Treatment Of Autoimmune Hepatitis Research Articles

Unmet needs in autoimmune hepatitis: Results of the prospective multicentre European Reference Network Registry (R-LIVER).

The European Reference Network on Hepatological Diseases (ERN RARE-LIVER) launched the prospective, multicentre, quality-controlled R-LIVER registry on rare liver diseases. The aim of this study was to assess the presentation and outcome of autoimmune hepatitis (AIH) after 1 year of treatment. Data were prospectively collected at the time of diagnosis and after 6 and 12 months follow-up. Complete biochemical response (CBR) was defined as normalization of alanine aminotransferase (ALT) and immunoglobulin G (IgG) serum levels. A total of 231 patients from six European centres were included in the analysis. After 6 months of treatment 50% (106/212), and after 12 months 63% (131/210) of patients reached CBR with only 27% (56/211) achieving a steroid-free CBR within the first year. Overall, 16 different treatment regimens were administered. Change of treatment, mostly due to intolerance, occurred in 30.4% within the first 6 months. In multivariate analysis, younger age at diagnosis (odds ratio [OR] = 1.03 [95% confidence interval (CI) 1.01-1.05]; p = .007), severe fibrosis (OR .38 [95% .16-.89], p = .026) and change of treatment within the first 6 months (OR .40 [95% CI .2-.86]; p = .018) were associated with a lesser chance of ALT normalization at 12 months follow-up. The landscape of AIH treatment in Europe is highly heterogeneous, even between expert centres. The results from this first European multicentre prospective registry reveal several unmet needs, highlighted by the overall low rates of CBR and the frequent failure to withdraw corticosteroids.

Autoimmune hepatitis: Current and future therapies.

Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease that can lead to cirrhosis and liver failure. AIH can present in all ages, races, and ethnicities, but it predominantly affects women. As a heterogeneous disease, AIH presents variably in different patients, making diagnosis and treatment a challenge. Currently, the standard treatment for AIH comprises immunosuppressants; however, their long-term use is associated with adverse effects. The pathogenesis of AIH is complex, involving T cells, macrophages, and plasma cells that invade the periportal parenchyma and lead to an inflammatory cascade that can result in liver damage. Due to the complexity of AIH pathogenesis, treatment targets several inflammatory pathways. However, unlike other autoimmune diseases in which targeted treatments have been approved, there has been little progress made in advancing the treatment paradigm for AIH. Major obstacles to progress include challenges in conducting clinical trials, particularly patient recruitment and ensuring a diverse range of backgrounds; poorly defined outcomes to assess treatment response and improved quality of life; and a lack of study designs that account for the stage of disease and variations in treatment. A focus on individualized and steroid-free treatment approaches is needed to improve AIH prognosis and minimize steroid-associated adverse effects.

Rituximab is a safe and effective alternative treatment for patients with autoimmune hepatitis: Results from the ColHai registry.

Small series suggest that rituximab could be effective as treatment for autoimmune hepatitis (AIH), although data are scarce. We aimed to evaluate the efficacy and safety of rituximab in different cohorts of patients with AIH. Multicentre retrospective analysis of the 35 patients with AIH and its variant forms treated with rituximab and included in the ColHai registry between 2015 and 2023. Most patients were female (83%), 10 (29%) had cirrhosis and four (11.4%) variant forms of AIH. Indication for rituximab were as follows: 14(40%) refractory AIH, 19(54%) concomitant autoimmune or haematological disorder, 2(6%) intolerance to prior treatments. In three (9%) subjects with a concomitant disorder, rituximab was the first therapy for AIH. Overall, 31 (89%) patients achieved or maintained complete biochemical response (CBR), including the three in first-line therapy. No difference in CBR was observed according to rituximab indication (refractory AIH 86% vs. concomitant disorders 90%, p = .824) or cirrhosis (80% vs. 92%, p = .319). Rituximab was associated with a significant reduction in corticosteroids (median dose: prior 20 vs. post 5 mg, p < .001) and the discontinuation of ≥1 immunosuppressant in 47% of patients. Flare-free rate at 1st, 2nd and 3rd year was 86%, 73% and 62% respectively. Flares were not associated with the development of liver failure and were successfully managed with repeated doses of rituximab and/or increased corticosteroids. Three (9%) patients experienced infusion-related adverse events (1 anaphylaxis and 2 flu-like symptoms) and five (14%) infections. Rituximab is safe and effective in patients with refractory AIH and those treated due to concomitant autoimmune or haematological disorders.

