The PNPLA3 p.I148M, TM6SF2 p.E167K, and MBOAT7 rs641738 variants represent genetic risk factors for nonalcoholic fatty liver disease (NAFLD). Here we investigate if these polymorphisms modulate both ...steatosis and fibrosis in patients with NAFLD. We recruited 515 patients with NAFLD (age 16–88 years, 280 female patients). Liver biopsies were performed in 320 patients. PCR-based assays were used to genotype the PNPLA3, TM6SF2, and MBOAT7 variants. Carriers of the PNPLA3 and TM6SF2 risk alleles showed increased serum aspartate aminotransferase and alanine transaminase activities (P < 0.05). The PNPLA3 genotype was associated with steatosis grades S2–S3 (P < 0.001) and fibrosis stages F2–F4 (P < 0.001). The TM6SF2 genotype was associated with steatosis (P = 0.003) but not with fibrosis (P > 0.05). The MBOAT7 variant was solely associated with increased fibrosis (P = 0.046). In the multivariate model, variants PNPLA3 (P = 0.004) and TM6SF2 (P = 0.038) were associated with steatosis. Fibrosis stages were affected by the PNPLA3 (P = 0.042) and MBOAT7 (P = 0.021) but not by the TM6SF2 polymorphism (P > 0.05). The PNPLA3, TM6SF2, and MBOAT7 variants are associated with increased liver injury. The TM6SF2 variant seems to modulate predominantly hepatic fat accumulation, whereas the MBOAT7 polymorphism is linked to fibrosis. The PNPLA3 polymorphism confers risk of both increased steatosis and fibrosis.
The coronavirus disease 2019 (COVID-19) pandemic poses an enormous challenge to healthcare systems in affected communities. Older patients and those with pre-existing medical conditions have been ...identified as populations at risk of a severe disease course. It remains unclear at this point to what extent chronic liver diseases should be considered as risk factors, due to a shortage of appropriate studies. However, patients with advanced liver disease and those after liver transplantation represent vulnerable patient cohorts with an increased risk of infection and/or a severe course of COVID-19. In addition, the current pandemic requires unusual allocation of healthcare resources which may negatively impact the care of patients with chronic liver disease that continue to require medical attention. Thus, the challenge hepatologists are facing is to promote telemedicine in the outpatient setting, prioritise outpatient contacts, avoid nosocomial dissemination of the virus to patients and healthcare providers, and at the same time maintain standard care for patients who require immediate medical attention.
Emerging data indicate that SARS-CoV-2-specific CD8
T cells targeting different viral proteins are detectable in up to 70% of convalescent individuals
. However, very little information is currently ...available about the abundance, phenotype, functional capacity and fate of pre-existing and induced SARS-CoV-2-specific CD8
T cell responses during the natural course of SARS-CoV-2 infection. Here, we define a set of optimal and dominant SARS-CoV-2-specific CD8
T cell epitopes. We also perform a high-resolution ex vivo analysis of pre-existing and induced SARS-CoV-2-specific CD8
T cells, applying peptide-loaded major histocompatibility complex class I (pMHCI) tetramer technology. We observe rapid induction, prolonged contraction and emergence of heterogeneous and functionally competent cross-reactive and induced memory CD8
T cell responses in cross-sectionally analyzed individuals with mild disease following SARS-CoV-2 infection and three individuals longitudinally assessed for their T cells pre- and post-SARS-CoV-2 infection. SARS-CoV-2-specific memory CD8
T cells exhibited functional characteristics comparable to influenza-specific CD8
T cells and were detectable in SARS-CoV-2 convalescent individuals who were seronegative for anti-SARS-CoV-2 antibodies targeting spike (S) and nucleoprotein (N). These results define cross-reactive and induced SARS-CoV-2-specific CD8
T cell responses as potentially important determinants of immune protection in mild SARS-CoV-2 infection.
Effectiveness of seasonal influenza vaccination varies between individuals and might be affected by vaccination history among other factors. Here we show, by monitoring frequencies of CD4 T cells ...specific to the conserved hemagglutinin epitope HA
and titres of IgG against the corresponding recombinant hemagglutinin protein, that antigen-specific CD4 T cell and antibody responses are closely linked to pre-existing immunity and vaccine history. Upon immunization, a strong early reaction is observed in all vaccine naïve participants and also in vaccine experienced individuals who have not received the respective seasonal vaccine in the previous year. This response is characterized by HA
specific CD4 T cells with a follicular helper T cell phenotype and by ascending titers of hemagglutinin-specific antibodies from baseline to day 28 following vaccination. This trend was observed in only a proportion of those participants who received the seasonal vaccine the year preceding the study. Regardless of history, levels of pre-existing antibodies and CD127 expression on CD4 T cells at baseline were the strongest predictors of robust early response. Thus, both pre-existing immunity and vaccine history contribute to the response to seasonal influenza vaccines.
