Die Fuchs-Endotheldystrophie (FED) ist eine alters- und genassoziierte Erkrankung der Hornhaut, welche durch einen beschleunigten Verlust von Hornhautendothelzellen und eine vermehrte Ablagerung von extrazellulärer Matrix (ECM) der darunter liegenden Basalmembran (Descemet-Membran) charakterisiert ist. Klinisch kommt es bei fortgeschrittener Erkrankung zu einem Hornhautödem mit konsekutiver Visusreduktion. Bei einem Großteil der Patienten mit fortgeschrittener FED zeigt sich an der Hornhautrückfläche eine fibrilläre Schicht (engl.: „fibrillar layer“ [FL]). Diese FL ist mehrheitlich im inferotemporalen Hornhautquadranten lokalisiert, markiert Bereiche mit signifikant reduzierter Endothelzelldichte sowie erhöhter Hornhautdicke im Sinne eines Ödems und lässt sich aufgrund erhöhter Rückstreuung mittels Scheimpflug-Rückstreuungsanalyse darstellen und vermessen. Die Fuchs-Endotheldystrophie stellt derzeit weltweit die häufigste Indikation für eine Hornhauttransplantation meist in Form einer Descemet-Membran-Endothel-Keratoplastik (DMEK) dar. Neue Therapieansätze umfassen Abwandlungen der DMEK-Operation wie eine Hemi- oder Quarter-DMEK mit individualisierten und kleineren Transplantaten oder das alleinige Descemet-Stripping („Descemet stripping only“ [DSO]). Für die FED-Progressionsbeurteilung und Planung chirurgischer Eingriffe könnte zukünftig die klinische Bildgebung der FL als besonders affektiertes Endothelareal von Bedeutung sein. Diese Arbeit bietet eine Übersicht über den aktuellen Stand der Forschung zu Klinik, Pathogenese, fibrillärer Schicht und individualisierter Therapie der FED.

Fuchs endothelial corneal dystrophy (FECD) is a genetic and age-associated corneal disease characterized by an accelerated loss of corneal endothelial cells and an increased subendothelial deposition of extracellular matrix (ECM). Clinically, advanced disease leads to corneal edema with subsequent reduction in visual acuity. In the majority of patients with advanced FECD, a fibrillar layer (FL) appears on the posterior corneal surface. This FL is mostly localized in the inferotemporal corneal quadrant, marks areas with significantly reduced endothelial cell density and increased corneal thickness in the sense of edema and can be visualized and measured using Scheimpflug backscatter analysis due to increased backscatter. FECD is currently the most common indication for corneal transplantation worldwide, usually in the form of Descemet membrane endothelial keratoplasty (DMEK). New treatment approaches include variations of DMEK surgery such as hemi- or quarter DMEK with individualized and smaller grafts or Descemet membrane stripping only (DSO). In the future, clinical imaging of the FL as a particularly affected endothelial area could be important for FECD progression assessment and planning of surgical interventions. This article provides an overview of the current state of research on the clinical aspects, pathogenesis, fibrillar layer and individualized treatment of FECD.

Angiogenesis and immune protection are essential at the onset of tumorigenesis. Angiogenesis serves to nourish the tumor, and prevention of immune defenses, for example, by dendritic cells (DCs), allows tumor growth. In this study, we investigated whether there are factors with dual functions that are both angiogenic and immunomodulatory and represent a therapeutic target. We analyzed 1) innate immune responses intratumorally and in draining lymph nodes and 2) angiogenic factors in conjunctival melanoma (CM), a potentially lethal malignant tumor at the ocular surface whose immune and vascular responses are largely unknown. For this purpose, an HGF-Cdk4R24C model in immunocompetent C57BL/6 mice was used and revealed that CD103- type 2 classical DC (cDC2s) were the most abundant DC subtype in healthy conjunctiva, whereas in CM, CD103- cDC2s, CD103+ type 1 cDCs, monocyte-derived DCs, and plasmacytoid DCs were significantly increased. In our analysis of angiogenic factors in CM, the examination of 53 angiogenesis-related factors that might interact with DCs identified osteopontin (OPN) as a major tumor -derived protein that interacts with DCs. Consistent with these findings, 3) a dual therapeutic strategy that inhibited tumor cell function by an OPN blocking Ab while enhancing the immune response by cDC2 vaccination resulted in 35% failure of tumor development. Moreover, tumor progression, monocyte-derived DC infiltration, and intratumoral angiogenesis were significantly reduced, whereas survival and CD8+ T cell infiltration were increased in treated mice compared with the control group. Therefore, we identified OPN blockade in combination with cDC2 vaccination as a potential future therapeutic intervention for early stages of CM by combining antiangiogenic and host immune stimulating effects. The Journal of Immunology, 2024,212: 487-499.

