Vaccines and the Eye: Current Understanding of the Molecular and Immunological Effects of Vaccination on the Eye.

Vaccination is a public health cornerstone that protects against numerous infectious diseases. Despite its benefits, immunization implications on ocular health warrant thorough investigation, particularly in the context of vaccine-induced ocular inflammation. This review aimed to elucidate the complex interplay between vaccination and the eye, focusing on the molecular and immunological pathways implicated in vaccine-associated ocular adverse effects. Through an in-depth analysis of recent advancements and the existing literature, we explored various mechanisms of vaccine-induced ocular inflammation, such as direct infection by live attenuated vaccines, immune complex formation, adjuvant-induced autoimmunity, molecular mimicry, hypersensitivity reactions, PEG-induced allergic reactions, Type 1 IFN activation, free extracellular RNA, and specific components. We further examined the specific ocular conditions associated with vaccination, such as uveitis, optic neuritis, and retinitis, and discussed the potential impact of novel vaccines, including those against SARS-CoV-2. This review sheds light on the intricate relationships between vaccination, the immune system, and ocular tissues, offering insights into informed discussions and future research directions aimed at optimizing vaccine safety and ophthalmological care. Our analysis underscores the importance of vigilance and further research to understand and mitigate the ocular side effects of vaccines, thereby ensuring the continued success of vaccination programs, while preserving ocular health.

Complement regulation in the eye: implications for age-related macular degeneration.

Careful regulation of the complement system is critical for enabling complement proteins to titrate immune defense while also preventing collateral tissue damage from poorly controlled inflammation. In the eye, this balance between complement activity and inhibition is crucial, as a low level of basal complement activity is necessary to support ocular immune privilege, a prerequisite for maintaining vision. Dysregulated complement activation contributes to parainflammation, a low level of inflammation triggered by cellular damage that functions to reestablish homeostasis, or outright inflammation that disrupts the visual axis. Complement dysregulation has been implicated in many ocular diseases, including glaucoma, diabetic retinopathy, and age-related macular degeneration (AMD). In the last two decades, complement activity has been the focus of intense investigation in AMD pathogenesis, leading to the development of novel therapeutics for the treatment of atrophic AMD. This Review outlines recent advances and challenges, highlighting therapeutic approaches that have advanced to clinical trials, as well as providing a general overview of the complement system in the posterior segment of the eye and selected ocular diseases.

Compartmentalized ocular lymphatic system mediates eye-brain immunity.

The eye, an anatomical extension of the central nervous system (CNS), exhibits many molecular and cellular parallels to the brain. Emerging research demonstrates that changes in the brain are often reflected in the eye, particularly in the retina1. Still, the possibility of an immunological nexus between the posterior eye and the rest of the CNS tissues remains unexplored. Here, studying immune responses to herpes simplex virus in the brain, we observed that intravitreal immunization protects mice against intracranial viral challenge. This protection extended to bacteria and even tumours, allowing therapeutic immune responses against glioblastoma through intravitreal immunization. We further show that the anterior and posterior compartments of the eye have distinct lymphatic drainage systems, with the latter draining to the deep cervical lymph nodes through lymphatic vasculature in the optic nerve sheath. This posterior lymphatic drainage, like that of meningeal lymphatics, could be modulated by the lymphatic stimulator VEGFC. Conversely, we show that inhibition of lymphatic signalling on the optic nerve could overcome a major limitation in gene therapy by diminishing the immune response to adeno-associated virus and ensuring continued efficacy after multiple doses. These results reveal a shared lymphatic circuit able to mount a unified immune response between the posterior eye and the brain, highlighting an understudied immunological feature of the eye and opening up the potential for new therapeutic strategies in ocular and CNS diseases.

[Anti-inflammatory Strategies by Focusing on the Particularity of Ocular Immunity].

