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COVID-19 has become one of the worst infectious disease outbreaks of recent times, with over 2.1 million cases and 120,000 deaths so far. Our study investigated the demographic, clinical, laboratory and imaging features of 63 patients with COVID-19 in Beijing. Patients were classified into four groups, mild, moderate, severe and critically ill. The mean age of our patients was 47 years of age (range 3-85) and there was a slight male predominance (58.7%). Thirty percent of our patients had severe or critically ill disease, but only 20% of severe and 33% of critically ill patients had been to Wuhan. Fever was the most common presentation (84.1%), but cough was present in only slightly over half of the patients. We found that lymphocyte and eosinophils count were significantly decreased in patients with severe disease (p = 0.001 and p = 0.000, respectively). Eosinopenia was a feature of higher levels of severity. Peripheral CD4+, CD8+ T lymphocytes, and B lymphocytes were significantly decreased in severe and critically ill patients, but there was only a non-statistically significant downward trend in NK cell numbers with severity. Of note is that liver function tests including AST, ALT, GGT and LDH were elevated, and albumin was decreased. The inflammatory markers CRP, ESR and ferritin were elevated in patients with severe disease or worse. IL-6 levels were also higher, indicating that the presence of a hyperimmune inflammatory state portends higher morbidity and mortality. In a binary logistic regression model, C-reactive protein level (OR 1.073, [CI, 1.013-1.136]; p = 0.017), CD8 T lymphocyte counts (OR 0.989, [CI, 0.979-1.000]; p = 0.043), and D-dimer (OR 5.313, [CI, 0.325-86.816]; p = 0.241) were independent predictors of disease severity.

Background. Over the last 20 years, the prevalence of hepatitis B virus (HBV) infection in China has decreased gradually due to the application of a national HBV vaccination program. In contrast, the prevalence of alcoholic liver disease (ALD), nonalcoholic fatty liver disease, autoimmune liver disease, and drug-induced liver injury has markedly increased. Methods. We conducted a retrospective review of 82,562 hospitalized patients diagnosed with liver cirrhosis in Beijing 302 Hospital from 2002 to 2013. Results. The top four etiologies of cirrhosis were HBV, HCV, ALD, and autoimmune liver disease. The percentage of HBV cirrhosis decreased from 81.53% in 2002 to 66.0% in 2013, whereas the frequency of alcoholic cirrhosis increased from 3.34% in 2002 to 8.40% in 2013. Females (84.34%) accounted for the majority of cirrhotic patients with autoimmune liver diseases. Males accounted for 80.16% of HBV cirrhosis patients and 98.02% of alcoholic cirrhosis patients. Conclusion. In Beijing 302 Hospital, the top four etiologies of cirrhosis were HBV, HCV, ALD, and autoimmune liver disease. Over the last 12 years, the prevalence of HBV cirrhosis has decreased gradually, whereas that of alcoholic cirrhosis has increased significantly.

Organ-specific and systemic autoimmune diseases share numerous features and often coexist in the same patient. Autoimmune cholangitis/primary biliary cirrhosis and Sjogren syndrome represent paradigmatic examples of the common grounds of different autoimmunity phenotypes based on similarities in clinical manifestations and immunopathogenesis. In fact, primary biliary cirrhosis and Sjogren's syndrome have both been coined as an autoimmune epithelitis in which apoptosis may be in both cases the key element to explain the organ-specific immune-mediated injury against the biliary and exocrine gland epithelia, respectively. Further, growing evidence supports in both diseases the view that B cells, T cytotoxic cells, and T helper cells are involved in chronic inflammation, likely via the altered expression of pro-inflammatory cytokines. The presence of estrogen receptors on the biliary and exocrine gland epithelia has been advocated as a key to the female predominance encountered in primary biliary cirrhosis and Sjogren's syndrome. Sadly, despite available data, therapeutic approaches remain largely unsatisfactory and recent studies with mechanistic approaches (as in the case of B cell depletion with rituximab) have been of partial benefit only. Future studies should focus on new molecular tools (single-cell transcriptomics, microRNA, epigenetics) to provide unique insights into common mechanisms.