Acta OphthalmologicaEarly View LETTER TO THE EDITOR Corneal crosslinking ameliorates the extent of corneal oedema in subsequent acute keratoconus in an ex vivo model Antonia Howaldt, Corresponding Author Antonia Howaldt [email protected] orcid.org/0000-0001-7596-8073 Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany Correspondence Antonia Howaldt, Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne D-50937, Germany. Email: [email protected]Search for more papers by this authorWei Zhang, Wei Zhang Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, GermanySearch for more papers by this authorShuya Deng, Shuya Deng Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, GermanySearch for more papers by this authorMartina Becker, Martina Becker Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, GermanySearch for more papers by this authorYanhong Hou, Yanhong Hou orcid.org/0000-0003-2248-8441 Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, GermanySearch for more papers by this authorThomas Clahsen, Thomas Clahsen Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany Center for Molecular Medicine (CMMC), University of Cologne, Cologne, GermanySearch for more papers by this authorFelix Bock, Felix Bock Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany Center for Molecular Medicine (CMMC), University of Cologne, Cologne, GermanySearch for more papers by this authorClaus Cursiefen, Claus Cursiefen Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany Center for Molecular Medicine (CMMC), University of Cologne, Cologne, Germany CECAD, Cluster of Excellence, University of Cologne, Cologne, GermanySearch for more papers by this author Antonia Howaldt, Corresponding Author Antonia Howaldt [email protected] orcid.org/0000-0001-7596-8073 Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany Correspondence Antonia Howaldt, Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne D-50937, Germany. Email: [email protected]Search for more papers by this authorWei Zhang, Wei Zhang Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, GermanySearch for more papers by this authorShuya Deng, Shuya Deng Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, GermanySearch for more papers by this authorMartina Becker, Martina Becker Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, GermanySearch for more papers by this authorYanhong Hou, Yanhong Hou orcid.org/0000-0003-2248-8441 Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, GermanySearch for more papers by this authorThomas Clahsen, Thomas Clahsen Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany Center for Molecular Medicine (CMMC), University of Cologne, Cologne, GermanySearch for more papers by this authorFelix Bock, Felix Bock Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany Center for Molecular Medicine (CMMC), University of Cologne, Cologne, GermanySearch for more papers by this authorClaus Cursiefen, Claus Cursiefen Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany Center for Molecular Medicine (CMMC), University of Cologne, Cologne, Germany CECAD, Cluster of Excellence, University of Cologne, Cologne, GermanySearch for more papers by this author First published: 31 May 2023 https://doi.org/10.1111/aos.15712 Antonia Howaldt and Wei Zhang contributed equally. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article. REFERENCES Ghanem, R.C., Santhiago, M.R., Berti, T.B., Thomaz, S. & Netto, M.V. (2010) Collagen crosslinking with riboflavin and ultraviolet-a in eyes with pseudophakic bullous keratopathy. Journal of Cataract and Refractive Surgery, 36, 273– 276. Raiskup, F., Theuring, A., Pillunat, L.E. & Spoerl, E. (2015) Corneal collagen crosslinking with riboflavin and ultraviolet-a light in progressive keratoconus: ten-year results. Journal of Cataract and Refractive Surgery, 41, 41– 46. Søndergaard, A.P., Ivarsen, A. & Hjortdal, J. (2013) Reduction of stromal swelling pressure after UVA-riboflavin cross-linking. Investigative Ophthalmology and Visual Science, 54, 1625– 1634. Spoerl, E., Hoyer, A., Pillunat, L.E. & Raiskup, F. (2011) Corneal cross-linking and safety issues. The open ophthalmology journal, 5, 14– 16. Stock, R.A., Thumé, T. & Bonamigo, E.L. (2017) Acute corneal hydrops during pregnancy with spontaneous resolution after corneal cross-linking for keratoconus: a case report. Journal of Medical Case Reports, 11, 1– 3. Early ViewOnline Version of Record before inclusion in an issue ReferencesRelatedInformation