Particularity of ocular immunity is manifested by "Immune privilege". For example, it has been generally known that corneal transplantation is a typically successful organ transplantation compared with other organs. This immune privilege can be explained by "immune-suppressive ocular microenvironment" and "anterior chamber-associated immune deviation, ACAID". This review focused on molecular mechanisms of the "immune-suppressive ocular microenvironment" and "ACAID", so that possible anti-inflammatory strategies could be raised. Especially, in murine ACAID model, anti-inflammatory actions were induced probably through induction of Treg cells. As an anti-inflammatory strategy, anti-inflammatory Treg cells could be induced in vitro. Treg cells that are specifically responsive for a specific antigen can be induced by culturing spleen cells with the antigen and transforming growth factor-ß (TGF-ß). The induced Treg cells were activated by stimulation with the specific antigen. When the induced Treg cells were adoptively transferred to recipient mice, antigen-induced inflammation was effectively suppressed. The Treg cells may be able to be efficiently induced by eye-based mechanisms. Further analyses of mechanisms underlying the ocular immune privilege can be useful for development of new anti-inflammatory strategies on the eye basis.

SARS-CoV-2 and the Eye: The Pandora's Box of Ocular Immunology.

The Pandora's box myth addresses the evilness in the world that undisputedly nowadays is identified in severe acute respiratory syndrome (SARS)-Coronavirus 2 (CoV-2), formerly known as Covid-19, which belongs to coronaviridae family, identified in Wuhan, Hubei district of the Republic of China in December 2019. Since then, SARS-CoV-2 has affected ∼180 million people and made almost 4 million victims, with a mortality rate of 6.1%, which is 6 times higher than influenza virus. However, coronaviruses are well known in the ophthalmology field because they were used in the so-called experimental coronavirus retinopathy model. That model certainly brings intriguing concepts for understanding coronavirus pathophysiology, which may have important implications on treatment strategies. Certainly, the recent availability of vaccines gives hope on the control of virus spreading; however, vaccines might create immune reactions involving the eye structure. In this study, we reviewed the literature and elaborated the available data to speculate on possible new interpretation of both pathophysiology and treatment of SARS-CoV-2.

An investigation on protective effects of the new killed vaccine against nervous necrosis virus (NNV) using histopathology and immunohistochemistry approach on the brain and eye tissues of Acipenser stellatus Pallas 1771.

The objective of this study was to analyze the efficiency of the killed vaccine against nervous necrosis virus on Acipenser stellutus. Heat inactivated VNN vaccine was administrated in 7 g juveniles of Acipenser stellutus as a laboratory model and it was included in three different adjuvants that were used as injection and immersion forms with different doses. Ten groups consisting of 30 A. stellutus fish in each group (group 1-4 with 3 replications, others with no replicate) were divided totally into 18 aquariums. Two steps of vaccination were done with a one-month interval and after that, all treatments and control groups were challenged by the virulent VNN virus. The mortality rate of immersion and injection groups were 12.9% and 19.8% respectively, compared to 100% mortality in the control group. Histopathology and immunohistochemistry findings were evaluated. According to the mortality rate one month after challenging, a low range mortality of 12.5% was seen in group 2 with no pathological lesion and negative IHC test in the brain and eye tissues, whereas 100% of the control group (unvaccinated group) died with severe vacuolation in the brain and eye tissues and also positive IHC test. The correlation assay between these results concluded that the immersion form with 75% of aquatic-specific Montanide IMS 1312 Seppic adjuvant made better immunization with no pathological sign or forming the complex of antigen-antibody in IHC assay. These findings are important because of the impossibility of injection in the larval stage and also due to the occurrence of the disease in the first stage of sturgeon life which could cause high mortality in susceptible fish in the larval stage.

Adenosine: The common target between cancer immunotherapy and glaucoma in the eye.

Adenosine, an endogenous purine nucleoside, is a well-known actor of the immune system and the inflammatory response both in physiologic and pathologic conditions. By acting upon particular, G-protein coupled adenosine receptors, i.e., A1, A2- a & b, and A3 receptors mediate a variety of intracellular and immunomodulatory actions. Several studies have elucidated Adenosine's effect and its up-and downstream molecules and enzymes on the anti-tumor response against several types of cancers. We have also targeted a couple of molecules to manipulate this pathway and get the immune system's desired response in our previous experiences. Besides, the outgrowth of the studies on ocular Adenosine in recent years has significantly enhanced the knowledge about Adenosine and its role in ocular immunology and the inflammatory response of the eye. Glaucoma is the second leading cause of blindness globally, and the recent application of Adenosine and its derivatives has shown the critical role of the adenosine pathway in its pathophysiology. However, despite a very promising background, the phase III clinical trial of Trabodenoson failed to achieve the non-inferiority goals of the study. In this review, we discuss different aspects of the abovementioned pathway in ophthalmology and ocular immunology; following a brief evaluation of the current immunotherapeutic strategies, we try to elucidate the links between cancer immunotherapy and glaucoma in order to introduce novel therapeutic targets for glaucoma.

