Liver immunity,autoimmunity,and inborn errors of immunity

The liver is the front line organ of the immune system.The liver contains the largest collection of phagocytic cells in the body that detect both pathogens that enter through the gut and endogenously produced antigens.This is possible by the highly developed differentiation capacity of the liver immune system between self-antigens or non-self-antigens,such as food antigens or pathogens.As an immune active organ,the liver functions as a gatekeeping barrier from the outside world,and it can create a rapid and strong immune response,under unfavorable conditions.However,the liver's assumed immune status is anti-inflammatory or immuno-tolerant.Dynamic interactions between the numerous populations of immune cells in the liver are key for maintaining the delicate balance between immune screening and immune tolerance.The anatomical structure of the liver can facilitate the preparation of lymphocytes,modulate the immune response against hepatotropic pathogens,and contribute to some of its unique immunological properties,particularly its capacity to induce antigen-specific tolerance.Since liver sinusoidal endothelial cell is fenestrated and lacks a basement membrane,circulating lymphocytes can closely contact with antigens,displayed by endothelial cells,Kupffer cells,and dendritic cells while passing through the sinusoids.Loss of immune tolerance,leading to an autoaggressive immune response in the liver,if not controlled,can lead to the induction of autoimmune or autoinflammatory diseases.This review mentions the unique features of liver immunity,and dysregulated immune responses in patients with autoimmune liver diseases who have a close association with inborn errors of immunity have also been the emphases.

Gastric cancer liver metastasis will reduce the efficacy of immunotherapy

Immune checkpoint inhibitors augment the antitumor activity of T cells by inhibiting the negative regulatory pathway of T cells,leading to notable efficacy in patients with non-small cell lung cancer,melanoma,and other malignancies through immunotherapy utilization.However,secondary malignant liver tumors not only lower the liver's sensitivity to immunotherapy but also trigger systemic immune suppression,resulting in reduced overall effectiveness of immune therapy.Patients receiving immunotherapy for non-small cell lung cancer and melanoma experience reduced response rates,progression-free survival,and overall survival when secondary malignant tumors develop in the liver.Through Liu's retrospective analysis,valuable insights are provided for the future clinical management of these patients.Therefore,in patients with gastric cancer(GC),the occurrence of liver metastasis might be indicative of reduced efficacy of immuno-therapy.Overcoming liver immune tolerance mechanisms and their negative impacts allows for the potential benefits of immunotherapy in patients with GC and liver metastasis.INTRODUCTION Gastric cancer(GC)ranks among the prevalent malignancies affecting the digestive system globally.Based on the latest epidemiological data[1,2],it holds the fifth position for incidence and the fourth position for mortality among all malignant tumors.GC cases and fatalities in China make up roughly half of the worldwide figures.Earlier investigations[3]have demonstrated that the median overall survival(mOS)among advanced GC patients left untreated typically ranges from 3 to 4 months.Systemic chemotherapy recipients often experience a mOS of around one year,accompanied by a marked improvement in the quality of life among patients with advanced GC.The mainstay of treatment for advanced GC patients involves chemotherapeutic medications such as fluoropyrimidines,platinum compounds,and taxanes.However,their efficacy in tumor control is constrained by acquired resistance and primary resistance.The rise of personalized precision therapy has propelled immunotherapy into the spotlight as a crucial component of comprehensive treatment[4].By blocking the negative regulatory pathways of T cells,immune checkpoint inhibitors(ICIs)boost the anti-tumor effect of T cells.Immunotherapy has brought about significant therapeutic benefits for patients diagnosed with non-small cell lung cancer,melanoma,and related illnesses[5,6],instilling newfound hope in those with advanced GC[7].However,phase III clinical trial data[8-12]reveals that the incorporation of immunotherapy into chemotherapy regimens improves overall survival(OS)outcomes for patients with advanced GC.The liver's immune-exempt nature renders it less responsive to immunotherapy when secondary malignant tumors are present,fostering systemic immune suppression and yielding unfavorable outcomes in immune therapy[13-15].In retrospective research[16-20]pertaining to non-small cell lung cancer and melanoma,it has been observed that the presence of secondary liver malignancies may lower the response rate,progression-free survival(PFS),and OS rates in patients treated with immunotherapy,independent of factors such as tumor mutation burden and PD-L1 expression.Despite this,there is a paucity of studies examining whether the existence of secondary malignant liver tumors affects the effectiveness of immunotherapy in patients diagnosed with advanced HER-2 negative GC.