Historically, the eye has been considered as an organ free of lymphatic vessels. In recent years, however, it became evident, that lymphatic vessels or lymphatic-like vessels contribute to several ocular pathologies at various peri- and intraocular locations. The aim of this review is to outline the pathogenetic role of ocular lymphatics, the respective molecular mechanisms and to discuss current and future therapeutic options based thereon. We will give an overview on the vascular anatomy of the healthy ocular surface and the molecular mechanisms contributing to corneal (lymph)angiogenic privilege. In addition, we present (i) current insights into the cellular and molecular mechanisms occurring during pathological neovascularization of the cornea triggered e.g. by inflammation or trauma, (ii) the role of lymphatic vessels in different ocular surface pathologies such as dry eye disease, corneal graft rejection, ocular graft versus host disease, allergy, and pterygium, (iii) the involvement of lymphatic vessels in ocular tumors and metastasis, and (iv) the novel role of the lymphatic-like structure of Schlemm's canal in glaucoma. Identification of the underlying molecular mechanisms and of novel modulators of lymphangiogenesis will contribute to the development of new therapeutic targets for the treatment of ocular diseases associated with pathological lymphangiogenesis in the future. The preclinical data presented here outline novel therapeutic concepts for promoting transplant survival, inhibiting metastasis of ocular tumors, reducing inflammation of the ocular surface, and treating glaucoma. Initial data from clinical trials suggest first success of novel treatment strategies to promote transplant survival based on pretransplant corneal lymphangioregression.

Purpose:To investigate the genetic cause, clinical characteristics, and potential therapeutic targets of infantile corneal myofibromatosis. Design:Case series with genetic and functional in vitro analyses. Participants:Four individuals from 2 unrelated families with clinical signs of corneal myofibromatosis were investigated. Methods:Exome-based panel sequencing for platelet-derived growth factor receptor beta gene (PDGFRB) and notch homolog protein 3 gene (NOTCH3) was performed in the respective index patients. One clinically affected member of each family was tested for the pathogenic variant detected in the respective index by Sanger sequencing. Immunohistochemical staining on excised corneal tissue was conducted. Functional analysis of the individual PDGFRB variants was performed in vitro by luciferase reporter assays on transfected porcine aortic endothelial cells using tyrosine kinase inhibitors. Protein expression analysis of mutated PDGFRB was analyzed by Western blot. Main Outcome Measures:Sequencing data, immunohistochemical stainings, functional analysis of PDGFRB variants, and protein expression analysis. Results:We identified 2 novel, heterozygous gain-of-function variants in PDGFRB in 4 individuals from 2 unrelated families with corneal myofibromatosis. Immunohistochemistry demonstrated positivity for alpha-smooth muscle actin and β-catenin, a low proliferation rate in Ki-67 (< 5%), marginal positivity for Desmin, and negative staining for Caldesmon and CD34. In all patients, recurrence of disease occurred after corneal surgery. When transfected in cultured cells, the PDGFRB variants conferred a constitutive activity to the receptor in the absence of its ligand and were sensitive to the tyrosine kinase inhibitor imatinib. The variants can both be classified as likely pathogenic regarding the American College of Medical Genetics and Genomics classification criteria. Conclusions:We describe 4 cases of corneal myofibromatosis caused by novel PDGFRB variants with autosomal dominant transmission. Imatinib sensitivity in vitro suggests perspectives for targeted therapy preventing recurrences in the future. Financial Disclosures:Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Lymphangiogenesis is a key player in several diseases such as tumor metastasis, obesity, and graft rejection. Endogenous regulation of lymphangiogenesis is only partly understood. Here we use the normally avascular cornea as a model to identify endogenous regulators of lymphangiogenesis. Quantitative trait locus analysis of a large low-lymphangiogenic BALB/cN x high-lymphangiogenic C57BL/6 N intercross and prioritization by whole-transcriptome sequencing identify a novel gene responsible for differences in lymphatic vessel architecture on chromosome 17, the cystathionine β-synthase (Cbs). Inhibition of CBS in lymphatic endothelial cells results in reduce proliferation, migration, altered tube-formation, and decrease expression of vascular endothelial growth factor (VEGF) receptor 2 (VEGF-R2) and VEGF-R3, but not their ligands VEGF-C and VEGF-D. Also in vivo inflammation-induced lymphangiogenesis is significantly reduce in C57BL/6 N mice after pharmacological inhibition of CBS. The results confirm CBS as a novel endogenous regulator of lymphangiogenesis acting via VEGF receptor 2 and 3-regulation and open new treatment avenues in diseases associated with pathologic lymphangiogenesis.