Cytokine expression in the eye and brain of chickens following infection with a very virulent plus Marek's disease virus strain.

Cytokine transcripts were evaluated chronologically in the brain and in the eye of chickens infected with the very virulent plus Marek's disease virus (vv + MDV) strain 648A. Brain and eye samples were collected from chickens that were either suffering from transient paralysis (TP) (11 days post inoculation, dpi) or had completely recovered from TP but started developing clinical signs of persistent neurological disease (PND) (18-31 dpi). Results obtained from samples collected at 11 dpi are referred as EL (early lesions) and results obtained from samples collected at later times (18-31 dpi) are referred as LL (late lesions). Marked differences were found in the cytokine transcripts in brain and eye. While proinflammatory cytokines (IL-1ß, IL-8, IL-18), iNOS, IFN-α, IFN-γ, and IL-15 were upregulated in the brain during EL and LL, only IL-8 and IFN-γ were upregulated in the eye at both times (EL and LL). The two evaluated viral transcripts (gB and meq) were found in both eye and brain during EL and LL. Levels of the two viral transcripts evaluated were higher at LL than at EL in both brain and eye. No differences were found in any of the viral transcripts between eye and brain during EL. However, during the LL, the levels of meq transcripts were higher in the eye than in the brain. Our results suggest that MDV elicits different immune responses in the brain and in the eye of infected chickens. Because immune responses in the eye of chickens have been poorly studied, further studies on the pathogenesis of MDV in the eye could greatly contribute to our knowledge on the chicken eye immunity.

A novel application of bubble-eye strain of Carassius auratus for ex vivo fish immunological studies.

In this study, we investigated a new application of bubble-eye goldfish (commercially available strain with large bubble-shaped eye sacs) for immunological studies in fishes utilizing the technical advantage of examining immune cells in the eye sac fluid ex vivo without sacrificing animals. As known in many aquatic species, the common goldfish strain showed an increased infection sensitivity at elevated temperature, which we demonstrate may be due to an immune impairment using the bubble-eye goldfish model. Injection of heat-killed bacterial cells into the eye sac resulted in an inflammatory symptom (surface reddening) and increased gene expression of pro-inflammatory cytokines observed in vivo, and elevated rearing temperature suppressed the induction of pro-inflammatory gene expressions. We further conducted ex vivo experiments using the immune cells harvested from the eye sac and found that the induced expression of pro-inflammatory cytokines was suppressed when we increased the temperature of ex vivo culture, suggesting that the temperature response of the eye-sac immune cells is a cell autonomous function. These results indicate that the bubble-eye goldfish is a suitable model for ex vivo investigation of fish immune cells and that the temperature-induced infection susceptibility in the goldfish may be due to functional impairments of immune cells.

The Eye as a Transplantation Site to Monitor Pancreatic Islet Cell Plasticity.

The endocrine cells confined in the islets of Langerhans are responsible for the maintenance of blood glucose homeostasis. In particular, beta cells produce and secrete insulin, an essential hormone regulating glucose uptake and metabolism. An insufficient amount of beta cells or defects in the molecular mechanisms leading to glucose-induced insulin secretion trigger the development of diabetes, a severe disease with epidemic spreading throughout the world. A comprehensive appreciation of the diverse adaptive procedures regulating beta cell mass and function is thus of paramount importance for the understanding of diabetes pathogenesis and for the development of effective therapeutic strategies. While significant findings were obtained by the use of islets isolated from the pancreas, in vitro studies are inherently limited since they lack the many factors influencing pancreatic islet cell function in vivo and do not allow for longitudinal monitoring of islet cell plasticity in the living organism. In this respect a number of imaging methodologies have been developed over the years for the study of islets in situ in the pancreas, a challenging task due to the relatively small size of the islets and their location, scattered throughout the organ. To increase imaging resolution and allow for longitudinal studies in individual islets, another strategy is based on the transplantation of islets into other sites that are more accessible for imaging. In this review we present the anterior chamber of the eye as a transplantation and imaging site for the study of pancreatic islet cell plasticity, and summarize the major research outcomes facilitated by this technological platform.