Worldwide, hepatitis B virus (HBV) infection is one of the leading causes of chronic liver disease. Because HBV is not a cytopathogenic virus, host immune responses induced by viral persistence are generally thought to be responsible for the disease progression of chronic HBV infection.1 Generally, HBV-specific T cells were believed to play important roles in inducing hepatocellular damage during chronic HBV infection2,3; however, recent studies have shown that these cells often display functional impairment, such as T cell exhaustion by up-regulation of programmed death 1,4,5 T cell attrition through the B cell lymphoma 2 interacting mediator,6 and impaired T cell receptor signaling through the ζ-chain.7 T cell impairment is even more pronounced in the livers of patients with chronic hepatitis B (CHB) versus their blood.5 Furthermore, activated HBV-specific CD8 T cells are often found to be present in the livers of patients without evident liver immunopathology, whereas non–virus-specific lymphocytes have usually massively infiltrated the livers of patients with hepatocellular damage.8 A model of HBV-transgenic mice has further confirmed that non–virus-specific lymphocytes can exacerbate the liver inflammation initiated by virus-specific CD8 T cells.9,10 These findings suggest that non–virus-specific inflammatory cells infiltrating the liver may actively participate in HBV-associated liver pathogenesis. Natural killer (NK) cells are abundant in the liver and serve as a major innate immune component against microbial infection.11 Recent studies have clearly suggested that NK cells may contribute to liver pathogenesis in rodent models12 and in patients with chronic hepatitis C virus (HCV) or HBV infection.13–16 Particularly during HCV infection, the viral infection results in an elevation of interferon-α (IFN-α) that subsequently polarizes NK cells toward cytolytic activity to induce liver injury.15 Emerging evidence indicates that during HBV infection, the early NK cell responses may lead to the initial control of the acute infection and allow the timely and efficient development of an adaptive immune response.17,18 However, if the virus persists, activated NK cells can mediate hepatocyte apoptosis by up-regulating tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) in hepatitis B e antigen (HBeAg)–negative patients with hepatic flares14 and Fas ligand (FasL) in patients with HBV-associated acute-on-chronic liver failure.16 Although these studies have partially defined the role of NK cells in liver injury, NK cells may also use some other ligands to mediate liver injury in various disease progression phases of chronic HBV infection. In addition, recently available data about NK cells in CHB patients were primarily obtained from the peripheral compartments18,19; detailed information about the roles of NK cells in the liver pathogenesis of chronic HBV infection is scarce, especially for HBeAg-positive subjects. HBeAg-positive individuals with chronic HBV infection are generally divided into two groups: immune-tolerant (IT) carriers and immune-activated (IA) patients. The former group is characterized by minimal liver damage, normal alanine aminotransferase (ALT) levels, and active viral replication; the latter, generally after the IT phase, have increased liver injury and decreased viral replication.1,20 In this study, we comprehensively characterized the hepatic NK cells in these HBV-infected individuals and demonstrated that NK cell–mediated liver pathogenesis depended on an imbalanced cytokine milieu in the livers of these IA patients. Our findings may facilitate the rational development of immunotherapeutic strategies for enhancing viral control while limiting or blocking liver injury and inflammation.

Aims: This study attempts to characterize the feature of immunologically competent cells (ICCs) and evaluate its clinical implication in patients with acute-on-chronic liver failure (ACLF) in relation to chronic hepatitis B virus (HBV) infection. Methods: Circulating ICCs were examined in ACLF patients (n = 75), as well as in patients with hepatitis B (CHB, n = 31), CHB-related liver cirrhosis (LC, n = 36), and normal controls (NC, n = 30). Intrahepatic ICCs in some patients were further analyzed via immunohistochemical and flow cytometric assays. Results: Total lymphocytes, CD4+ T cells, CD8+ T cells, and NK cells in circulation were numerically lower in the ACLF and LC groups compared to the CHB and NC groups. Importantly, the number of these cells was significantly lower in non-surviving ACLF patients compared with surviving ACLF patients. In comparison to NC, ACLF patients displayed a significantly higher ratio of liver-infiltrating CD4+ T-cell frequency than its circulating counterpart, suggesting that the possiblility of the ICCs compartmentalization from the peripheral blood into the liver in ACLF. Immunohistochemical analysis showed that intrahepatic CD4+ cells, CD8+ cells, and CD56+ cells were significantly higher in the ACLF group compared with the other three groups, suggesting a stronger cellular immune response-mediated inflammation in ACLF group than other patient groups. Conclusions: The abnormal prevalence of circulating and intrahepatic ICCs possibly acts as an important factor that may drive the progression of HBV-related ACLF.