Bifidobacterium mitigates autoimmune hepatitis by regulating IL-33-induced Treg/Th17 imbalance via the TLR2/4 signaling pathway.

The present work aims to evaluate the efficacy of Live Combined Bifidobacterium, Lactobacillus and Enterococcus Capsules (LCBLECs), a probiotic drug containing Bifidobacterium, in the treatment of autoimmune hepatitis (AIH). In this study, a mouse model of experimental autoimmune hepatitis (EAH) was established to investigate the effects of LCBLECs on AIH. The results showed that LCBLECs improved dysbiosis of gut microbiota, reduced liver injury, restored liver function, and maintained Treg/Th17 balance in EAH mice. In addition, LCBLECs restored Treg/Th17 balance in EAH mice by downregulating IL-33 production. Besides, LCBLECs also suppress IL-33 upregulation in EAH mice by inhibiting the TLR2/4 signaling pathway. Furthermore, LCBLECs also mitigated dysbiosis of gut microbiota and enhanced the efficacy of conventional treatment for AIH patients. To sum up, our findings revealed that LCBLECs exerted therapeutic effects on EAH mice by improving Treg/Th17 imbalance in an IL-33-dependent manner via the TLR2/4 signaling pathway and relieved the clinical symptoms of AIH patients, indicating Bifidobacterium supplementation with LCBLECs might be a potential adjuvant therapy for AIH treatment.

Succinic Acid Ameliorates Concanavalin A-Induced Hepatitis by Altering the Inflammatory Microenvironment and Expression of BCL-2 Family Proteins.

Autoimmune hepatitis (AIH) is a severe immune-mediated inflammatory liver disease that currently lacks feasible drug treatment methods. Our study aimed to evaluate the protective effect of succinic acid against AIH and provide a reliable method for the clinical treatment of AIH. We performed an in vivo study of the effects of succinic acid on concanavalin A (ConA)-induced liver injury in mice. We examined liver transaminase levels, performed hematoxylin and eosin (HE) staining, and observed apoptotic phenotypes in mice. We performed flow cytometry to detect changes in the number of neutrophils and monocytes, and used liposomes to eliminate the liver Kupffer cells and evaluate their role. We performed bioinformatics analysis, reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and western blotting to detect mitochondrial apoptosis-induced changes in proteins from the B-cell lymphoma 2(Bcl-2) family. Succinic acid ameliorated ConA-induced AIH in a concentration-dependent manner, as reflected in the survival curve. HE and TUNEL staining and terminal deoxynucleotidyl transferase dUTP nick end labeling revealed decreased alanine transaminase and aspartate aminotransferase levels, and reduced liver inflammation and apoptosis. RT-qPCR and enzyme-linked immunosorbent assay revealed that succinic acid significantly reduced liver pro-inflammatory cytokine levels. Flow cytometry revealed significantly decreased levels of liver neutrophils. Moreover, the protective effect of succinic acid disappeared after the Kupffer cells were eliminated, confirming their important role in the effect. Bioinformatics analysis, RT-qPCR, and western blotting showed that succinic acid-induced changes in proteins from the Bcl-2 family involved mitochondrial apoptosis, indicating the molecular mechanism underlying the protective effect of succinic acid. Succinic acid ameliorated ConA-induced liver injury by regulating immune balance, inhibiting pro-inflammatory factors, and promoting anti-apoptotic proteins in the liver. This study provides novel insights into the biological functions and therapeutic potential of succinic acid in the treatment of autoimmune liver injury.

