• AAV
• T cell
• adeno-associated virus
• age
• eye
• gene therapy
• inflammation
• microglia
• retinal degeneration
• sex-related differences

• Animals
• Dependovirus/genetics
• Mice
• Female
• Male
• Genetic Vectors/genetics
• Genetic Vectors/administration & dosage
• Genetic Vectors/adverse effects
• Inflammation/etiology
• Inflammation/pathology
• Genetic Therapy/methods
• Genetic Therapy/adverse effects
• Microglia/metabolism
• Age Factors
• Sex Factors
• Disease Models, Animal
• Humans

• Autoimmune uveitis
• EAU
• Microglia
• Retinal transcriptome

• Animals
• Microglia/metabolism
• Microglia/pathology
• Mice
• Retinitis/pathology
• Retinitis/metabolism
• Retinitis/immunology
• Retinitis/genetics
• Retinitis/chemically induced
• Retina/metabolism
• Retina/pathology
• Uveitis/pathology
• Uveitis/immunology
• Uveitis/metabolism
• Uveitis/chemically induced
• Uveitis/genetics
• Disease Models, Animal
• Humans
• Autoimmune Diseases/pathology
• Female
• Eye Proteins

• ME4050/12-1, ME4050/13-1 Deutsche Forschungsgemeinschaft
• Lipid Immune Neuropathy Consortium BMBF
• DOG

• Autoimmune diseases
• Autoimmunity
• Cellular immune response
• Neutrophils
• Ophthalmology

• Extracellular Traps/immunology
• Extracellular Traps/metabolism
• Animals
• Mice
• Humans
• Uveitis/immunology
• Uveitis/pathology
• Uveitis/metabolism
• Cellular Senescence/immunology
• CD4-Positive T-Lymphocytes/immunology
• Disease Models, Animal
• Endothelial Cells/immunology
• Endothelial Cells/metabolism
• Neutrophils/immunology
• Neutrophils/metabolism
• Male
• Female
• Retina/immunology
• Retina/pathology
• Autoimmune Diseases/immunology
• Autoimmune Diseases/pathology
• Membrane Proteins/metabolism
• Mice, Inbred C57BL
• Nucleotidyltransferases/metabolism
• Adult
• Middle Aged

• National Natural Science Foundation of China
• China Postdoctoral Science Foundation

• Animals
• Uveitis/immunology
• Uveitis/pathology
• Mice, Inbred C57BL
• Autoimmune Diseases/immunology
• Autoimmune Diseases/pathology
• Macrophages/immunology
• Macrophages/pathology
• Macrophages/metabolism
• Mice
• Lens Capsule, Crystalline/pathology
• Lens Capsule, Crystalline/immunology
• T-Lymphocytes, Regulatory/immunology
• Female
• Disease Models, Animal
• Acute Disease
• Interleukin-10/metabolism

• R01 EY021784 NEI NIH HHS

• apoptosis
• crystallin β-b2
• experimental autoimmune uveitis
• neuroprotection
• retinal ganglion cell

• Cyclo(His‐Pro)
• HDAC3
• dialysis
• mitochondria
• peritoneal fibrosis

• Animals
• Histone Deacetylases/metabolism
• Histone Deacetylases/genetics
• Peritoneal Fibrosis/metabolism
• Peritoneal Fibrosis/prevention & control
• Peritoneal Fibrosis/pathology
• Mice
• Humans
• Male
• Mice, Inbred C57BL
• Signal Transduction/drug effects
• Peritoneal Dialysis/adverse effects
• Peritoneum/pathology
• Peritoneum/metabolism

• 0620190730 Seoul National University Hospital (SNUH)
• 0320190030 Seoul National University Hospital (SNUH)
• 0411-20190075 Seoul National University Hospital (SNUH)

• Autoimmune diseases
• Cancer
• Inflammation
• Myeloid-derived suppressor cells
• Therapeutics

• Humans
• Myeloid-Derived Suppressor Cells/immunology
• Myeloid-Derived Suppressor Cells/metabolism
• Animals
• Autoimmune Diseases/immunology
• Autoimmune Diseases/metabolism
• Autoimmune Diseases/pathology
• Neoplasms/pathology
• Neoplasms/immunology
• Neoplasms/metabolism
• Hypersensitivity/immunology