Mapping the origin and fate of myeloid cells in distinct compartments of the eye by single-cell profiling.

Similar to the brain, the eye is considered an immune-privileged organ where tissue-resident macrophages provide the major immune cell constituents. However, little is known about spatially restricted macrophage subsets within different eye compartments with regard to their origin, function, and fate during health and disease. Here, we combined single-cell analysis, fate mapping, parabiosis, and computational modeling to comprehensively examine myeloid subsets in distinct parts of the eye during homeostasis. This approach allowed us to identify myeloid subsets displaying diverse transcriptional states. During choroidal neovascularization, a typical hallmark of neovascular age-related macular degeneration (AMD), we recognized disease-specific macrophage subpopulations with distinct molecular signatures. Our results highlight the heterogeneity of myeloid subsets and their dynamics in the eye that provide new insights into the innate immune system in this organ which may offer new therapeutic targets for ophthalmological diseases.

Plasmacytoid dendritic cells in the eye.

Plasmacytoid dendritic cells (pDCs) are a unique subpopulation of immune cells, distinct from classical dendritic cells. pDCs are generated in the bone marrow and following development, they typically home to secondary lymphoid tissues. While peripheral tissues are generally devoid of pDCs during steady state, few tissues, including the lung, kidney, vagina, and in particular ocular tissues harbor resident pDCs. pDCs were originally appreciated for their potential to produce large quantities of type I interferons in viral immunity. Subsequent studies have now unraveled their pivotal role in mediating immune responses, in particular in the induction of tolerance. In this review, we summarize our current knowledge on pDCs in ocular tissues in both mice and humans, in particular in the cornea, limbus, conjunctiva, choroid, retina, and lacrimal gland. Further, we will review our current understanding on the significance of pDCs in ameliorating inflammatory responses during herpes simplex virus keratitis, sterile inflammation, and corneal transplantation. Moreover, we describe their novel and pivotal neuroprotective role, their key function in preserving corneal angiogenic privilege, as well as their potential application as a cell-based therapy for ocular diseases.

Molecular Mimicry and Uveitis.

Molecular or antigenic mimicry is a term for the similarity of different antigens, which can be confused by the immune system. Antigen recognition by antibodies and T cell receptors is specific, but not restricted to a single antigen. Both types of receptors specifically recognize antigens and are expressed with a very high but still restricted variability compared to the number of different antigens they potentially could bind. T cell receptors only can bind to antigen peptides presented on certain self-MHC-molecules by screening only some amino acid side chains on both the presented peptides and the MHC molecule. The other amino acids of the peptide are not directly perceived by the T cell, offering the opportunity for a single T cell to recognize a variety of different antigens with the same receptor, which significantly increases the immune repertoire. The immune system is usually tolerant to autoantigens, especially to those of immune privileged sites, like the eye. Therefore, autoimmune diseases targeting these organs were hard to explain, unless a T cell is activated by an environmental peptide (e.g. pathogen) that is similar, but not necessarily identical with an autoantigen. Here we describe antigenic mimicry of retinal autoantigens with a variety of non-ocular antigens resulting in the induction of intraocular inflammation. T cells that are activated by mimotopes outside of the eye can pass the blood-retina barrier and enter ocular tissues. When reactivated in the eye by crossreaction with autoantigens they induce uveitis by recruiting inflammatory cells.

Transcriptional analysis of immune response genes during pathogenesis of cytomegalovirus retinitis in mice with murine acquired immunodeficiency syndrome.