PIM1 inhibitor SMI-4a attenuated concanavalin A-induced acute hepatitis through suppressing inflammatory responses.

Serine/threonine kinase 1 (PIM1) plays a crucial role in cell growth, differentiation, and apoptosis. However, its role in the pathogenesis of concanavalin A (ConA)-induced acute hepatitis is not well understood. PIM1 kinase inhibitor can reduce the expression of PIM1. This study aims to investigate the effects of PIM1 kinase inhibitor and its protective mechanism in ConA-induced acute hepatitis. C57/BL six mice were injected with ConA (20, 15, and 12 mg/kg) to induce acute hepatitis, and PIM1 kinase inhibitor SMI-4a (60 mg/kg) was administered orally 24 h before ConA injection. The survival rate of the mice was observed after ConA injection. The levels of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were measured. Serum inflammatory factors were detected by enzyme-linked immunosorbent assay (ELISA). Hematoxylin-eosin (HE) staining was performed on liver tissue collected at different time points. The major cytokines expression in liver tissue was detected by quantitative real-time polymerase chain reaction (qRT-PCR). The number of macrophages, T-cell and neutrophils in liver tissue were detected by flow cytometry (FCM). PIM1 in liver tissue was detected by western blot (WB) and qRT-PCR. SMI-4a (80 µM) was pretreated for 24 h and ConA (400 µg/mL) was stimulated for 12 h in RAW264.7 cell model. Phosphorylated p65 (p-p65) and cleaved caspase-3 (c-caspase-3) in liver tissue and macrophages were detected by WB. Different concentrations of ConA caused different acute hepatitis mortality, 12 mg/kg concentration within 24 h of the mortality showed a gradient increase. The levels of AST and ALT increased significantly at 12 h after ConA injection. PIM1 expression was upregulated at 12 h. SMI-4a can suppress the PIM1 expression. SMI-4a suppressed cytokines production, AST, and ALT in ConA-treated serum. SMI-4a suppressed the major cytokines in liver tissue. Tests in liver tissue showed that SMI-4a reduced the number of T cells, neutrophils, and macrophages. SMI-4a inhibited the inflammatory response by downregulating the expression of p-p65. Meanwhile, apoptosis was decreased by decreasing the expression of c-caspase-3. In conclusion, the protective effect of SMI-4a against acute hepatitis is by reducing the inflammatory response and apoptosis. These findings suggest that SMI-4a may have therapeutic potential in the treatment of autoimmune hepatitis.

Characteristics of peripheral blood mononuclear cells and potential related molecular mechanisms in patients with autoimmune hepatitis: a single-cell RNA sequencing analysis.

Autoimmune hepatitis (AIH) is an immune disorder characterized by hypergammaglobulinemia, autoantibodies, and chronic active hepatitis on liver histology. However, immune cell population characteristics in AIH patients remain poorly understood. This study was designed to analyze peripheral blood mononuclear cell (PBMC) characteristics in AIH through single-cell RNA sequencing (scRNA-seq) and explore potential AIH-related molecular mechanisms. We generated 3690 and 3511 single-cell transcriptomes of PBMCs pooled from 4 healthy controls (HCs) and 4 AIH patients, respectively, by scRNA-seq. These pooled PBMC transcriptomes were used for cell cluster identification and differentially expressed gene (DEG) identification. GO functional enrichment analysis was performed on the DEGs to determine the most active AIH immune cell biological functions. Although the PCA-based uniform manifold approximation and projection (UMAP) algorithm was used to cluster cells with similar expression patterns in the two samples, 87 up- and 12 downregulated DEGs were retained in monocytes and 101 up- and 15 downregulated DEGs were retained in NK cells from AIH PBMCs. Moreover, enriched GO terms in the PBMC-derived monocyte and NK cell clusters were related mainly to antigen processing and presentation, IFN-γ-mediated signaling, and neutrophil degranulation and activation. These potential molecular mechanisms may be important targets for AIH treatment.

