lacking. METHODS: To explore the function of DMF in uveitis and its underlying mechanisms, we conducted single-cell RNA sequencing (scRNA-seq) on the cervical draining lymph node (CDLN) cells of normal, experimental autoimmune uveitis (EAU), and DMF-treated EAU mice. Additionally, we integrated scRNA-seq data of the retina and CDLNs to identify the potential impact of DMF on ocular immune cell infiltration. Flow cytometry was conducted to verify the potential target molecules of DMF. RESULTS: Our study showed that DMF treatment effectively ameliorated EAU symptoms. The proportional and transcriptional alterations in each immune cell type during EAU were reversed by DMF treatment. Bioinformatics analysis in our study indicated that the enhanced expression of Pim1 and Cxcr4 in EAU was reversed by DMF treatment. Further experiments demonstrated that DMF restored the balance between effector T (Teff) /regulatory T (Treg) cells through inhibiting the pathway of PIM1-protein kinase B (AKT)-Forkhead box O1 (FOXO1). By incorporating the scRNA-seq data of the retina from EAU mice into analysis, our study identified that T cells highly expressing Pim1 and Cxcr4 were enriched in the retina. DMF repressed the ocular infiltration of Teff cells, and this effect might depend on its inhibition of PIM1 and CXCR4 expression. Additionally, our study indicated that DMF might reduce the proportion of plasma cells by inhibiting PIM1 expression in B cells. CONCLUSIONS: DMF effectively attenuated EAU symptoms. During EAU, DMF reversed the Teff/Treg cell imbalance and suppressed the ocular infiltration of Teff cells by inhibiting PIM1 and CXCR4 expression. Thus, DMF may act as a new drug option for the treatment of AU.

Theoretical Studies of DNA Microarray Present Potential Molecular and Cellular Interconnectivity of Signaling Pathways in Immune System Dysregulation.

Autoimmunity is defined as the inability to regulate immunological activities in the body, especially in response to external triggers, leading to the attack of the tissues and organs of the host. Outcomes include the onset of autoimmune diseases whose effects are primarily due to dysregulated immune responses. In past years, there have been cases that show an increased susceptibility to other autoimmune disorders in patients who are already experiencing the same type of disease. Research in this field has started analyzing the potential molecular and cellular causes of this interconnectedness, bearing in mind the possibility of advancing drugs and therapies for the treatment of autoimmunity. With that, this study aimed to determine the correlation of four autoimmune diseases, which are type 1 diabetes (T1D), psoriasis (PSR), systemic sclerosis (SSc), and systemic lupus erythematosus (SLE), by identifying highly preserved co-expressed genes among datasets using WGCNA. Functional annotation was then employed to characterize these sets of genes based on their systemic relationship as a whole to elucidate the biological processes, cellular components, and molecular functions of the pathways they are involved in. Lastly, drug repurposing analysis was performed to screen candidate drugs for repositioning that could regulate the abnormal expression of genes among the diseases. A total of thirteen modules were obtained from the analysis, the majority of which were associated with transcriptional, post-transcriptional, and post-translational modification processes. Also, the evaluation based on KEGG suggested the possible role of TH17 differentiation in the simultaneous onset of the four diseases. Furthermore, clomiphene was the top drug candidate for regulating overexpressed hub genes; meanwhile, prilocaine was the top drug for regulating under-expressed hub genes. This study was geared towards utilizing transcriptomics approaches for the assessment of microarray data, which is different from the use of traditional genomic analyses. Such a research design for investigating correlations among autoimmune diseases may be the first of its kind.

Frequency of infections during rituximab treatment of autoimmune blistering diseases.

This study investigates the frequency of infections in autoimmune blistering disease (AIBD) patients treated with rituximab and evaluates the difference in infectious complications in patients on concomitant antibiotic and/or antiviral prophylaxis. The study retrospectively reviewed 43 AIBD patients who received rituximab over a five-year interval. The patients were categorized based on prophylaxis type (antibiotic, antiviral, or both) and concomitant immunosuppression status, which we defined as treatment with an immunosuppressive medication during the time frame they were given Rituximab. Our findings suggest that concomitant immunosuppression alongside rituximab did not significantly increase the risk of developing infectious complications compared to rituximab monotherapy. Results revealed that 34.4% of patients with concomitant immunosuppression had a secondary bacterial infection, defined as bacterial complications requiring hospitalization, consistent with prior studies. Moreover, antibiotic prophylaxis did not significantly reduce infection risk in patients on rituximab, with 45.1% of these patients experiencing bacterial complications. There was an absence of pneumocystis pneumonia in the study population. Despite the small sample size and limited timeline, this study suggests that antibiotic prophylaxis may not significantly mitigate the risk of infections in AIBD patients receiving rituximab, and the risk of infection with concomitant immunosuppression with rituximab requires additional investigation for definitive causal risk.

A case of immunotherapy-responsive autoimmune hemichorea.