Central subendothelial geographic deposits are formed as a fibrillar layer (FL) in advanced Fuchs endothelial corneal dystrophy (FECD). Previous studies demonstrated a significant decrease in corneal endothelial cell (CEC) density and an increase in focal corneal backscatter in the FL area. The present study investigated the association of the FL with edema formation and its localization. Patients (n = 96) presenting for Descemet membrane endothelial keratoplasty (DMEK) for advanced FECD were included. Slit-lamp biomicroscopy with FECD grading was followed by Scheimpflug imaging with en face backscatter analysis and pachymetric analysis. FL dimensions were measured, and correlation with pachymetric values was performed. An FL was detected in 74% of all eyes (n = 71). Pachymetric values in FL-positive versus FL-negative eyes were for corneal thickness at the apex (ACT) 614 ± 52 µm and 575 ± 46 µm (p = 0.001), for peripheral corneal thickness at 1 mm (PCT1mm) 616 ± 50 µm and 580 ± 44 µm (p = 0.002), for PCT2mm 625 ± 48 µm and 599 ± 41 µm (p = 0.017), for PCT3mm 651 ± 46 µm and 635 ± 40 µm (p = 0.128) and for PCT4mm 695 ± 52 µm and 686 ± 43 µm (p = 0.435), respectively. Correlation analysis indicated a weak correlation for the FL maximum vertical caliper diameter with ACT and PCT1mm values but no further relevant correlations. In FL-positive eyes, increased focal corneal backscatter and increased corneal thickness showed primarily central and inferotemporal localization. In conclusion, Scheimpflug imaging shows an association of the FL with increased corneal thickness in advanced FECD and shows localization of the FL and increased corneal thickness in the central and inferotemporal region. This may provide important information for progression assessment and therapeutic decision making in FECD patients in the future.