• NRF-2016R1A6A1A03007648 National Research Foundation of Korea

• ERU
• IL8
• LPS
• PMA
• PMN
• differential proteomics
• granulocyte
• granulocyte heterogeneity
• innate immune cell activation
• pathway analysis

• DFG DE 719/4-3 Deutsche Forschungsgemeinschaft

• behçet
• uveitis
• interleukin-8
• neutrophil extracellular traps

• Animals
• Female
• Humans
• Mice
• Behcet Syndrome
• DNA/metabolism
• Extracellular Traps/metabolism
• Histones
• Interleukin-8/metabolism
• Mice, Inbred C57BL
• Mitogen-Activated Protein Kinases/metabolism
• NADP/metabolism
• Neutrophils
• Peroxidase/metabolism
• Uveitis/drug therapy

• T cells
• chronic autoimmune uveitis
• immunological memory
• retinal inflammation

• Mice
• Humans
• Animals
• Autoimmune Diseases
• Disease Models, Animal
• Uveitis
• CD4-Positive T-Lymphocytes
• Inflammation
• Retinal Diseases

• P30 EY003790 NEI NIH HHS
• R21 EY031781 NEI NIH HHS

In the pathophysiology of autoimmune-mediated uveitis, granulocytes have emerged as possible disease mediators and were shown to be pre-activated in equine recurrent uveitis (ERU), a spontaneous disease model. We therefore used granulocytes from ERU horses to identify early molecular mechanisms involved in this dysregulated innate immune response. Primary granulocytes from healthy and ERU horses were stimulated with IL8, and cellular response was analyzed with differential proteomics, which revealed significant differences in protein abundance of 170 proteins in ERU. Subsequent ingenuity pathway analysis identified three activated canonical pathways “PKA signaling”, “PTEN signaling” and “leukocyte extravasation”. Clustered to the leukocyte extravasation pathway, we found the membrane-type GPI-anchored protease MMP25, which was increased in IL8 stimulated ERU granulocytes. These findings point to MMP25 as a possible regulator of granulocyte extravasation in uveitis and a role of this molecule in the impaired integrity of the blood-retina-barrier. In conclusion, our analyses show a clearly divergent reaction profile of pre-activated granulocytes upon IL8 stimulation and provide basic information for further in-depth studies on early granulocyte activation in non-infectious ocular diseases. This may be of interest for the development of new approaches in uveitis diagnostics and therapy. Raw data are available via ProteomeXchange with identifier PXD013648.

• Animals
• Autoimmune Diseases
• Granulocytes/metabolism
• Horse Diseases/metabolism
• Horses
• Interleukin-8
• Proteomics
• Recurrence
• Uveitis/metabolism

• Autoimmunity
• CD4 T cells
• MHC class Il structure
• Polymorphism

• antibody therapy
• predictive markers
• neuroscience
• mechanisms of disease

• Diabetic Retinopathy/drug therapy
• Diabetic Retinopathy/metabolism
• Fibrosis
• Glycoproteins/metabolism
• Humans
• Inflammation
• Vascular Endothelial Growth Factor A

• MR/L002973/1 Medical Research Council
• G1000466 Medical Research Council
• PG/16/50/32182 British Heart Foundation
• 206413/Z/17/Z Wellcome Trust
• Wellcome Trust
• Diabetes UK
• RCUK | Biotechnology and Biological Sciences Research Council (BBSRC)
• Wellcome Trust (Wellcome)
• RCUK | Medical Research Council (MRC)
• British Heart Foundation (BHF)
• Rosetrees Trust

• autoimmune diseases
• myeloid-derived suppressor cells (MDSCs)
• nanoparticle
• regulatory B cells (Bregs)
• regulatory T cells (Tregs)

Ocular inflammation imposes a high medical burden on patients and substantial costs on the health-care systems that mange these often chronic and debilitating diseases. Many clinical phenotypes are recognized and classifying the severity of inflammation in an eye with uveitis is an ongoing challenge. With the widespread application of optical coherence tomography in the clinic has come the impetus for more robust methods to compare disease between different patients and different treatment centers. Models can recapitulate many of the features seen in the clinic, but until recently the quality of imaging available has lagged that applied in humans. In the model experimental autoimmune uveitis (EAU), we highlight three linked clinical states that produce retinal vulnerability to inflammation, all different from healthy tissue, but distinct from each other. Deploying longitudinal, multimodal imaging approaches can be coupled to analysis in the tissue of changes in architecture, cell content and function. This can enrich our understanding of pathology, increase the sensitivity with which the impacts of therapeutic interventions are assessed and address questions of tissue regeneration and repair. Modern image processing, including the application of artificial intelligence, in the context of such models of disease can lay a foundation for new approaches to monitoring tissue health.