INTRODUCTION: Subacute adult-acquired hemichorea is a striking presentation with a broad differential, including ischemic, metabolic, and inflammatory causes. CASE: We encountered a 74-year-old woman with rapid onset of hemichorea and associated encephalopathy. Following a thorough workup without identification of clear imaging or laboratory abnormalities, we empirically treated with IVIg. Her hemichorea dramatically improved. Due to relapses of hemichorea, she required repeat immunotherapy with IVIg or high dose steroids followed by maintenance mycophenolate. DISCUSSION: This case of seronegative autoimmune hemichorea highlights the importance of a high index of suspicion for an inflammatory etiology of chorea when other causes are ruled out and performing an immunotherapy trial.

Coenzyme Q10 and Autoimmune Disorders: An Overview.

Some 90 autoimmune disorders have been described in medical literature, affecting most of the tissues within the body. Autoimmune disorders may be difficult to treat, and there is a need to develop novel therapeutic strategies for these disorders. Autoimmune disorders are characterised by mitochondrial dysfunction, oxidative stress, and inflammation; there is therefore a rationale for a role for coenzyme Q10 in the management of these disorders, on the basis of its key role in normal mitochondrial function, as an antioxidant, and as an anti-inflammatory agent. In this article, we have therefore reviewed the potential role of CoQ10, in terms of both deficiency and/or supplementation, in a range of autoimmune disorders.

Nanoparticle-neutrophils interactions for autoimmune regulation.

Neutrophils play an essential role as 'first responders' in the immune response, necessitating many immune-modulating capabilities. Chronic, unresolved inflammation is heavily implicated in the progression and tissue-degrading effects of autoimmune disease. Neutrophils modulate disease pathogenesis by interacting with the inflammatory and autoreactive cells through effector functions, including signaling, degranulation, and neutrophil extracellular traps (NETs) release. Since the current gold standard systemic glucocorticoid administration has many drawbacks and side effects, targeting neutrophils in autoimmunity provides a new approach to developing therapeutics. Nanoparticles enable targeting of specific cell types and controlled release of a loaded drug cargo. Thus, leveraging nanoparticle properties and interactions with neutrophils provides an exciting new direction toward novel therapies for autoimmune diseases. Additionally, recent work has utilized neutrophil properties to design novel targeted particles for delivery into previously inaccessible areas. Here, we outline nanoparticle-based strategies to modulate neutrophil activity in autoimmunity, including various nanoparticle formulations and neutrophil-derived targeting.

Management of pregnancy in autoimmune rheumatic diseases: maternal disease course, gestational and neonatal outcomes and use of medications in the prospectiveItalian P-RHEUM.it study.

OBJECTIVES: To investigate pregnancy outcomes in women with autoimmune rheumatic diseases (ARD) in the Italian prospective cohort study P-RHEUM.it. METHODS: Pregnant women with different ARD were enrolled for up to 20 gestational weeks in 29 Rheumatology Centres for 5 years (2018-2023). Maternal and infant information were collected in a web-based database. RESULTS: We analysed 866 pregnancies in 851 patients (systemic lupus erythematosus was the most represented disease, 19.6%). Maternal disease flares were observed in 135 (15.6%) pregnancies. 53 (6.1%) pregnancies were induced by assisted reproduction techniques, 61 (7%) ended in miscarriage and 11 (1.3%) underwent elective termination. Obstetrical complications occurred in 261 (30.1%) pregnancies, including 2.3% pre-eclampsia. Two cases of congenital heart block were observed out of 157 pregnancies (1.3%) with anti-Ro/SSA. Regarding treatments, 244 (28.2%) pregnancies were treated with glucocorticoids, 388 (44.8%) with hydroxychloroquine, 85 (9.8%) with conventional synthetic disease-modifying anti-rheumatic drugs and 122 (14.1%) with biological disease-modifying anti-rheumatic drugs. Live births were 794 (91.7%), mostly at term (84.9%); four perinatal deaths (0.5%) occurred. Among 790 newborns, 31 (3.9%) were small-for-gestational-age and 169 (21.4%) had perinatal complications. Exclusive maternal breast feeding was received by 404 (46.7%) neonates. The Edinburgh Postnatal Depression Scale was compiled by 414 women (52.4%); 89 (21.5%) scored positive for emotional distress. CONCLUSIONS: Multiple factors including preconception counselling and treat-to-target with pregnancy-compatible medications may have contributed to mitigate disease-related risk factors, yielding limited disease flares, good pregnancy outcomes and frequency of complications which were similar to the Italian general obstetric population. Disease-specific issues need to be further addressed to plan preventative measures.

Tofacitinib and peficitinib inhibitors of Janus kinase for autoimmune disease treatment: a quantum biochemistry approach.