Cellular immune function and liver damage in post hepatitic cirrhosis

AIM To study the cellular immune function in patients with post hepatitic cirrhosis (PHC) and its relation with different liver damages.

Influence of heme oxygenase-1 expression on immune liver fibrosis induced by cobalt protoporphyrin in rats

AIM:To investigate the effect of heme oxygenase-1 (HO-1)expression on immune liver fibrosis induced by cobalt protoporphyrin(CoPP)in rats. METHODS:An immune liver fibrosis model of rat was established by administering human serum albumin (HSA).The rats were divided into CoPP,liver fibrosis and normal control groups.Rats in the CoPP group received intraperitoneal CoPP concurrently with HSA. Expression of HO-1 protein was observed by Western blotting and immunohistochemistry.Hematoxylin and eosin(HE)staining was performed to assess fibrosis proliferation and distribution,proliferation extent of fibroblasts,and alterations in hepatocytes and inflammatory cells.TypeⅠandⅢcollagens were detected with Van Gieson’s(VG)staining and Foot’s reticular fiber staining,respectively.In addition, spindle-shaped cells existing at perisinusoidal locations beyond portal and septa areas were investigated with HE staining. RESULTS:Western blotting and immunohistochemistry showed that the expression of HO-1 protein was higher in the CoPP group than in the liver fibrosis group(P<0.05).Compared with the liver fibrosis group,the serological index of hepatic fibrosis in the CoPP group decreased significantly(P<0.05).HE,VG and Foot’s staining revealed that administration of CoPP reduced the extent of hepatic fibrosis.The levels of serological indicators and the number of spindle-shaped cells at perisinuous locations beyond the portal and septa areas were reduced in the CoPP group.Only a few inflammatory cells were seen around the portal areas and central veins in the CoPP group. CONCLUSION:Increased endogenous HO-1 may suppress liver fibrosis by protecting liver cells, inhibiting inflammatory cell infiltration and hepatic stellate cell transformation.

Effect of 2-amino-2-[2-(4-octylphenyl) ethyl] propane- 1,3-diol hydrochloride (FTY 720) on immune liver injury in mice

AIM: To investigate the protective effect against two immune liver injury models in mice by 2-amino-2-[2-(4-octylphenyl) ethyl] propane-l,3-diol hydrochloride and its possible mechanisms in Con A-induced liver damage. METHODS: Liver tissue or hepatocyte injury was monitored biochemically by measuring alanine aminotransferase (sALT) and aspartate aminotransferase (sAST) activity. Hematoxylin & eosin (HE) staining was used for histopathological examination. To evaluate the role of IFN-γ and IL-4 in the liver injury, serum levels of IFN-γ and IL-4 were determined using commercially available ELISA kit at 12 h after Con A challenge. We also determined FTY 720-induced spleen cell apoptosis by flow cytometry analysis or spleen cell proliferation test. RESULTS: Different doses of FTY 720 treatment dramatically reduced circulating markers of hepatocyte injury in two kinds of immunological liver injury models. FTY 720 dramatically reduced the elevated serum IFN-γ and IL-4 levels after Con A injection. Effect of spleen cell supernatants treated with Con A or FTY 720 on hepatocytes showed that ALT activities in cultured hepatocyte supernatants in Con A treatment group increased markedly and FTY 720 could reduce this elevated ALT activities in FTY 720 treatment group. FTY 720 dose-dependently increased the percentage of apoptotic cells in T cells and inhibited splenocyte proliferation induced by Con A. CONCLUSION: Pretreatment with FTY 720 was shown to produce protective effect on the immune liver injury in mice. The possible mechanism of FTY 720 on Con A-induced liver damage is that it could inhibit lymphocyte proliferation and induce lymphocyte apoptosis, resulting in the reduction of IL-4 or IFN-γ release, and subsequently protecting liver from being damaged by Con A.

FGF4 protects the liver from immune-mediated injury by activating CaMKKβ-PINK1 signal pathway to inhibit hepatocellular apoptosis