The significance of gut microbiota in the etiology of autoimmune hepatitis: a narrative review.

Autoimmune hepatitis (AIH) is a chronic inflammatory disease of the liver that is mediated by autoimmunity and has complex pathogenesis. Its prevalence has increased globally. Since the liver is the first organ to be exposed to harmful substances, such as gut-derived intestinal microbiota and its metabolites, gut health is closely related to liver health, and the "liver-gut axis" allows abnormalities in the gut microbiota to influence the development of liver-related diseases such as AIH. Changes in the composition of the intestinal microbiota and its resultant disruption of the intestinal barrier and microbial transport are involved in multiple ways in the disruption of immune homeostasis and inflammation, thereby influencing the development of AIH. In terms of the mechanisms involved in immune, the gut microbiota or its metabolites, which is decreased in secondary bile acids, short-chain fatty acids (SCFAs), and polyamines, and increased in lipopolysaccharide (LPS), branched-chain amino acids (BCAA), tryptophan metabolite, amino acid, and bile acid, can disrupt immune homeostasis by activating various immune cells and immune-related signaling pathways, resulting in aberrant activation of the immune system. Clarifying this mechanism has significant clinical implications for the treatment of AIH with drugs that target intestinal microbiota and related signaling pathways. Therefore, this narrative review summarizes the progress in exploring the involvement of gut microbiota in the pathogenesis of AIH, with the aim of helping to improve the precise targeting of therapeutic treatments against AIH for the benefit of clinical AIH treatment.

The evolving phenotype of autoimmune hepatitis across the millennium: The 40-year experience of a referral centre in Italy.

During recent years, there have been major insight into the pathogenesis, diagnosis and treatment of autoimmune hepatitis (AIH). We aim to evaluate modifications of the clinical-epidemiological phenotype of AIH patients from 1980 to our days. Single-centre, tertiary care retrospective study on 507 consecutive Italian patients with AIH. Patients were divided into four subgroups according to the decade of diagnosis: 1981-1990, 1991-2000, 2001-2010 and 2011-2020. We assessed clinical, laboratory and histological features at diagnosis, response to treatment and clinical outcomes. Acute presentation is defined as transaminase levels >10-fold the upper limit and/or bilirubin >5 mg/dL. Complete response is defined as the normalization of transaminases and IgG after 12 months. Clinical progression is defined as the development of cirrhosis in non-cirrhotic patients and hepatic decompensation/hepatocellular carcinoma development in compensated cirrhosis. Median age at diagnosis increased across decades (24, 31, 39, 52 years, p < .001). Acute onset became more common (39.6%, 44.4%, 47.7%, 59.5%, p = .019), while cirrhosis at diagnosis became less frequent (36.5%, 16.3%, 10.8%, 8.7%, p < .001). Complete response rates rose (11.1%, 49.4%, 72.7% 76.2%, p < .001) and clinical progression during follow-up decreased (54.3%, 29.9%, 16.9%, 11.2%, p < .001). Anti-nuclear antibodies positivity increased (40.7%, 52.0%, 73.7%, 79.3%, p < .001), while IgG levels/upper limit progressively decreased (1.546, 1.515, 1.252, 1.120, p < .001). Liver-related death and liver transplantation reduced from 17.1% to 2.1% (p < .001). In the new millennium, the typical AIH patient in Italy is older at diagnosis, more often presents with acute hepatitis, cirrhosis is less frequent and response to treatment is more favourable.