• EAU
• OCT
• automated analysis
• image processing
• uveitis

• Immunosuppression
• Myeloid-derived suppressor cells
• Neuroinflammatory
• Tumor disease

• National Natural Science Foundation of China
• Natural Science Foundation of Shandong Province
• National Training Program of Innovation and Entrepreneurship for Undergraduates
• Jining Medical University Training Program of Innovation and Entrepreneurship for Undergraduates

• Dry eye disease
• Mesenchymal stem cell
• Mesenchymal stromal cell
• Ocular autoimmune disease
• Sjögren's syndrome
• Uveitis
• Uveoretinitis

• Autoimmunity
• Inflammation
• MDSC
• Rheumatoid arthritis

Horses worldwide suffer from equine recurrent uveitis (ERU), an organ-specific, immune-mediated disease with painful, remitting-relapsing inflammatory attacks alternating with periods of quiescence, which ultimately leads to blindness. In course of disease, both eyes can eventually be affected and since blind horses pose a threat to themselves and their surroundings, these animals have to be killed. Therefore, this disease is highly relevant for veterinary medicine. Additionally, ERU shows strong clinical and pathological resemblance to autoimmune uveitis in man. The exact cause for the onset of ERU is unclear to date. T cells are believed to be the main effector cells in this disease, as they overcome the blood retinal barrier to invade the eye, an organ physiologically devoid of peripheral immune cells. These cells cause severe intraocular inflammation, especially in their primary target, the retina. With every inflammatory episode, retinal degeneration increases until eyesight is completely lost. In ERU, T cells show an activated phenotype, with enhanced deformability and migration ability, which is reflected in the composition of their proteome and downstream interaction pathways even in quiescent stage of disease. Besides the dysregulation of adaptive immune cells, emerging evidence suggests that cells of the innate immune system may also directly contribute to ERU pathogenesis. As investigations in both the target organ and the periphery have rapidly evolved in recent years, giving new insights on pathogenesis-associated processes on cellular and molecular level, this review summarizes latest developments in ERU research.

• Mueller glia
• complement system
• cytokines
• granulocyte
• lymphocyte
• retina
• serum
• vitreous

• Autoimmune uveitis
• Calgranulin B
• Equine recurrent uveitis (ERU)
• Innate immune cell
• Neutrophil degranulation

• PD-1/PD-L1
• S100A8/A9
• STAT3
• dendritic cells
• macrophages
• natural killer cells

• autoimmunity
• immune response
• mathematical model
• stochasticity

• Animals
• Autoimmune Diseases/pathology
• Disease Models, Animal
• Humans
• Mice
• Models, Theoretical
• Stochastic Processes

• Inflammation
• Myeloid-derived suppressor cells (MDSCs)
• rheumatoid arthritis (RA)

Myeloid cells, such as granulocytes/neutrophils and macrophages, have responsibilities that include pathogen destruction, waste material degradation, or antigen presentation upon inflammation. During persistent stress, myeloid cells can remain partially differentiated and adopt immunosuppressive functions. Myeloid-derived suppressor cells (MDSCs) are primarily beneficial upon restoring homeostasis after inflammation. Because of their ability to suppress adaptive immunity, MDSCs can also ameliorate autoimmune diseases and semi-allogenic responses, e.g., in pregnancy or transplantation. However, immunosuppression is not always desirable. In certain conditions, such as cancer or chronically inflamed tissue, MDSCs prevent restorative immune responses and thereby aggravate disease progression. Age-related macular degeneration (AMD) is the most common disease in Western countries that severely threatens the central vision of aged people. The pathogenesis of this multifactorial disease is not fully elucidated, but inflammation is known to participate in both dry and wet AMD. In this paper, we provide an overview about the potential role of MDSCs in the pathogenesis of AMD.

