Retinoic acid and TGF-β orchestrate organ-specific programs of tissue residency.

Tissue-resident memory T (T) cells are integral to tissue immunity, persisting in diverse anatomical sites where they adhere to a common transcriptional framework. How these cells integrate distinct local cues to adopt the common T cell fate remains poorly understood. Here, we show that whereas skin T cells strictly require transforming growth factor β (TGF-β) for tissue residency, those in other locations utilize the metabolite retinoic acid (RA) to drive an alternative differentiation pathway, directing a TGF-β-independent tissue residency program in the liver and synergizing with TGF-β to drive T cells in the small intestine.

Intergenic risk variant rs56258221 skews the fate of naive CD4 T cells via miR4464-BACH2 interplay in primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) is an immune-mediated liver disease of unknown pathogenesis, with a high risk to develop cirrhosis and malignancies. Functional dysregulation of T cells and association with genetic polymorphisms in T cell-related genes were previously reported for PSC. Here, we genotyped a representative PSC cohort for several disease-associated risk loci and identified rs56258221 (BACH2/MIR4464) to correlate with not only the peripheral blood T cell immunophenotype but also the functional capacities of naive CD4 T (CD4 T) cells in people with PSC.

is a risk haplotype for primary sclerosing cholangitis mediating activation of NKp44+ NK cells.

Objective: Primary sclerosing cholangitis (PSC) is characterised by bile duct strictures and progressive liver disease, eventually requiring liver transplantation. Although the pathogenesis of PSC remains incompletely understood, strong associations with HLA-class II haplotypes have been described. As specific HLA-DP molecules can bind the activating NK-cell receptor NKp44, we investigated the role of HLA-DP/NKp44-interactions in PSC.

The co-inhibitory receptor TIGIT regulates NK cell function and is upregulated in human intrahepatic CD56 NK cells.

The crosstalk between NK cells and their surrounding environment is enabled through activating and inhibitory receptors, which tightly control NK cell activity. The co-inhibitory receptor TIGIT decreases NK cell cytotoxicity and is involved in NK cell exhaustion, but has also been associated with liver regeneration, highlighting that the contribution of human intrahepatic CD56 NK cells in regulating tissue homeostasis remains incompletely understood. A targeted single-cell mRNA analysis revealed distinct transcriptional differences between matched human peripheral blood and intrahepatic CD56 NK cells.

Single-cell atlas of hepatic T cells reveals expansion of liver-resident naive-like CD4 T cells in primary sclerosing cholangitis.

Background & Aims: Little is known about the composition of intrahepatic immune cells and their contribution to the pathogenesis of primary sclerosing cholangitis (PSC). Herein, we aimed to create an atlas of intrahepatic T cells and thereby perform an in-depth characterization of T cells in inflamed human liver.

Methods: Different single-cell RNA sequencing methods were combined with in silico analyses on intrahepatic and peripheral T cells from patients with PSC (n = 11) and healthy donors (HDs, n = 4).

Failure of thymic deletion and instability of autoreactive Tregs drive autoimmunity in immune-privileged liver.

The liver is an immune-privileged organ that can deactivate autoreactive T cells. Yet in autoimmune hepatitis (AIH), autoreactive T cells can defy hepatic control and attack the liver. To elucidate how tolerance to self-antigens is lost during AIH pathogenesis, we generated a spontaneous mouse model of AIH, based on recognition of an MHC class II-restricted model peptide in hepatocytes by autoreactive CD4+ T cells.

IL-17A/F enable cholangiocytes to restrict T cell-driven experimental cholangitis by upregulating PD-L1 expression.

Background & Aims: IL-17A-producing T cells are present in autoimmune cholestatic liver diseases; however, little is known about the contribution of IL-17 to periductal immune responses. Herein, we investigated the role of IL-17 produced by antigen-specific CD8 T cells in a mouse model of cholangitis and in vitro in human cholangiocyte organoids.

Methods: K14-OVAp mice express a major histocompatibility complex I-restricted ovalbumin (OVA) peptide sequence (SIINFEKL) on cholangiocytes.

Monocytes as Potential Mediators of Pathogen-Induced T-Helper 17 Differentiation in Patients With Primary Sclerosing Cholangitis (PSC).