Immune-mediated liver injury (ILI) is a condition where an aberrant immune response due to various triggers causes the destruction of hepatocytes. Fibroblast growth factor 4 (FGF4) was recently identified as a hepatoprotective cytokine;however, its role in ILI remains unclear. In patients with autoimmune hepatitis (type of ILI) and mouse models of concanavalin A (ConA)- or S-100-induced ILI, we observed a biphasic pattern in hepatic FGF4 expression, characterized by an initial increase followed by a return to basal levels. Hepatic FGF4 deficiency activated the mitochondria-associated intrinsic apoptotic pathway, aggravating hepatocellular apoptosis. This led to intrahepatic immune hyper-reactivity, inflammation accentuation, and subsequent liver injury in both ILI models. Conversely, administration of recombinant FGF4 reduced hepatocellular apoptosis and rectified immune imbalance, thereby mitigating liver damage. The beneficial effects of FGF4 were mediated by hepatocellular FGF receptor 4, which activated the Ca^(2+)/calmodulin-dependent protein kinasekinase 2 (CaMKKβ) and its downstream phosphatase and tensin homologue-induced putative kinase 1 (PINK1)-dependent B-cell lymphoma 2-like protein 1-isoform L (Bcl-XL) signalling axis in the mitochondria. Hence, FGF4 serves as an early response factor and plays a protective role against ILI, suggesting a therapeutic potential of FGF4 and its analogue for treating clinical immune disorder-related liver injuries.

Cell cycle-related kinase reprograms the liver immune microenvironment to promote cancer metastasis

The liver is an immunologically tolerant organ and a common metastatic site of multiple cancer types.Although a role for cancer cell invasion programs has been well characterized,whether and how liver-intrinsic factors drive metastatic spread is incompletely understood.Here,we show that aberrantly activated hepatocyte-intrinsic cell cycle-related kinase(CCRK)signaling in chronic liver diseases is critical for cancer metastasis by reprogramming an immunosuppressive microenvironment.Using an inducible liverspecific transgenic model,we found that CCRK overexpression dramatically increased both B16F10 melanoma and MC38 colorectal cancer(CRC)metastasis to the liver,which was highly infiltrated by polymorphonuclear-myeloid-derived suppressor cells(PMNMDSCs)and lacking natural killer T(NKT)cells.Depletion of PMN-MDSCs in CCRK transgenic mice restored NKT cell levels and their interferon gamma production and reduced liver metastasis to 2.7% and 0.7%(metastatic tumor weights)in the melanoma and CRC models,respectively.Mechanistically,CCRK activated nuclear factor-kappa B(NF-κB)signaling to increase the PMN-MDSC trafficking chemokine C-X-C motif ligand 1(CXCL1),which was positively correlated with liver-infiltrating PMN-MDSC levels in CCRK transgenic mice.Accordingly,CRC liver metastasis patients exhibited hyperaaivation of hepatic CCRK/NF-κB/CXCL1 signaling,which was associated with accumulation of PMN-MDSCs and paucity of NKT cells compared to healthy liver transplantation donors.In summary,this study demonstrates that immunosuppressive reprogramming by hepatic CCRK signaling undermines antimetastatic immunosurveillance.Our findings offer new mechanistic insights and therapeutic targets for liver metastasis intervention.

Immunomodulation and liver protection of Yinchenhao decoction against concanavalin A-induced chronic liver injury in mice

OBJECTIVE：This study investigated the immunoregulatory and protective roles of Yinchenhao decoction,a compound of Chinese herbal medicine,in a mouse model of concanavalin A（Con A）-induced chronic liver injury.METHODS：Female Bal B/c mice were randomly divided into 4 groups：normal control,Con A model,Con A model treated with Yinchenhao decoction（400 mg/kg,orally）,and Con A model treated with dexamethasone（0.5 mg/kg,orally）.All treatments were given once a day for 28 d.Except of the normal control,mice received tail vein injection of Con A（10 mg/kg）on days 7,14,21,and 28,at 1 h after treatment with Yinchenhao decoction or dexamethasone or saline to induce chronic liver injury.RESULTS：Repeated Con A injection induced chronic liver injury,which was evidenced by infl ammatory cell infi ltration and necrosis,increased serum alanine aminotranferease activities,decreased albumin levels,and an imbalanced expression of immunoregulatory genes in the liver tissues including signifi cantly enhanced interferon-γ,interleukin-4,monocyte chemotactic protein-1,and cluster of differentiation 163 m RNA levels,and reduced tumor necrosis factor-αand interleukin-6 m RNA levels.Treatment with Yinchenhao decoction signifi cantly reversed the Con A-induced changes in immunoregulatory gene expression in the liver tissues,reduced serum alanine aminotranferease activity,enhanced serum albumin level,and attenuated the extent of liver infl ammation and necrosis.Furthermore,Yinchenhao decoction did not result in hepatocyte degeneration and spleen weight loss that were observed in mice received long-term treatment with dexamethasone.CONCLUSION：Yinchenhao decoction treatment protected liver against the Con A-induced chronic liver damage and improved liver function,which were associated with the modulation of gene expression related to immune/infl ammatory response.