Human cytomegalovirus (HCMV) is an opportunistic human herpesvirus that causes a sight-threatening retinitis in immunosuppressed patients, especially those with AIDS. Using an established model of experimental murine cytomegalovirus (MCMV) retinitis in mice with retrovirus-induced immunodeficiency (MAIDS), we have been attempting to define with greater clarity the immunologic mechanisms that contribute to the progression of AIDS-related HCMV retinitis in the unique immunosuppressive setting of HIV infection. Toward this end, we provide herein a comprehensive assessment of immune response gene expression during the onset and development of MAIDS-related MCMV retinitis employing NanoString nCounter. In so doing, we analyzed and compared the intraocular expressions of 561 immune response genes within MCMV-infected eyes of groups of healthy mice, MCMV-infected mice with MAIDS of 4 weeks' (MAIDS-4) duration, and MCMV-infected eyes of mice with MAIDS of 10 weeks' (MAIDS-10) duration. These animal groups show a progression of retinal disease from absolute resistance to retinitis development in healthy mice to the development of classic full-thickness retinal necrosis in MAIDS-10 mice but through an intermediate stage of retinal disease development in MAIDS-4 mice. Our findings showed that increased susceptibility to MCMV retinitis during the progression of MAIDS is associated with robust upregulation or downregulation of a surprisingly large number of immune response genes that operate within several immune response pathways often unique to each animal group. Analysis of 14 additional immune response genes associated with programmed cell death pathways suggested involvement of necroptosis and pyroptosis during MAIDS-related MCMV retinitis pathogenesis. Use of the NanoString nCounter technology provided new and unexpected information on the immunopathogenesis of retinitis within MCMV-infected eyes of mice with retrovirus-induced immunosuppression. Our findings may provide new insights into the immunologic events that operate during the pathogenesis of AIDS-related HCMV retinitis.

Cluster Analysis of Dry Eye Disease Models Based on Immune Cell Parameters - New Insight Into Therapeutic Perspective.

Dry eye disease (DED) can be represented as a display of disease in the mucosal part of the eye. It is quite distinct from the retinal side of the eye which connects with the neurons and thus represents the neuroimmunological disease. DED can occur either by the internal damage of the T cells inside the body or by microbial infections. Here we summarize the most common animal model systems used for DED relating to immune factors. We aimed to identify the most important immune cell/cytokine among the animal models of the disease. We also show the essential immune factors which are being tested for DED treatment. In our results, both the mechanism and the treatment of its animal models indicate the involvement of Th1 cells and the pro-inflammatory cytokine (IL-1ß and TNF-α) related to the Th1-cells. The study is intended to increase the knowledge of the animal models in the field of the ocular surface along with the opening of a dimension of thoughts while designing a new animal model or treatment paradigm for ocular surface inflammatory disorders.

[On the inflammatory origins of AMD]. / Sur les origines inflammatoires de la DMLA.

Age-related macular degeneration (AMD) is a complex, highly heritable, multifactorial disease caused by the interplay of age and genetic and environmental risk factors. No treatment has yet been found to treat the slowly progressing atrophic form of AMD. All forms of AMD are invariably associated with an accumulation of mononuclear phagocytes (MP) in the subretinal space, a family of cells that include inflammatory and resident macrophages. We here present an overview of the inflammatory process occurring in AMD and discuss the origin of MPs and the consequences of their accumulation in the subretinal space. Finally, we will review the role played by the established risk factors for AMD to promote the switch from beneficial inflammation in early stage to a deleterious inflammation in the advanced stage of the disease.

TITLE: Sur les origines inflammatoires de la DMLA. ABSTRACT: La dégénérescence maculaire liée à l'âge (DMLA) est une maladie multifactorielle hautement héréditaire qui survient chez le sujet âgé et est causée par une combinaison de facteurs de risques génétiques et environnementaux. Les formes atrophiques de la maladie constituent aujourd'hui une impasse thérapeutique. La physiopathologie de la DMLA est invariablement associée à une accumulation dans l'espace sous-rétinien, de phagocytes mononucléés (PM), une famille de cellules qui inclue des macrophages résidents et inflammatoires. Nous aborderons dans cette revue l'ensemble des mécanismes de cette inflammation spécifique, de l'origine des PM aux conséquences de leur accumulation dans l'espace sous-rétinien. Finalement, nous discuterons de l'impact des facteurs de risques génétiques et environnementaux établis de la DMLA sur le passage d'une inflammation bénéfique aux stades précoces de la maladie à une inflammation délétère aux stades avancés.

Flavonoid and cannabinoid impact on the ocular surface.