Background And Aims: T cells from patients with primary sclerosing cholangitis (PSC) show a prominent interleukin (IL)-17 response upon stimulation with bacteria or fungi, yet the reasons for this dominant T-helper 17 (Th17) response in PSC are not clear. Here, we analyzed the potential role of monocytes in microbial recognition and in skewing the T-cell response toward Th17.

Approach And Results: Monocytes and T cells from blood and livers of PSC patients and controls were analyzed ex vivo and in vitro using transwell experiments with cholangiocytes.

The Transcription Factor Promyelocytic Leukemia Zinc Finger Protein Is Associated With Expression of Liver-Homing Receptors on Human Blood CD56 Natural Killer Cells.

The transcription factor promyelocytic leukemia zinc finger protein (PLZF) is involved in the development of natural killer (NK) cells and innate lymphoid cells, including liver-resident NK cells in mice. In human NK cells, the role of PLZF in liver residency is still unknown. Expression of PLZF in matched human peripheral blood- and liver-derived NK cells and the association of PLZF expression with surface molecules and transcription factors relevant for tissue residency were investigated using multiparameter flow cytometry and assessing single-cell messenger RNA (mRNA) levels.

CD49a Expression Identifies a Subset of Intrahepatic Macrophages in Humans.

Macrophages play central roles in inflammatory reactions and initiation of immune responses during infections. More than 80% of total tissue macrophages are described to be located in the liver as liver-resident macrophages, also named Kupffer cells (KCs). While studies in mice have established a central role of liver-resident KCs in regulating liver inflammation, their phenotype and function are not well-characterized in humans.

Interferon-γ-dependent immune responses contribute to the pathogenesis of sclerosing cholangitis in mice.

Background And Aims: Primary sclerosing cholangitis (PSC) is an idiopathic, chronic cholestatic liver disorder characterized by biliary inflammation and fibrosis. Increased numbers of intrahepatic interferon-γ- (IFNγ) producing lymphocytes have been documented in patients with PSC, yet their functional role remains to be determined.

Methods: Liver tissue samples were collected from patients with PSC.

CCL21-expression and accumulation of CCR7 NK cells in livers of patients with primary sclerosing cholangitis.

The pathogenesis of primary sclerosing cholangitis (PSC), an autoimmune liver disease, remains unknown. The aim of this study was to characterize peripheral blood and intrahepatic NK cells from patients with PSC. Peripheral blood samples from patients with PSC, other autoimmune liver diseases, and from healthy control individuals were used, as well as liver tissues from PSC patients undergoing liver transplantation.

Human liver-derived CXCR6 NK cells are predominantly educated through NKG2A and show reduced cytokine production.

NK cells have been implicated to affect the outcome of numerous liver diseases. In particular, members of the killer-cell Ig-like receptor (KIR) family, predominantly expressed by NK cells, have been associated with the outcome of hepatitis C virus infection and clearance of hepatocellular carcinoma. Inhibitory KIRs tune NK cell function through interaction with HLA class I, a process termed education.

Interactions Between KIR3DS1 and HLA-F Activate Natural Killer Cells to Control HCV Replication in Cell Culture.

Killer-cell immunoglobulin-like receptors (KIRs) are transmembrane glycoproteins expressed by natural killer (NK) cells. Binding of KIR3DS1 to its recently discovered ligand, HLA-F, activates NK cells and has been associated with resolution of hepatitis C virus (HCV) infection. We investigated the mechanisms by which KIR3DS1 contributes to the antiviral immune response.

Tissue-resident NK cells differ in their expression profile of the nutrient transporters Glut1, CD98 and CD71.

Metabolism is a critical basis for immune cell functionality. It was recently shown that NK cell subsets from peripheral blood modulate their expression of nutrient receptors following cytokine stimulation, demonstrating that NK cells can adjust to changes in metabolic requirements. As nutrient availability in blood and tissues can significantly differ, we examined NK cells isolated from paired blood-liver and blood-spleen samples and compared expression of the nutrient transporters Glut1, CD98 and CD71.

Mechanistic peculiarities of activation-induced mobilization of cytotoxic effector proteins in human T cells.