• adaptive immunity
• age-related macular degeneration
• inflammation
• innate immunity
• myeloid-derived suppressor cell

Myeloid-derived suppressor cells (MDSCs) represent a heterogeneous population of immature myeloid cells with major regulatory functions and rise during pathological conditions, including cancer, infections and autoimmune conditions. MDSC expansion is generally linked to inflammatory processes that emerge in response to stable immunological stress, which alter both magnitude and quality of the myelopoietic output. Inability to reinstate physiological myelopoiesis would fall in an “emergency state” that perpetually reprograms myeloid cells toward suppressive functions. While differentiation and reprogramming of myeloid cells toward an immunosuppressive phenotype can be considered the result of a multistep process that originates in the bone marrow and culminates in the tumor microenvironment, the identification of its driving events may offer potential therapeutic approaches in different pathologies. Indeed, whereas expansion of MDSCs, in both murine and human tumor bearers, results in reduced immune surveillance and antitumor cytotoxicity, placing an obstacle to the effectiveness of anticancer therapies, adoptive transfer of MDSCs has shown therapeutic benefits in autoimmune disorders. Here, we describe relevant mechanisms of myeloid cell reprogramming leading to generation of suppressive MDSCs and discuss their therapeutic ductility in disease.

• autoimmune diseases
• cancer
• emergency myelopoiesis
• immunosuppression
• myeloid-derived suppressor cells (MDSCs)

To compare lymphocyte populations present within inflamed eyes in two rat models of autoimmune uveitis.

Experimental autoimmune uveitis (EAU) and primed mycobacterial uveitis (PMU) were initiated in Lewis rats. Aqueous and vitreous were collected at peak inflammation (PMU at day 2, EAU at day 14). The number of cells in the aqueous and vitreous was determined and compared for each eye and between the two models. Intraocular CD-19⁺ B cells, CD3⁺ T cells, and CD4⁺ or CD8⁺ T-cell subpopulations were identified by flow cytometry and compared between EAU and PMU.

The median number of cells/mL collected from PMU aqueous (7.98 × 10⁷ cells/mL), was not significantly different from the number of cells collected from EAU aqueous (1.61 × 10⁷ cells/mL, P = 0.94). EAU aqueous contains a significantly larger mononuclear population (median 61%, interquartile range [IQR] 44%–67%) than PMU (median 9%, IQR 8%–10% [P < 0.0001]). Within the mononuclear population, EAU and PMU aqueous demonstrate similar proportions of CD3⁺, CD4⁺ T cells. However, EAU has a larger CD3⁺, CD8⁺, T-cell population than PMU, and this population also demonstrates co-expression of CD45R. B cells comprise a significantly larger median percentage of cells in EAU aqueous (median 18%, IQR 15%–20%) compared to PMU (median 13%, IQR 9%–15%, P = 0.006).

Flow cytometry analysis of intraocular lymphocytes from EAU and PMU identifies similarities and differences between the T-cell and B-cell populations present at peak inflammation. Complementary animal models that have well-defined mechanistic differences will improve our ability to test potential new therapies and bring meaningful advances into clinical practice for patients with uveitis.

Uveitis is an intraocular inflammatory disease which can lead to serious visual impairment. Genetic factors have been shown to be involved in its development. However, few databases have focused on the information of associations between single nucleotide polymorphisms (SNPs) and uveitis. To discover the exact genetic background of uveitis, we developed an SNP database specific for uveitis, “UVEOGENE,” which includes 370 genes and 918 SNPs covering 14 uveitis entities and 40 populations from 286 PubMed English‐language papers. Stratification analyses by gender, HLA status, and different clinical features were also extracted from the publications. As a result, 371 associations were judged as “statistically significant.” These associations were also shared with Global Variome shared Leiden Open Variation Database (LOVD) (https://databases.lovd.nl/shared/genes). Based on these associations, we investigated the genetic relationship among three widely studied uveitis entities including Behcet's disease (BD), Vogt–Koyanagi–Harada (VKH) disease, and acute anterior uveitis (AAU). Furthermore, “UVEOGENE” can be used as a reliable and informative resource to identify similarities as well as differences in the genetic susceptibility among uveitis and other autoimmune diseases. UVEOGENE is freely accessible at http://www.uvogene.com.