Purpose: A central collagen-rich subendothelial fibrillar layer (FL) correlates with areas of accentuated loss of corneal endothelial cells in advanced Fuchs endothelial corneal dystrophy (FECD). The present study sought to investigate whether the FL may be visualized by en face Scheimpflug backscatter imaging in vivo. Design: Retrospective analysis of a prospective observational case series. Methods: A total of 34 eyes (34 subjects) undergoing Descemet membrane endothelial keratoplasty (DMEK) surgery with preoperative high-quality Scheimpflug backscatter imaging data were included. The Descemet endothelium complex (DEC) was retrieved during DMEK surgery, and immunofluorescence staining was performed for collagens I, III, and IV. The FL morphology in en face Scheimpflug backscatter and immunofluorescence imaging was compared and agreement of FL parameters was analyzed using intraclass correlation coefficients (ICC) and Bland-Altman plots. Results: Scheimpflug backscatter imaging delineated the FL in 26 eyes and was FL negative in 8 eyes with deviation compared to immunofluorescence in 1 case and good agreement of morphology characteristics. Horizontical caliper diameter +/- SD was 4.84 +/- 0.85 mm, vertical caliper diameter was 3.92 +/- 0.78 mm, maximum caliper diameter was 5.12 +/- 0.82 mm, and surface area was 12.43 +/- 4.74 mm(2). Compared to immunofluorescence imaging, mean difference (95% limits of agreement) and intraclass correlation coefficients were for horizontal caliper diameter 0.13 mm (-0.81 to 1.1 mm) and 0.88, vertical caliper diameter 0.23 mm (-0.76 to 1.2 mm) and 0.81, maximum caliper diameter 0.06 mm (-1.1 to 1.2 mm) and 0.86, and surface area 1.4 mm(2) (-3.9 to 6.7 mm(2)) and 0.85. Conclusions: Scheimpflug backscatter imaging facilitates visualization of the FL in advanced FECD eyes, offering the potential to identify particularly diseased areas of the FECD endothelium in vivo. ((C) 2021 Elsevier Inc. All rights reserved.)

PURPOSE: We sought to assess the correlation of corneal endothelial cell (CEC) density to alterations of collagen composition of Descemet membrane (DM) in advanced Fuchs endothelial corneal dystrophy (FECD) and to image such changes by slit-lamp biomicroscopy in vivo. DESIGN: Prospective, observational consecutive case series. METHODS: Fifty eyes (50 subjects) with advanced FECD were enrolled. After slit-lamp biomicroscopy and corneal Scheimpflug imaging, the Descemet endothelium complex (DEC) was retrieved during DM endothelial keratoplasty (DMEK) surgery. The expression of collagens I, III, and IV (COL I, COL III, and COL IV) and corresponding CEC density were analyzed by immunofluorescence flat mount-staining. Presence, diameter and surface area of collagen expression, and CEC density served as the main outcome measures. RESULTS: Immunofluorescence staining revealed central coherent collagen positive areas (mean surface area = 10 mm(2) +/- 6 mm(2)) corresponding to a fibrillar layer burying the guttae of DM in 84% (42/50) of DECs. CEC density overlying the fibrillar layer compared with the periphery was significantly reduced (- 54.8%, P < .0001) with a steep decline of CEC density at its borders. Subgroup analysis revealed that the fibrillar layer may be imaged by slit-lamp biomicroscopy in vivo with significant positive correlation of mean maximum diameter detected by slit-lamp biomicroscopy (d(SL max) = 4.1 mm +/- 0.9 mm) and by immunofluorescence staining (d(IF max) = 4.7 mm +/- 1.1 mm; r = 0.76; P = .001). CONCLUSION: A fibrillar layer with a clear geographic pattern marks areas of pronounced loss of CEC density in advanced FECD eyes and may be imaged by slit-lamp biomicroscopy in vivo. (C) 2020 Elsevier Inc. All rights reserved.

PURPOSE:To explore the impact of iris color on the outcome of Descemet membrane endothelial keratoplasty (DMEK).METHODS:Consecutive cases of Fuchs endothelial dystrophy after DMEK were retrospectively analyzed from the prospective Cologne DMEK database between 2011 and 2017 at the University of Cologne, Germany. Iris pictures were graded by color into blue, green, or brown and compared regarding outcome parameters including best-corrected visual acuity (converted to logarithm of the minimal angle of resolution), central corneal thickness, endothelial cell density (ECD), each at preoperative (baseline) and postoperative 12 months, rebubbling rates, cystoid macular edema (CME), and immune rejections after surgery.RESULTS:One thousand one hundred six eyes of 814 patients were included in this study that consisted of 354 blue eyes, 418 green eyes, and 244 brown eyes. There was no significant correlation between iris color and any parameter (best corrected visual acuity; P = 0.064 at preoperatively, P = 0.959 at 12 months) (ECD; P = 0.158 preoperatively, P = 0.859 at 12 months) (central corneal thickness; P = 0.148 preoperatively, P = 0.252 at 12 months). The loss of ECD at 12 months after surgery was 37.2% ± 1.0% in blue eyes, 37.2% ± 0.9% in green eyes, and 37.2% ± 1.2% in brown eyes (P = 0.999). Immune rejections were 1.7%, 2.9%, and 0.8% (P = 0.168) in blue, green, and brown eyes, respectively. Rebubbling rates and CME incidence were similar in each group (P = 0.129, and P = 0.552 respectively).CONCLUSIONS:The iris color has no significant impact on the outcome after DMEK. Thus, DMEK can be applied effectively, regardless of the iris color.

