Search

Monitoring hepatocyte proliferation in situ following partial hepatectomy is widely used to characterize cytokines, growth factors and signaling molecules and pathways as well as the regulatory mechanisms involved in liver regeneration. Periodic measurement of the liver/body mass ratio estimates the rate of liver regeneration, which is often supplemented by evaluating the proportion of proliferating hepatocytes using a synthetic nucleoside analog such as 5-bromo-2'-deoxyuridine (BrdU) or the nuclear accumulation of proliferating cell nuclear antigen (PCNA) in proliferating cells. The introduction of the thymidine analog 5-ethynyl-2'deoxyuridine (EdU) and its detection by "click chemistry" using fluorescently labeled reagents has simplified the evaluation of live cell proliferation as it eliminates certain limitations of antibody-mediated detection of BrdU. Here, we describe the EdU-based measurement of hepatocyte proliferation during liver regeneration and correlate the results with that of Ki67 and PCNA-based assays.

Chronic HBV infection (CHI) is associated with a diverse natural history that includes immune-tolerant (IT), HBeAg-positive chronic hepatitis B (CHB) (EP-CHB), inactive carrier, and HBeAg-negative CHB (EN-CHB) phases. A hallmark of CHI is impairment of HBV-specific T-cell response. Recently, myeloid-derived suppressor cells (MDSCs) have emerged as key regulator of T cells, and their properties are sculpted by their microenvironment. Here, we investigated the distinctive features of MDSCs during CHI, identified factors responsible for their functional discrepancies, and studied their impact on HBV-specific T-cell response and homing. Influence of antiviral therapy on MDSC profile and T-cell response was also assessed.Flow cytometric analysis indicated that MDSCs in EP-CHB/EN-CHB patients had profound suppressive ability, expressing arginase 1 (Arg1)/inducible nitric oxide synthase (iNOS)/programmed death ligand 1 (PD-L1)/cytotoxic T lymphocyte-associated protein 4 (CTLA-4)/CD40 at significantly greater levels relative to healthy controls (HC). However, in IT, only Arg1Diversity of MDSCs during CHI affects HBV-specific T-cell response and homing. Hence, therapeutic targeting of MDSCs could boost anti-HBV immunity.

Overview: Long-term survival of T lymphocytes in quiescent state is essential to maintain their cell numbers in secondary lymphoid organs and in peripheral circulation. In the BioBreeding diabetes-prone strain of rats (BB-DP), loss of functional GIMAP5 (GTPase of the immune associated nucleotide binding protein 5) results in profound peripheral T lymphopenia. This discovery heralded the identification of a new family of proteins initially called Immune-associated nucleotide binding protein (IAN) family. In this review we will use ‘GIMAP’ to refer to this family of proteins. Recent studies suggest that GIMAP proteins may interact with each other and also be involved in the movement of the cellular cargo along the cytoskeletal network. Here we will summarize the current knowledge on the characteristics and functions of GIMAP family of proteins.

Interleukin-15 (IL-15) is a member of the IL-2 family of cytokines, which use receptor complexes containing the common gamma (γc) chain for signaling. IL-15 plays important roles in innate and adaptative immune responses and is implicated in the pathogenesis of several immune diseases. The IL-15 receptor consists of 3 subunits namely, the ligand-binding IL-15Rα chain, the β chain (also used by IL-2) and the γc chain. IL-15 uses a unique signaling pathway whereby IL-15 associates with IL-15Rα during biosynthesis, and this complex is 'trans-presented' to responder cells that expresses the IL-2/15Rβγc receptor complex. IL-15 is subject to post-transcriptional and post-translational regulation, and evidence also suggests that IL-15 cis-signaling can occur under certain conditions. IL-15 has been implicated in the pathology of various autoimmune diseases such as rheumatoid arthritis, autoimmune diabetes, inflammatory bowel disease, coeliac disease and psoriasis. Studies with pre-clinical models have shown the beneficial effects of targeting IL-15 signaling in autoimmunity. Unlike therapies targeting other cytokines, anti-IL-15 therapies have not yet been successful in humans. We discuss the complexities of IL-15 signaling in autoimmunity and explore potential immunotherapeutic approaches to target the IL-15 signaling pathway.