• autoimmune disease
• database
• immune system pathways
• single nucleotide polymorphism
• uveitis

Myeloid-derived suppressor cells (MDSCs) are identified as a heterogeneous population of cells with the function to suppress innate as well as adaptive immune responses. The initial studies of MDSCs were primarily focused on the field of animal tumor models or cancer patients. In cancer, MDSCs play the deleterious role to inhibit tumor immunity and to promote tumor development. Over the past few years, an increasing number of studies have investigated the role of MDSCs in autoimmune diseases. The beneficial effects of MDSCs in autoimmunity have been reported by some studies, and thus, immunosuppressive MDSCs may be a novel therapeutic target in autoimmune diseases. There are some controversial findings as well. Many questions such as the activation, differentiation, and suppressive functions of MDSCs and their roles in autoimmune diseases remain unclear. In this review, we have discussed the current understanding of MDSCs in autoimmune diseases.

• Chemokines
• Inflammation
• Macrophages
• Ophthalmology
• endothelial cells

• Inflammation
• MDSC
• Myeloid cell
• Organ
• Plasticity
• T cell

The key transcription factors of T helper cell subpopulations, including T-bet, GATA3, RORγt, and Foxp3 are involved in various autoimmune diseases. Whether methylation of these master transcription factors is associated with the development of experimental autoimmune uveitis (EAU) and the possible epigenetic regulatory mechanisms involved has however not yet been addressed. In our study, significant methylation changes in both Tbx21 and Rorc were observed in one CpG site in the retinas of EAU mice. Two CpG sites of Tbx21 and one CpG site of Rorc showed significant dynamic methylation changes in the RPE-choroid complex during EAU. The mRNA expressions of Tbx21 and Rorc in both the retinas and RPE-choroid complexes correlated with the methylation changes at the various time points during EAU development. The methylation changes were associated with the production of the Th1/Th17 cells' signature cytokines, IFN-γ and IL-17. Dynamic changes in mRNA expression of DNA methyltransferases (DNMT1) were also noted, which may be related to the observed methylation changes of these genes. The present study provides evidence that DNA methylation of Tbx21 and Rorc may be associated with the development of EAU. DNMT1 activation may have an important effect on regulating DNA methylation dynamics.

Ocular function depends on a high level of anatomical integrity. This is threatened by inflammation, which alters the local tissue over short and long time-scales. Uveitis due to autoimmune disease, especially when it involves the retina, leads to persistent changes in how the eye interacts with the immune system. The normal pattern of immune surveillance, which for immune privileged tissues is limited, is re-programmed. Many cell types, that are not usually present in the eye, become detectable. There are changes in the tissue homeostasis and integrity. In both human disease and mouse models, in the most extreme cases, immunopathological findings consistent with development of ectopic lymphoid-like structures and disrupted angiogenesis accompany severely impaired eye function. Understanding how the ocular environment is shaped by persistent inflammation is crucial to developing novel approaches to treatment.

• Angiogenesis
• EAU
• Ectopic lymphoid tissue
• Immunosurveillance
• Uveitis

• Annexin A1
• endotoxin-induced uveitis
• experimental autoimmune uveitis
• inflammation
• uveitis

• autoimmune diseases
• cancers
• inflammation
• myeloid regulatory cells
• myeloid-derived suppressor cells

Infliximab is an antibody that neutralizes TNF-α and is used principally by systemic administration to treat many inflammatory disorders. We prepared the antibody mimetic Fab-PEG-Fab (FpF_infliximab) for direct intravitreal injection to assess whether such formulations have biological activity and potential utility for ocular use. FpF_infliximab was designed to address side effects caused by antibody degradation and the presence of the Fc region. Surface plasmon resonance analysis indicated that infliximab and FpF_infliximab maintained binding affinity for both human and murine recombinant TNF-α. No Fc mediated RPE cellular uptake was observed for FpF_infliximab. Both Infliximab and FpF_infliximab suppressed ocular inflammation by reducing the number of CD45+ infiltrate cells in the EAU mice after a single intravitreal injection at the onset of peak disease. These results offer an opportunity to develop and formulate for ocular use, FpF molecules designed for single and potentially multiple targets using bi-specific FpFs.