Primary biliary cirrhosis occurs more frequently in women, and previous studies indicated that the average age of primary biliary cirrhosis (PBC) onset makes pregnancy in PBC patients uncommon. However, more recently, improved diagnostic testing has enabled detection of PBC in younger women, including those of childbearing age. This has led investigators to become increasingly interested in the relationship between the ontogeny of PBC and pregnancy. Published cases indicate that the typical age for pregnant women to be diagnosed with PBC is in the early 30s, and that during gestation, pruritus and jaundice are the most common symptoms. During gestation, susceptible women may experience onset of PBC resulting from the drastic changes in female hormones; this would include not only the mitochondrial damage due to accumulation of bile acids but also changes in the immune response during the different stages of pregnancy that might play an important role in the breakdown of self-tolerance. The mechanisms underlying the potential relationship between PBC and pregnancy warrant further investigation. For women first diagnosed with PBC during gestation, or those for whom first appearance of a flare up occurs during and postpartum, investigation of the immune response throughout gestation could provide new avenues for immunologic therapeutic intervention and the discovery of new treatment strategies for PBC.

There is increasing interest in the role of T follicular helper (Tfh) cells in autoimmunity from the perspective of both their role in breach of tolerance and their effects on the natural history of disease progression. Indeed, the critical role of Tfh cells in autoimmunity is further highlighted based on their location in the germinal center (GC), a pathogenic hot spot for development of autoreactivity. To address the role of Tfh cells in primary biliary cirrhosis (PBC), we comprehensively evaluated the immunobiology of CXCR5+CD4+ Tfh cells in 69 patients with PBC, including a nested subgroup of 16 autoimmune hepatitis (AIH) and 20 healthy controls (HC), followed for 1 year. We report herein several key observations. First, there was an increased frequency of circulating Tfh cells in patients with PBC compared to AIH (P

BACKGROUND: Extensive mononuclear cell infiltration is strongly correlated with liver damage in patients with chronic hepatitis B virus (CHB) infection. Macrophages and infiltrating monocytes also participate in the development of liver damage and fibrosis in animal models. However, little is known regarding the immunopathogenic role of peripheral blood monocytes and intrahepatic macrophages. METHODOLOGY/PRINCIPAL FINDINGS: The frequencies, phenotypes, and functions of peripheral blood and intrahepatic monocyte/macrophage subsets were analyzed in 110 HBeAg positive CHB patients, including 32 immune tolerant (IT) carriers and 78 immune activated (IA) patients. Liver biopsies from 20 IA patients undergoing diagnosis were collected for immunohistochemical analysis. IA patients displayed significant increases in peripheral blood monocytes and intrahepatic macrophages as well as CD16(+) subsets, which were closely associated with serum alanine aminotransferase (ALT) levels and the liver histological activity index (HAI) scores. In addition, the increased CD16(+) monocytes/macrophages expressed higher levels of the activation marker HLA-DR compared with CD16(-) monocytes/macrophages. Furthermore, peripheral blood CD16(+) monocytes preferentially released inflammatory cytokines and hold higher potency in inducing the expansion of Th17 cells. Of note, hepatic neutrophils also positively correlated with HAI scores. CONCLUSIONS: These distinct properties of monocyte/macrophage subpopulations participate in fostering the inflammatory microenvironment and liver damage in CHB patients and further represent a collaborative scenario among different cell types contributing to the pathogenesis of HBV-induced liver disease.