Spontaneous or treatment induced seroconversion in chronic HBV infection is rare and generation of anti-HBs antibodies is the current goal of HBV therapeutics. Here we investigated B and follicular T helper (Tfh) cell defects that persist in HBV infection despite long-term nucleos(t)ide analog (NUC) treatment and possible mechanisms behind them. RNA sequencing revealed that patient B cells have upregulated expression of multiple inhibitory receptors including members of FcRL family and downregulation of genes involved in antigen presentation. An expansion of atypical memory CD19+CD10−CD27−CD21− subset of B cells, that express high levels of FcRL5, is persistently present in patients. HBs antigen specific IgG response is concentrated in classical memory and not in atypical memory subset, confirming dysfunction of this subset. Activated Tfh, which expressed excessive CD40L upon polyclonal stimulation, were present in patients. Incubation of B cells from healthy individuals with HBV core (HBc) or CD40L resulted in induction of inhibitory receptors FcRL4, FcRL5 and PD-1 on CD19+ cells and resulted in altered B cell phenotypes. Mechanistically, HBc binds B cells and causes proliferation specifically of FcRL5+ B cell subset. Our results provide evidence that HBV directly causes upregulation of inhibitory pathways in B cells resulting in an accumulation of atypical B cells that lack anti-HBs function.

During chronic hepatitis B (CHB), CD8

Highlights • ADE increases viraemia in DHF and in FCoV infections. • In SARS-CoV infections ADE promotes inflammation. • The underlying cause of hyperinflammation is not clear in Covid-19., The COVID-19 pandemic has rapidly spread around the world with significant morbidity and mortality in a subset of patients including the elderly. The poorer outcomes are associated with ‘cytokine storm-like’ immune responses, otherwise referred to as ‘hyperinflammation’. While most of the infected individuals show minimal or no symptoms and recover spontaneously, a small proportion of the patients exhibit severe symptoms characterized by extreme dyspnea and low oxygen tissue levels, with extensive damage to the lungs referred to as acute respiratory distress symptom (ARDS). The consensus is that the hyperinflammatory response of the host is akin to the cytokine storm observed during sepsis and is the major cause of death. Uncertainties remain on the factors that lead to hyperinflammatory response in some but not all individuals. Hyperinflammation is a common feature in different viral infections such as dengue where existing low-titer antibodies to the virus enhances the infection in immune cells through a process called antibody-dependent enhancement or ADE. ADE has been reported following vaccination or secondary infections with other corona, Ebola and dengue virus. Detailed analysis has shown that antibodies to any viral epitope can induce ADE when present in sub-optimal titers or is of low affinity. In this review we will discuss ADE in the context of dengue and coronavirus infections including Covid-19.

The hepatic fibrogenic response is a protective mechanism activated by hepatocyte damage and is resolved upon elimination of the cause. However, persistent injuries cause liver fibrosis (LF) to evolve into cirrhosis, which promotes the development of hepatocellular carcinoma (HCC). Development of efficient treatments for LF requires better understanding the underlying molecular pathogenic mechanisms. The loss of suppressor of cytokine signaling 1 (SOCS1) expression promotes LF and HCC in human and mice, but the underlying mechanisms remain unclear. SOCS1 is a key regulator of immune cell activation. To investigate the anti-fibrogenic functions of SOCS1 in hepatocytes and macrophages, we generated mice lacking SOCS1 in hepatocytes (Socs1fl/flAlbCre) or macrophages (Socs1fl/flLysMCre) and evaluated hepatic fibrogenic response to carbon tetrachloride (CCl4). Socs1fl/flAlbCre and Socs1fl/flLysMCre mice showed severe LF characterized by increased collagen deposition, hydroxyproline content, myofibroblast accumulation along with elevated expression of Acta2 and Col1a1 genes. CCl4 treatment triggered significant damage to hepatocytes in Socs1fl/flAlbCre mice but not in Socs1fl/flLysMCre mice. In both mice CCl4 treatment reduced the expression of Mmp2 and increased the expression of Timp1. SOCS1 deficiency in hepatocytes or macrophages did not affect Il6, Tnfa or Tgfb, but diminished Infg and augmented Pdgfb expression. Both Socs1fl/flAlbCre and Socs1fl/flLysMCre livers showed increased mononuclear cell infiltration accompanied by elevated Ccl2 expression. Our findings show that SOCS1 exerts non-redundant functions in hepatocytes and macrophages to regulate the hepatic fibrogenic response possibly through limiting hepatocyte damage and the inflammatory response of macrophages, and support the idea of exploiting SOCS1 in LF treatment.