In chronic hepatitis C virus (HCV) infection, exhausted HCV-specific CD8
T cells comprise memory-like and terminally exhausted subsets. However, little is known about the molecular profile and fate ...of these two subsets after the elimination of chronic antigen stimulation by direct-acting antiviral (DAA) therapy. Here, we report a progenitor-progeny relationship between memory-like and terminally exhausted HCV-specific CD8
T cells via an intermediate subset. Single-cell transcriptomics implicated that memory-like cells are maintained and terminally exhausted cells are lost after DAA-mediated cure, resulting in a memory polarization of the overall HCV-specific CD8
T cell response. However, an exhausted core signature of memory-like CD8
T cells was still detectable, including, to a smaller extent, in HCV-specific CD8
T cells targeting variant epitopes. These results identify a molecular signature of T cell exhaustion that is maintained as a chronic scar in HCV-specific CD8
T cells even after the cessation of chronic antigen stimulation.
Hepatitis C virus (HCV)-specific T cell responses are closely linked to the clinical course of infection. While T cell responses in self-limiting infection are typically broad and multi-specific, ...they display several distinct features of functional impairment in the chronic phase. Moreover, HCV readily adapts to immune pressure by developing escape mutations within epitopes targeted by T cells. Much of our current knowledge on HCV-specific T cell responses has been gathered under the assumption that this might eventually pave the way for a therapeutic vaccine. However, with the development of highly efficient direct acting antivirals (DAAs), there is less interest in the development of a therapeutic vaccine for HCV and the scope of T cell research has shifted. Indeed, the possibility to rapidly eradicate an antigen that has persisted over years or decades, and has led to T cell exhaustion and dysfunction, provides the unique opportunity to study potential T cell recovery after antigen cessation in a human in vivo setting. Findings from such studies not only improve our basic understanding of T cell immunity but may also advance immunotherapeutic approaches in cancer or chronic hepatitis B and D infection. Moreover, in order to edge closer to the WHO goal of HCV elimination by 2030, a prophylactic vaccine is clearly required. Thus, in this review, we will summarize our current knowledge on HCV-specific T cell responses and also provide an outlook on the open questions that require answers in this field.
Immunization with two mRNA vaccine doses elicits robust spike-specific CD8
T cell responses, but reports of waning immunity after COVID-19 vaccination prompt the introduction of booster vaccination ...campaigns. However, the effect of mRNA booster vaccination on the spike-specific CD8
T cell response remains unclear. Here we show that spike-specific CD8
T cells are activated and expanded in all analyzed individuals receiving the 3
and 4
mRNA vaccine shots. This CD8
T cell boost response is followed by a contraction phase and lasts only for about 30-60 days. The spike-specific CD8
T memory stem cell pool is not affected by the 3
vaccination. Both 4
vaccination and breakthrough infections with Delta and Omicron rapidly reactivate CD8
T memory cells. In contrast, neutralizing antibody responses display little boost effect towards Omicron. Thus, COVID-19 mRNA booster vaccination elicits a transient T effector cell response while long-term spike-specific CD8
T cell immunity is conserved to mount robust memory recall targeting emerging variants of concern.
During the early stages of the coronavirus disease 2019 (COVID-19) pandemic, EASL and ESCMID published a position paper to provide guidance for physicians involved in the care of patients with ...chronic liver disease. While some healthcare systems are returning to a more normal routine, many countries and healthcare systems have been, or still are, overwhelmed by the pandemic, which is significantly impacting on the care of these patients. In addition, many studies have been published focusing on how COVID-19 may affect the liver and how pre-existing liver diseases might influence the clinical course of COVID-19. While many aspects remain poorly understood, it has become increasingly evident that pre-existing liver diseases and liver injury during the disease course must be kept in mind when caring for patients with COVID-19. This review should serve as an update on the previous position paper, summarising the evidence for liver disease involvement during COVID-19 and providing recommendations on how to return to routine care wherever possible.
Leptospirosis or Weil's disease is caused by pathogenic spirochete bacteria called Leptospira. It is considered the most common zoonosis in the world and is usually transmitted by urine of rodents ...and dogs with an incubation time of 7-14 days. The clinical spectrum ranges from a subclinical infection to a fulminant septic course.
Here, we report the case of a German patient with acute pancreatitis associated with Leptospira interrogans causing fulminant septic shock. The patient was successfully treated with intravenous antibiotics and left the hospital fully recovered after 18 days.
To our knowledge, this is the first case of leptospirosis with acute pancreatitis as the leading clinical manifestation in Central Europe. Serologic and molecular genetic tests for leptospirosis should be considered, if no other causes for pancreatitis can be identified.
Type 1 diabetes (T1D) is characterized by destruction of glucose-responsive insulin-producing pancreatic β-cells and exhibits immune infiltration of pancreatic islets, where CD8 lymphocytes are most ...prominent. Curative transplantation of pancreatic islets is seriously hampered by the persistence of autoreactive immune cells that require high doses of immunosuppressive drugs. An elegant approach to confer graft protection while obviating the need for immunosuppression is the use of encapsulation devices that allow for the transfer of oxygen and nutrients, yet prevent immune cells from making direct contact with the islet grafts. Here we demonstrate that macroencapsulation devices (TheraCyte™) loaded with neonatal pancreatic tissue and transplanted into RIP-LCMV.GP mice prevented disease onset in a model of virus-induced diabetes mellitus. Histological analyses revealed that insulin-producing cells survived within the device in animal models of diabetes. Our results demonstrate that these encapsulation devices can protect from an immune-mediated attack and can contain a sufficient amount of insulin-producing cells to prevent overt hyperglycemia.
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