STAT3-Dependent Effects of Polymeric Immunoglobulin Receptor in Regulating Interleukin-17 Signaling and Preventing Autoimmune Hepatitis

One-third of patients with autoimmune hepatitis (AIH) have cirrhosis at the time of diagnosis. The relevance of these variables, although unknown, is believed to be critical in AIH because of suspected interactions between the gut microbiome and genetic factors. Dysbiosis of the gut flora and elevated polymeric immunoglobulin receptor (pIgR) levels have been observed in both patients and mouse models. Moreover, there is a direct relationship between pIgR expression and transaminase levels in patients with AIH. In this study, we aimed to explore how pIgR influences the secretion of regenerating islet-derived 3 beta (Reg3b) and the flora composition in AIH using in vivo experiments involving patients with AIH and a concanavalin A-induced mouse model of AIH. Reg3b expression was reduced in pIgR gene (Pigr)-knockout mice compared to that in wild-type mice, leading to increased microbiota disruption. Conversely, exogenous pIgR supplementation increased Reg3b expression and maintained microbiota homeostasis. RNA sequencing revealed the participation of the interleukin (IL)-17 signaling pathway in the regulation of Reg3b through pIgR. Furthermore, the introduction of external pIgR could not restore the imbalance in gut microbiota in AIH, and the decrease in Reg3b expression was not apparent following the inhibition of signal transducer and activator of transcription 3 (STAT3). In this study, pIgR facilitated the upregulation of Reg3b via the STAT3 pathway, which plays a crucial role in preserving the balance of the intestinal microbiota in AIH. Through this research, we discovered new molecular targets that can be used for the diagnosis and treatment of AIH.

Research progress on the mechanism of traditional Chinese medicine in the treatment of autoimmune hepatitis

Research progress on the mechanism of traditional Chinese medicine in the treatment of autoimmune hepatitis

Have serum vitamin D and ferritin a role in predicting the prognosis of autoimmune hepatitis treatment in children?

To investigate whether serum ferritin and vitamin D levels before starting autoimmune hepatitis (AIH) treatment have a role in disease prognosis regarding a therapeutic response. The prospective study included 100 children diagnosed with AIH according to simplified criteria for diagnosis of AIH. They attended the Pediatric Hepatology Department, National Liver Institute, Menoufia University. The patients underwent measurement of liver transaminases before starting AIH treatment after 6 months from starting therapy. They underwent liver biopsy before starting treatment for proper diagnosis, grading, and staging; only 25 cases were compliant and underwent liver biopsy before treatment withdrawal. Serum ferritin and 25 hydroxy vitamin D levels were significantly higher among those with a complete response (1000-3100 ng/ml, 29-48 ng/ml) than a partial response (550-600 ng/ml, 23-28 ng/ml) and non-response (29.28-92.14, 2.16-8.72) (p < 0.001). Our study showed a relation between serum vitamin D before starting AIH treatment, the severity of AIH and response to therapy. This opens a new area of research on the potential use of vitamin D in patients with AIH. Also, hyperferritinemia at the diagnosis can predict the treatment response.

Development and characterization of Tinospora cordifolia extract-loaded SLNs for the treatment of autoimmune hepatitis

Solid Lipid Nanoparticles (SLNs) have emerged as promising drug delivery systems with the potential to enhance the therapeutic efficacy of bioactive compounds. In this study, T. Cordifolia extract-loaded SLNs were developed and characterized for their application in the treatment of autoimmune hepatitis. T. Cordifolia, known for its immunomodulatory and anti-inflammatory properties, was chosen as the active ingredient. The formulations were systematically evaluated for drug-excipient compatibility, particle size, zeta potential, drug loading efficiency, drug release kinetics, encapsulation efficiency, in-vitro release, and stability. The results indicated "No Change" in drug-excipient compatibility, ensuring the formulation's stability. The SLNs exhibited nanoscale particle sizes (159.30 nm to 172.12 nm) with narrow size distributions, facilitating consistent drug delivery. Negative zeta potentials (-28.28 mV to -35.44 mV) indicated colloidal stability. High drug loading efficiencies (up to 32.23%) and controlled drug release kinetics were observed, suggesting the potential for sustained and targeted drug delivery. Encapsulation efficiencies of up to 83.41% highlighted efficient drug loading within the SLNs. In-vitro release studies revealed that SLN2 and SLN4 exhibited superior drug release profiles compared to other formulations. These findings indicate the potential of these formulations for controlled drug delivery. In-vivo efficacy studies in murine models of autoimmune hepatitis are recommended to assess the therapeutic benefits of T. Cordifolia extract-loaded SLNs. Additionally, stability studies demonstrated the maintenance of critical parameters, such as particle size, zeta potential, and drug loading efficiency, under different storage conditions.