Autoimmune inflammatory diseases, such as rheumatoid arthritis (RA) and ulcerative colitis, are associated with an uncontrolled production of cytokines leading to the pronounced inflammatory response of these disorders. Their therapy is currently focused on the inhibition of cytokine receptors, such as the Janus kinase (JAK) protein family. Tofacitinib and peficitinib are JAK inhibitors that have been recently approved to treat rheumatoid arthritis. In this study, an in-depth analysis was carried out through quantum biochemistry to understand the interactions involved in the complexes formed by JAK1 and tofacitinib or peficitinib. Computational analyses provided new insights into the binding mechanisms between tofacitinib or peficitinib and JAK1. The essential amino acid residues that support the complex are also identified and reported. Additionally, we report new interactions, such as van der Waals; hydrogen bonds; and alkyl, pi-alkyl, and pi-sulfur forces, that stabilize the complexes. The computational results revealed that peficitinib presents a similar affinity to JAK1 compared to tofacitinib based on their interaction energies.

Ivermectin ameliorates acute myocarditis via the inhibition of importin-mediated nuclear translocation of NF-κB/p65.

BACKGROUND: Myocarditis is an important clinical issue which lacks specific treatment by now. Ivermectin (IVM) is an inhibitor of importin α/ß-mediated nuclear translocation. This study aimed to explore the therapeutic effects of IVM on acute myocarditis. METHODS: Mouse models of coxsackie B3 virus (CVB3) infection-induced myocarditis and experimental autoimmune myocarditis (EAM) were established to evaluate the effects of IVM. Cardiac functions were evaluated by echocardiography and Millar catheter. Cardiac inflammatory infiltration was assessed by histological staining. Cytometric bead array and quantitative real-time PCR were used to detect the levels of pro-inflammatory cytokines. The macrophages and their M1/M2 polarization were analyzed via flow cytometry. Protein expression and binding were detected by co-immunoprecipitation, Western blotting and histological staining. The underlying mechanism was verified in vitro using CVB3-infected RAW264.7 macrophages. Cyclic polypeptide (cTN50) was synthesized to selectively inhibit the nuclear translocation of NF-κB/p65, and CVB3-infected RAW264.7 cells were treated with cTN50. RESULTS: Increased expression of importin ß was observed in both models. IVM treatment improved cardiac functions and reduced the cardiac inflammation associated with CVB3-myocarditis and EAM. Furthermore, the pro-inflammatory cytokine (IL-1ß/IL-6/TNF-α) levels were downregulated via the inhibition of the nuclear translocation of NF-κB/p65 in macrophages. IVM and cTN50 treatment also inhibited the nuclear translocation of NF-κB/p65 and downregulated the expression of pro-inflammatory cytokines in RAW264.7 macrophages. CONCLUSIONS: Ivermectin inhibits the nuclear translocation of NF-κB/p65 and the expression of major pro-inflammatory cytokines in myocarditis. The therapeutic effects of IVM on viral and non-viral myocarditis models suggest its potential application in the treatment of acute myocarditis.

Rho kinase inhibitor Y-27632 downregulates IL-1ß expression in mice with experimental autoimmune myocarditis.

Autoimmune myocarditis is the limited or diffuse inflammation of the myocardium due to dysfunctional cellular and humoral immunity mechanisms. We constructed mouse models of experimental autoimmune myocarditis (EAM) using peptide MyHC-α614-629. On the day after secondary immunization, the mice were intraperitoneally injected with Rho kinase (ROCK) inhibitor Y-27632. On day 21, the cardiac tissues were harvested and weighed. The hearts of EAM mice were significantly enlarged and whitened. Furthermore, body weight (BW) slowly increased during the treatment period, the heart weight (HW) and the ratio of HW/eventual BW were increased, and inflammatory infiltration and fibrosis were aggravated in the myocardial tissue. Y-27632 treatment improved the aforementioned phenotypic and pathological features of EAM mice. Mechanistic analysis revealed a significant increase in Notch1, Hes1, Jag2, Dil1, Toll-like receptor (Tlr) 2, and interleukin (IL)-1ß expression in the myocardial tissue of EAM mice. Notably, IL-1ß expression was correlated with that of Notch1 and Tlr2. Following Y-27632 treatment, the expression of key target genes of the Notch signaling pathway (Notch1, Hes1, Dil1, and Jag2) and Tlr2 were obviously decreased. Y-27632 treatment also decreased the number of monocytes in the spleen of EAM mice. Thus, ROCK inhibitor Y-27632 exerted a protective effect in EAM mice by downregulating IL-1ß expression. This study aimed to provide a reference point for the future treatment of myocarditis in clinical settings.

Novel and potential future therapeutic options in systemic autoimmune diseases.

Autoimmune inflammation is caused by the loss of tolerance to specific self-antigens and can result in organ-specific or systemic disorders. Systemic autoimmune diseases affect a significant portion of the population with an increasing rate of incidence, which means that is essential to have effective therapies to control these chronic disorders. Unfortunately, several patients with systemic autoimmune diseases do not respond at all or just partially respond to available conventional synthetic disease-modifying antirheumatic drugs and targeted therapies. However, during the past few years, some new medications have been approved and can be used in real-life clinical settings. Meanwhile, several new candidates appeared and can offer promising novel treatment options in the future. Here, we summarize the newly available medications and the most encouraging drug candidates in the treatment of systemic lupus erythematosus, rheumatoid arthritis, Sjögren's disease, systemic sclerosis, systemic vasculitis, and autoimmune myositis.