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PurposeTo identify the characteristics and initial disease severity of patients with nonalcoholic fatty liver disease (NAFLD) and assess incidence and risk factors for disease progression in a retrospective study.MethodsPatients ≥18 years of age without alcoholism or other liver diseases (eg, hepatitis B/C) were selected from Geisinger Health System electronic medical record data from 2004 to 2015. Initial disease stage was stratified into uncomplicated NAFLD, advanced fibrosis, cirrhosis, hepatocellular carcinoma (HCC), and liver transplant using clinical biomarkers, diagnosis, and procedure codes. Disease progression was defined as stage progression or death and analyzed via Kaplan–Meier plots and multistate models.ResultsIn the NAFLD cohort (N=18,754), 61.5% were women, 39.0% had type 2 diabetes mellitus (T2DM), and the mean body mass index was 38.2±10.2 kg/m2. At index, 69.9% had uncomplicated NAFLD, 11.7% had advanced fibrosis, and 17.8% had cirrhosis. Of 18,718 patients assessed for progression, 17.3% progressed (11.0% had stage progression, 6.3% died without evidence of stage progression) during follow-up (median=842 days). Among subgroups, 12.3% of those without diabetes mellitus progressed vs 24.7% of those with T2DM. One-year mortality increased from 0.5% in uncomplicated NAFLD to 22.7% in HCC. After liver transplant, mortality decreased to 5.6% per year.ConclusionsIn 2.3 years of follow-up, approximately 17% of patients progressed or died without evidence of stage progression. T2DM was associated with approximately twice the risk of disease progression, and mortality risk increased with disease stage. Early diagnosis and monitoring of disease progression, especially in patients with T2DM, is warranted.

SUMMARY Follicular helper T cells (T FH ) are critical for vaccine and infection elicitation of long-lived humoral immunity, but exaggerated T FH responses can promote autoimmunity and other pathologies. It is unfortunate that no clinical interventions exist for the selective depletion of follicular T cells to alleviate these diseases. We engineered a chimeric antigen receptor (CAR) facilitating the specific targeting of cells with high expression levels of human programmed cell death protein 1 (PD-1), a cardinal feature of follicular T cells. CAR-expressing human natural killer (NK) cells robustly and discriminately eliminated PD-1 high follicular human T cells in vitro and in a humanized mouse model of lupus-like disease while sparing B cells and other PD-1 low T cell subsets, including regulatory T cells. These results establish a strategy for specific targeting of PD-1 high T cells that can be advanced as a clinical tool for the selective depletion of pathogenic follicular T cells or other PD-1 high target cells in certain disease states.

This study tests the hypothesis that activation of MAPK by physiologically relevant concentrations of IL‐33 contributes to enhanced cytokine expression by IL‐12 stimulated human NK cells. While IL‐33 canonically triggers type 2 cytokine responses, this cytokine can also synergize with type 1 cytokines like IL‐12 to provoke IFN‐γ. We show that picogram concentrations of IL‐12 and IL‐33 are sufficient to promote robust secretion of IFN‐γ by human NK cells that greatly exceeds resposes to either cytokine alone. Nanogram doses of IL‐33, potentially consistent with levels in tissue microenvironments, synergize with IL‐12 to induce secretion of additional cytokines, including TNF and GM‐CSF. IL‐33‐induced activation of the p38 MAPK pathway in human NK cells is crucial for enhanced release of IFN‐γ and TNF in response to IL‐12. Mechanistically, IL‐33‐induced p38 MAPK signaling enhances stability of IFNG transcripts and triggers A disintegrin and metalloproteinase domain 17 (ADAM17) mediated cleavage of TNF from the cell surface. These data support our hypothesis and suggest that altered sensitivity of NK cells to IL‐12 in the presence of IL‐33 may have important consequences in diseases associated with mixed cytokine milieus, like asthma and chronic obstructive pulmonary disease.

Natural killer (NK) cells play a multitude of antiviral roles that are significant enough to provoke viral counterefforts to subvert their activity. As innate lymphocytes, NK cells provide a rapid source of pro-inflammatory antiviral cytokines and bring to bear cytolytic activities that are collectively meant to constrain viral replication and dissemination. Additionally, NK cells participate in adaptive immunity both by shaping virus-specific T-cell responses and by developing adaptive features themselves, including enhanced antibody-dependent effector functions. The relative importance of different functional activities of NK cells are poorly understood, thereby obfuscating clinical use of these cells. Here we focus on opposing efforts of NK cells and viruses to gain tactical superiority during infection.

Cancer immunotherapy with CPIs is associated with a multitude of IMRs, especially colitis and pneumonitis. Individual CPIs had variable IMR signals, and pharmacoepidemiologic studies are required to evaluate the identified signals.

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