Diagnosis and Treatment of Autoimmune Hepatitis: Questions, Answers, and Illustrative Cases: Endorsed by Autoimmune Liver Diseases Special Interest Group, Turkish Association for the Study of Liver.

Autoimmune hepatitis (AIH) is a rare, immune-mediated liver disease. It has a heterogeneous nature with varied clinical presentations. The management of patients with AIH is challenging in many ways. The main difficulties are inexperience due to the rarity of the disease, diagnostic confusion in controversial areas such as variant/overlap cases, acute presentations, the presence of non-alcoholic fatty liver disease or drug-induced liver injury features, and the long and complex course of treatment. Here, we provide a clear, concise, and visualized review regarding the diagnosis and treatment of AIH, including illustrative cases.

A nomogram for analyzing risk factors of poor treatment response in patients with autoimmune hepatitis.

The objective of this study was to identify biochemical and clinical predictors of poor response (including incomplete response and non-response) to standard treatment in autoimmune hepatitis (AIH) patients. This study retrospectively collected clinical data from 297 patients who were first diagnosed with AIH in Beijing Ditan Hospital from 2010 to 2019. Finally, 149 patients were screened out. Risk factors were screened by univariate and multifactorial logistic regression. Then they were used to establish the nomogram. The ROC curve, calibration curve, decision curves analysis (DCA) and clinical impact curves (CIC) were used to evaluate the nomogram. 149 patients were divided into two groups: the response group (n = 120, 80%) and the poor response group (n = 29, 20%). Multivariate logistic regression analysis found that IgG > 26.5 g/L (OR: 22.016; 95% CI: 4.677-103.640) in AIH patients increased the risk. In contrast, treatment response status was better in women (OR: 0.085; 95% CI: 0.015-0.497) aged >60 years (OR: 0.159; 95% CI: 0.045-0.564) with AST > 4.49 × ULN (OR: 0.066; 95% CI: 0.009-0.494). The C index (0.853) and the calibration curve show that the nomogram is well differentiated and calibrated; the DCA and CIC indicate that the model has good clinical benefits and implications. The study found that male patients aged ≤ 60 years with IgG > 26.5 g/L and elevated AST ≤ 4.49 × ULN were more likely to have a non-response/incomplete response to standard treatment.

SFgl2 gene-modified MSCs regulate the differentiation of CD4+ T cells in the treatment of autoimmune hepatitis