• Glioma
• Immunotherapy
• Myeloid derived suppressor cells
• T cells
• Tumor microenvironment

Myeloid cells make a pivotal contribution to tissue homeostasis during inflammation. Both tissue-specific resident populations and infiltrating myeloid cells can cause tissue injury through aberrant activation and/or dysregulated activity. Reliable identification and quantification of myeloid cells within diseased tissues is important to understand pathological inflammatory processes. Flow cytometry is a valuable technique for leukocyte analysis, but a standardized flow cytometric method for myeloid cell populations in the eye is lacking. Here, we validate a reproducible flow cytometry gating approach to characterize myeloid cells in several commonly used models of ocular inflammation. We profile and quantify myeloid subsets across these models, and highlight the value of this strategy in identifying phenotypic differences using Ccr2-deficient mice. This method will aid standardization in the field and facilitate future investigations into the roles of myeloid cells during ocular inflammation.

• Choroidal neovascularization
• Endotoxin-induced uveitis
• Experimental autoimmune uveoretinitis
• Flow cytometry
• Monocytes
• Myeloid cells
• Neutrophils
• Retinal microglia

• monocyte‐derived macrophages
• neuroprotection
• optic nerve crush
• retinal ganglion cells
• retinal pigment epithelium

Diabetic retinopathy is a sight-threatening complication of diabetes, affecting 65% of patients after 10 years of the disease. Diabetic metabolic insult leads to chronic low-grade inflammation, retinal endothelial cell loss and inadequate vascular repair. This is partly due to bone marrow (BM) pathology leading to increased activity of BM-derived pro-inflammatory monocytes and impaired function of BM-derived reparative circulating angiogenic cells (CACs). We propose that diabetes has a significant long-term effect on the nature and proportion of BM-derived cells that circulate in the blood, localize to the retina and home back to their BM niche. Using a streptozotocin mouse model of diabetic retinopathy with GFP BM-transplantation, we have demonstrated that BM-derived circulating pro-inflammatory monocytes are increased in diabetes while reparative CACs are trapped in the BM and spleen, with impaired release into circulation. Diabetes also alters activation of splenocytes and BM-derived dendritic cells in response to LPS stimulation. A majority of the BM-derived GFP cells that migrate to the retina express microglial markers, while others express endothelial, pericyte and Müller cell markers. Diabetes significantly increases infiltration of BM-derived microglia in an activated state, while reducing infiltration of BM-derived endothelial progenitor cells in the retina. Further, control CACs injected into the vitreous are very efficient at migrating back to their BM niche, whereas diabetic CACs have lost this ability, indicating that the in vivo homing efficiency of diabetic CACs is dramatically decreased. Moreover, diabetes causes a significant reduction in expression of specific integrins regulating CAC migration. Collectively, these findings indicate that BM pathology in diabetes could play a role in both increased pro-inflammatory state and inadequate vascular repair contributing to diabetic retinopathy.

• Animals
• Bone Marrow Cells/cytology
• Bone Marrow Transplantation
• Cell Count
• Chimera
• Dendritic Cells/pathology
• Diabetic Retinopathy/immunology
• Diabetic Retinopathy/pathology
• Endothelial Cells/pathology
• Green Fluorescent Proteins/metabolism
• Inflammation/pathology
• Lipopolysaccharides/pharmacology
• Male
• Mice, Inbred C57BL
• Microglia/pathology
• Microvessels/drug effects
• Microvessels/pathology
• Monocytes/pathology
• Retina/pathology
• Spleen/pathology

• R01 EY012601 NEI NIH HHS
• R01 EY007739 NEI NIH HHS
• R01 EY016077 NEI NIH HHS
• EY-12601 NEI NIH HHS
• DK-09-0730 NIDDK NIH HHS
• R01 EY025383 NEI NIH HHS
• P30 DK020572 NIDDK NIH HHS
• EY-01-6077 NEI NIH HHS
• EY-07739 NEI NIH HHS

• IL-10
• myeloid-derived suppressor cell
• nitric oxide synthase
• prostaglandin E2
• regulatory T cell

• autoimmunity
• chronic inflammation
• epitope spreading
• retina
• uveitis