PURPOSE OF REVIEW: To evaluate the impact of flavonoids and cannabinoids as anti-inflammatory and antiallergic treatments on the anterior surface of the eye. RECENT FINDINGS: Allergic conjunctivitis and dry eye syndrome are common ocular surface diseases that have been treated with traditional pharmacological measures, e.g. corticosteroids, antihistamines. Given the side-effect profiles of these medications and the growing interest in complementary treatment modalities as part of integrative medical interventions, well known flavonoids, such as quercetin and catechin, are under investigation for topical and systemic application methods for relief. As flavonoid derivatives, pycnogenol and epigallocatechin gallate have alleviated dry eye symptoms, including lacrimal gland inflammation, tear secretion, and the stability of the tear film. Research on ocular cannabinoid receptors and response to synthetic cannabinoids are also being considered for therapy of anterior ocular disorders. The expansion of herbal formulations provides a framework for future treatment regimens for ocular surface disorders. SUMMARY: Flavonoids and cannabinoids show promise as potential complementary treatment for allergic diseases because of their anti-inflammatory and antiallergic properties. Several studies implementing ocular and systemic application of these compounds show potential in becoming adjuvant treatment strategies for improving quality of life while also managing ocular surface disease processes.

Ophthalmic manifestations and management of common and rare autoimmune syndromes.

PURPOSE OF REVIEW: This article reviews the ocular findings in patients with a myriad of autoimmune syndromes. This review will provide guidance and heighten awareness for the allergist or eye care provider to pay heed to the manifestations and treatments of autoimmune syndromes. RECENT FINDINGS: Autoimmune syndromes can present with varied manifestations on the ocular surface known to potentially cause significant visual morbidity. In particular, sterile corneal ulcers are the most devastating and common finding in uncontrolled autoimmune disease. Ophthalmic manifestations of autoimmune syndromes have been reported individually; however, herein we present a comprehensive review of typical and atypical syndromes that may present with sterile corneal ulceration. SUMMARY: Autoimmune inflammatory syndromes are known to be associated with ocular surface inflammatory processes ranging from bothersome dry eye syndromes to vision-threatening sterile corneal ulceration. It is important to pay heed to the clinical presentation of common and uncommon presentations of the syndromes in the eye. We propose best practice for management of ocular surface disease in these clinical entities.

Allergic conjunctivitis in children: current understanding and future perspectives.

PURPOSE OF REVIEW: The rising global burden of allergic diseases, particularly in the pediatric population, is of serious concern. Ocular allergy is one of the most common ocular pathologies met in clinical practice. A large proportion of children and adolescents suffer from allergic eye diseases (AEDs), which affect their quality of life. The available treatments and surgical modalities have their limitations and side effects. Therefore, the development of novel and alternate strategies is the need of the hour and requires a timely review of currently available knowledge. RECENT FINDINGS: The current review covers the incidence and prevalence of AEDs, factors influencing occurrence and severity of AED (age, sex, socioeconomic status etc.), underlying mechanisms, role of allergy testing and immunotherapy in children, development of diagnostic markers and novel therapies including cells and molecules. SUMMARY: Understanding the demographics, clinical patterns and risk factors of AED can help formulate appropriate preventive and therapeutic strategies for the effective management of this common cause of ocular morbidity. The future therapeutics for AED seems to rely primarily on cells (mesenchymal stem cells, Tregs, mast cells), cell products, molecules with immunosuppressive potential and immunotherapy.

Contribution of inflammasome complex in inflammatory-related eye disorders and its implications for anti-inflammasome therapy.

Inflammasome complex is regarded as a major molecular regulator that exerts a significant function in caspase-1 activation and consequently, the development of cytokines like interleukin-1ß (IL-1ß) and interleukin-18 (IL-18). The secretion of these cytokines may induce inflammation. The role of inflammasomes in the pathologic process of eye-related illnesses like glaucoma, age-related macular degeneration (AMD), and diabetic retinopathy has been well studied over the past decade. However, the detailed pathogenic mechanism of inflammasomes in these retinal diseases is still unknown. Therefore, further investigation and understanding various aspects of inflammasome complexes as well as their pivotal roles in the immunopathology of human ocular illnesses are essential. The present review aims to describe the significant involvement of inflammasomes in the immunopathology of important inflammatory retinal illnesses, including glaucoma, age-related macular degeneration (AMD), and diabetic retinopathy focusing on anti-inflammasome therapy as a promising approach in the treatment of inflammation-related eye diseases.