It is widely accepted that cytotoxic T and NK cells store effector proteins including granzymes, perforin and Fas ligand (FasL) in intracellular granules, often referred to as secretory lysosomes. Upon target cell encounter, these organelles are transported to the cytotoxic immunological synapse, where they fuse with the plasma membrane to release the soluble effector molecules and to expose transmembrane proteins including FasL on the cell surface. We previously described two distinct species of secretory vesicles in T and NK cells that differ in size, morphology and protein loading, most strikingly regarding FasL and granzyme B.

Proliferative capacity exhibited by human liver-resident CD49a+CD25+ NK cells.

The recruitment and retention of Natural Killer (NK) cells in the liver are thought to play an important role during hepatotropic infections and liver cirrhosis. The aims of this study were to determine differences between liver-derived and peripheral blood-derived NK cells in the context of liver inflammation and cirrhosis. We conducted a prospective dual-center cross-sectional study in patients undergoing liver transplantation or tumor-free liver resections, in which both liver tissue and peripheral blood samples were obtained from each consenting study participants.

[Pseudoaneurysm of the hepatic artery presenting with hemobilia--a complication of laparoscopic cholecystectomy].

Introduction: Hemobilia, defined as a bleeding into the bile duct, is a rare disease. One of its infrequent causes is a hepatic artery pseudoaneurysm, usually developed after arterial iatrogenic leasion.

Material And Methods: A case review, presenting right hepatic artery pseudoaneurysm with a biliovascular fistula as a consequence of hepatic artery and bile duct injuries during "uncomplicated" laparoscopic cholecystectomy.

[Infliximab in the treatment of Wegener's granulomatosis: case report].

Purpose: to evaluate the efficacy of monoclonal anti-tumor necrosis factor alpha antibody infliximab in treatment of refractory Wegene's granulomatosis. Clinical manifestations of Wegener's granulomatosis at the time of infliximab initiation were: proptosis of both eyes due to progressive retrobulbar granulomas, visual impairment, optic disc edema, progressive diplopia, sinus and renal involvement. The disease was refractory to a treatment with various immunosuppressants, including intravenous cyclophosphamide or high doses of mycophenolate mofetil in combination with corticosteroids.

[The chemiluminescence test in the laboratory evaluation of effects of immunostimulatory therapy].

Background: Number of patients treated by general practitioners with various immunomodulatory drugs has recently increased. Effects of such medication on the immune system were not usually monitored. The aim of our work was to evaluate effect of selected immunomodulatory drugs on the phagocytic and metabolic activities of the phagocytes.

[CD5-positive B lymphocytes and antinuclear antibodies].

Background: The production of natural autoantibodies incl. antinuclear antibodies (ANA) is ascribed to lymphocytes which have a CD5 molecule on their surface. The role of CD5 positive B lymphocytes in the induction of autoimmunity is obscure so far.

[Behcet's disease].

The author evaluates diagnostic and therapeutic results in nine patients with Behcet's disease investigated at the uveological ambulance of the First Ophthalmological Clinic, Medical Faculty Charles University in Prague during 1987-1996. Anterior uveitis with hypopyon was recorded twice as frequently as retinal vasculitis. Chronic CME, secondary glaucoma and occlusive vasculitis were the most serious complications of ophthalmological manifestations of BD.

[Diagnosis and therapy of Wegener's granulomatosis based on ocular changes].

The authors draw attention to the different ophthalmological manifestations of Wegener's granulomatosis in two patients examined at the First Ophthalmological Clinic of the First Medical Faculty, Charles University, Prague. The patients complaints led later to establishment of the diagnosis of WG or its relapse. Combined immunosuppressive treatment with steroids and cyclophosphamide relieved the ocular as well as general manifestations of WG.

[Acute anterior uveitis, systemic diseases and HLA-B27].

The author investigated the rate of phenotype HLA-B27 and systemic diseases in patients with acute anterior uveitis (AAU) in our geographical area. The evaluated clinical differences of AAU manifestations in HLA-B27 positive and HLA-B27 negative patients in a group of 104 subjects followed up for a 10-year period. The patients were under 40 years of age.

[Diagnosis of uveitis with laboratory tests and specialized examinations].

The authors evaluated the importance of a large scale of laboratory examinations and specialized examinations in a group of 174 patients with endogenous uveitis examined at the uveological ambulance of the First Ophthalmological Clinic of the First Faculty, Charles University Prague. Laboratory examinations which are part of screening examinations are of little value for the diagnosis of uveitis. Alone they are unable to assess its type or prognosis.