Under normal conditions, the cornea, being the transparent “windscreen” of the eye, is free of both blood and lymphatic vessels. However, various diseases of the eye, like infections, can interfere with the balance between promoting and inhibiting factors, which leads to ingrowth of blood and lymphatic vessels. The newly formed lymphatic vessels increase the risk of graft rejection after subsequent corneal transplantation. Corneal transplantation is one of the most commonly performed transplantations worldwide, with more than 40,000 surgeries per year in Europe. To date, various anti-hem- and anti-lymphangiogenic treatment strategies have been developed specifically for the corneal vascular endothelial growth factor (VEGF) pathway. Currently, however, no treatment strategies are clinically available to specifically modulate lymphangiogenesis. In this review, we will give an overview about endogenous regulators of hem- and lymphangiogenesis and discuss potential new strategies for targeting pathological lymphangiogenesis. Furthermore, we will review recently identified modulators and demonstrate that the cornea is a suitable model for the identification of novel endogenous modulators of lymphangiogenesis. The identification of novel modulators of lymphangiogenesis and a better understanding of the signaling pathways involved will contribute to the development of new therapeutic targets for the treatment of pathological lymphangiogenesis. This, in turn, will improve graft rejection, not only for the cornea.

BACKGROUND & AIMS:Aberrant lymphocyte homing could potentially link inflammatory processes in the intestine and the liver, as distinct hepatobiliary diseases frequently develop as extra-intestinal manifestations in inflammatory bowel disease. In this study, we examined the role of the gut-tropic leukocyte adhesion molecule β7 integrin and its endothelial ligand mucosal addressin cell-adhesion molecule-1 (MAdCAM-1) in immune-mediated hepatitis in mice. METHODS:Wild-type (WT) mice, MAdCAM-1-deficient mice, β7 integrin-deficient mice, RAG-2-deficient mice, RAG-2/MAdCAM-1 double-deficient mice, and RAG-2/β7 integrin double-deficient mice were subjected to concanavalin A (ConA)-induced hepatitis. The degree of hepatitis was evaluated by histology, flow cytometry, and expression analysis of inflammatory mediators. The motility of lymphocytes in progressive liver damage was assessed by intravital laser scanning multiphoton microscopy. RESULTS:Ablation of MAdCAM-1 or β7 integrin ameliorated ConA-induced hepatitis in mice. β7 integrin-deficient lymphocytes caused less liver damage than WT lymphocytes in ConA-treated RAG-2-deficient mice. Moreover, WT lymphocytes caused less liver damage in ConA-treated RAG-2/β7 integrin double-deficient mice than in similarly treated RAG-2-deficient mice, indicating that β7 integrin expression contributes significantly to the liver damage mediated by innate immune cells. MAdCAM-1 expression was dependent on β7 integrin expression on adaptive and innate immune cells. Most importantly, lymphocytes in ConA-treated MAdCAM-1-deficient mice displayed more motility and less adhesion in the liver sinusoids in vivo, than lymphocytes in similarly treated WT mice. CONCLUSIONS:These data suggest that β7 integrin expression on lymphocytes and innate immune cells contributes to MAdCAM-1 upregulation and liver damage in acute immune-mediated hepatitis, most likely by facilitating lymphocyte/sinusoidal endothelial cell interactions.