BackgroundAutoimmune hepatitis (AIH) is a T-cell-mediated autoimmune liver disease that can lead to liver injury and has a poor long-term prognosis. Mesenchymal stromal cells (MSCs) have immunosuppressive effects and can treat AIH. CD4+ T cells express the unique inhibitory Fcγ receptor (FcγRIIB), which is the only receptor for the immunosuppressive factor soluble fibrinogen-like protein 2 (sFgl2). This study aimed to examine the therapeutic effect of sFgl2 gene-modified MSCs (sFgl2-MSCs) on AIH.MethodsMSCs were obtained from the inguinal fat of mice and cocultured with CD4+ T cells sorted from mouse spleens. FcγRIIB expression on CD4+ T cells was determined by flow cytometry. sFgl2 expression in MSCs transfected with lentiviral vectors carrying the Fgl2 gene and a green fluorescent protein-encoding sequence was determined by enzyme-linked immunosorbent assay. The percentages of Th1 cells Th17 cells and regulatory T cells (Tregs) were determined by flow cytometry And the levels of p-SHP2 and p-SMAD2/3 were detected by Western blotting after the cells were cocultured with MSCs for 72 h. After locating MSCs by in vivo imaging Con A-induced experimental AIH mice were randomly divided into 4 groups and administered different treatments. After 24 h histopathological scores liver function and cytokine levels were examined and the proportions of CD4+ T cells CD8+ T cells Tregs Th17 cells and Th1 cells in the spleen and liver were determined by flow cytometry. In addition immunohistochemical staining was used to detect the liver infiltration of T-bet-, Foxp3- and RORγ-positive cells.ResultsFcγRIIB expression on CD4+ T cells was upregulated after coculture with MSCs. After coculture with sFgl2-MSCs, the proportion of Tregs among CD4+ T cells increased, the proportion of Th17 and Th1 cells decreased, and the levels of p-SHP2 and p-SMAD2/3 increased. In vivo, sFgl2-MSCs significantly improved liver function, decreased liver necrosis area, decreased tumor necrosis factor-α, interleukin (IL)-1β and IL-6 expression, increased IL-10 expression, reduced liver infiltration of CD4+ T and CD8+ T cells, increased the proportion of Tregs and reduced the proportions of Th17 and Th1 cells in mice.ConclusionBy promoting Tregs differentiation and inhibiting Th17 and Th1 cell differentiation, sFgl2 gene-modified MSCs have a more powerful therapeutic effect on Con A-induced experimental AIH and may represent a strategy for the clinical treatment of AIH.

Liver Disease and Sickle Cell Disease: Auto-Immune Hepatitis more than a Coincidence; A Systematic Review of the Literature.

In patients with SCD, chronic liver damage is a common manifestation. More than 50% of SCD patients have elevated liver enzymes. Common underlying aetiologies include sickle cell hepatic crisis, viral hepatitis, sickle cell intrahepatic cholestasis and hepatic sequestration in the acute setting, and cholelithiasis and iron overload in the chronic setting. Autoimmune hepatitis (AIH) is a rare disease that appears to occur more commonly in the sickle cell disease (SCD) population than in the general population. There are many schools of thought as to why this is the case, including the phosphatidylserine hypothesis, the heme inflammatory hypothesis, the complement generation hypothesis, and the transfusion alloimmunization hypothesis. Due to the natural history of the two illnesses, SCD is almost always diagnosed first in cases of dual pathology. Symptoms such as jaundice, fatigue, and abdominal pain are common in SCD, as are abnormal liver function tests (LFTs). These abnormalities, attributed to the other more frequent liver involvements in SCD, can lead to delays in AIH diagnosis in this population. Corticosteroids, sometimes with other immunosuppressive agents, such as azathioprine, are the cornerstone of acute AIH treatment. However, corticosteroid use in the SCD population has been shown to carry an increased risk of vaso-occlusive crises, providing a treatment dilemma. The following is a review of AIH in the SCD population, where we explore the pathophysiology behind the association between the two disorders, discuss an approach to investigating abnormal LFTs in SCD, and examine treatment options in this population with co-existing diseases.

The progress of autoimmune hepatitis research and future challenges.

Autoimmune hepatitis (AIH) is a chronic liver inflammatory disease with various immune system manifestations, showing a global trend of increased prevalence. AIH is diagnosed through histological abnormalities, clinical manifestations, and biochemical indicators. The biochemical markers involve interfacial hepatitis, transaminase abnormalities, positive autoantibodies, etc. Although AIH pathogenesis is unclear, gene mutations and immunological factors could be the leading factors. AIH usually presents as a chronic liver disease and sometimes as acute hepatitis, making it challenging to distinguish it from drug-related hepatitis due to similar clinical symptoms. Normalizing transaminases and serum IgG levels is essential in assessing the remission status of AIHtreatment. Glucocorticoids and azathioprine are the first-line AIH treatment, with lifelong maintenance therapy in some patients. The quality of life and survival can be improved after appropriate treatment. However, certain limitations jeopardize the quality of treatment, including long treatment cycles, side effects, poor patient compliance, and inability to inhibit liver fibrosis and cirrhosis. Accurate AIH animal models will help us understand the pathophysiology of the disease while providing fresh perspectives for avoiding and treating AIH. This review will help us understand AIH better, from the cellular and molecular causes to the clinical features, and will provide insight into new therapy techniques with fewer side effects.

TPN10475 alleviates concanavalin A-induced autoimmune hepatitis by limiting T cell development and function through inhibition of PI3K-AKT pathway

Autoimmune hepatitis (AIH) is an inflammatory liver disease in which the autoimmune system instigates an attack on the liver, causing inflammation and liver injury, and its incidence has increased worldwide in recent years. The mouse model of acute hepatitis established by concanavalin A (Con A) is a typical and recognized mouse model for the study of T-cell-dependent liver injury. In this study, we aimed to investigate whether the artemisinin derivative TPN10475 could alleviate AIH and its possible mechanisms. TPN10475 effectively inhibited lymphocyte proliferation and IFN-γ+ T cells production in vitro, alleviated liver injury by decreasing infiltrating inflammatory T cells producing IFN-γ in the liver and peripheral immune tissues, and demonstrated that TPN10475 weakened the activation and function of T cells by inhibiting PI3K-AKT signaling pathway. These results suggested that TPN10475 may be a potential drug for the treatment of AIH, and the inhibition of PI3K-AKT signaling pathway may provide new ideas for the study of the pathogenesis of AIH.

Umbilical Cord-Derived Mesenchymal Stem Cells Attenuate S100-Induced Autoimmune Hepatitis via Modulating Th1 and Th17 Cell Responses in Mice.

Currently, the first-line treatment for autoimmune hepatitis (AIH) is still the combination of glucocorticoids or immunosuppressants. However, hormone and immunosuppressive therapy can cause serious side effects, such as Cushing syndrome and bone marrow suppression. Previous studies reported on the applicability and safety of mesenchymal stem cells (MSCs) to ameliorate liver inflammation and fibrosis. However, the characteristics of MSCs sources directly contribute to the different conclusions on the mechanisms underlying MSC-mediated immunoregulation. Bone marrow-derived MSCs can exert an immunosuppression effect to ameliorate the S100-induced AIH model by inhibiting several proinflammatory cytokines and upregulating of PD-L1 in liver tissue. It is not clear whether human umbilical cord-derived MSCs (hUC-MSCs) could directly inhibit liver inflammation and ultimately alleviate the dysfunction of hepatocytes in the AIH model. First, hUC-MSCs were extracted from umbilical cord tissue, and the basic biological properties and multilineage differentiation potential were examined. Second, 1 × 106 hUC-MSCs were administered intravenously to AIH mice. At the peak of the disease, serum levels of alanine aminotransferase and aspartate aminotransferase and pathologic damage to liver tissue were measured to evaluate liver function and degree of inflammation. We also observed that the infiltration of CD4+ T cells in the liver was significantly reduced. Furthermore, the frequency of the splenic IFNγ- and IL-17A- producing CD4+ T cells were also significantly decreased, while we only observed an increasing trend in Treg cells in liver tissue. Third, an RNA sequencing analysis of liver tissue was performed, which showed that in the UC-MSC-treated group, the transcriptional profiles of inflammation-related signaling pathways were significantly negatively regulated compared to those of phosphate-buffered saline-treated mice. Collectively, these findings indicated the potential of hUC-MSC to suppress immune responses in immune anomaly mediated liver disease, thus offering a potential clinical option to improve AIH.