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Ocular immune system

Ocular immune system protects the eye from infection and regulates healing processes following injuries. The interior of the eye lacks lymph vessels but is highly vascularized, and many immune cells reside in the uvea, including mostly macrophages, dendritic cells, and mast cells.

Innate Immunity at the Ocular Surface Function of the Innate Immune System
Innate immunity aims at the detection and destruction of microbial pathogens. To do so effectively, it relies on a limited number of conserved and genetically determined receptors that work alone or in combination with innate effector cells, mainly phagocytes. Pattern recognition receptors are able to bind to pathogen-associated molecular patterns on microbes such as lipopolysaccharides, flagellin, and CpG-DNA etc. and initiate respective immune responses. Innate immune responses defend against pathogens and toxin in a non-discriminatory manner. They provide an inherent barrier against corneal infection while also serving as a primary mode of defense that is present from birth. For instance, the orbit and the eyelid can guard against both traumatic events [4] and exterior debris that may contain microorganisms. Other components of the ocular innate immune system include tears, epithelial cells, keratocytes, corneal nerves, the complement system, and interferons

Toll-Like Receptors;
-Different Toll-like receptors (TLR) are present in the mouse eye and induce the secretion of CXC chemokines which leads to neutrophil recruitment, a possible mechanism of corneal pathology in early stages of microbial infection. -Following bacterial exposure, TLR induces inflammation on human corneal cells. Then, cells of the ocular surface secrete inflammatory cytokines (IL-6 and IL-8). Other results may point into a different direction because it was found that although TLR2, TLR3 and TLR4 occur in human corneal epithelial cells, they do not induce inflammatory immune responses to lipopolysaccharides as a potential mechanism to prevent constant ocular surface inflammation.

1-Mucosal Immune Defense Mechanisms at the Ocular Surface:


-The anatomy and leukocyte cell types clearly show that a mucosal immune system is maintained at the normal human ocular surface and mucosal adnexa. -It is termed eye-associated lymphoid tissue (EALT) and is integrated into the mucosal immune system of the body. -It has certain specializations suggesting immune privilege. Mucosal, like systemic, immunity uses two approaches for defense, the innate and the adaptive immune system. These have almost opposing characteristics . -The lacrimal glands and the conjunctiva contribute to ocular defenses via secretion of both immunoglobulins and lymphoid tissues. The latter is understood to be organized into clumps of lymphoid follicles as well as diffuse lymphoid tissues. In the follicular form of MALT, antigens are taken up by the follicles and presented to lymphocytes by antigen presenting cells. This leads to activation of B and T cells that carry out the immune reaction.

The eye-associated lymphoid tissue (EALT) is the mucosa-associated lymphoid tissue for immune protection of the ocular surface and its mucosal adnexa. It is anatomically continuous from the lacrimal gland throughout the conjunctiva- and lacrimal drainage-associated lymphoid tissue (i.e. CALT and LDALT, respectively). It consists of a diffuse lymphoid tissue of T lymphocytes and IgA-secreting plasma cells, including accessory leukocyte populations in all organs and of lymphoid follicles in conjunctiva- and lacrimal drainage-associated lymphoid tissue . Protective as well as aggressive factors inside the tear film, which connects the different parts of the ocular surface and protects it from the external environment, are a major component of ocular surface immunity.

2-Corneal immune response: a-Corneal epithelial cells


Corneal epithelial cells present a physical barrier to prevent microbes from reaching the interior of the eye chamber. At the same time, corneal epithelial cells also secrete cytokines to activate microbial defense. One cytokine, interleukin (IL)-1, is stored in epithelial cells and automatically released when the cell membrane is ruptured by infection or trauma. However, long-term effects of IL-1 can lead to not only enhanced immune inflitration of the cornea, but also neovascularization (formation of new blood vessels), which can lead to a loss of corneal transparency.

b-Corneal keratocytes
Keratocytes are flattened cells found dispersed within the corneal stroma. The primary role of this sparse population of cells is thought to be in maintaining the extracellular matrix of collagen lamellae that surround them. However, keratocytes also play a defensive role during pathogenic invasion. They can be influenced by IL-1 (secreted by corneal epithelial cells) and tumor necrosis factor (TNF)- to produce both IL-6 and defensins. Of these, the former is found to combine synergistically with other interleukins to increase co-stimulation of other immune aspects as well as increase antibody secretion. The latter, defensins, have a wide range of antimicrobial affects against bacteria, fungi, and viruses, as well as effects in accelerating healing of damaged epithelial cells.

c-Corneal nerves
Corneal nerves serve as a form of defense by detecting the presence of foreign bodies on the corneal surface. This leads to reflexive reactions such as increased lacrimal secretion, blinking, and release of neuropeptides, which can induce cytokine activation .

3-Innate Effector Cells at the Ocular Surface:


Phagocytes are important innate effector cells that contribute to defense during infection. Macrophages act almost exclusively by phagocytosis (e.g. in Acanthamoeba infection), but also perform antigen processing and presentation, which are necessary for the development of an acquired immune response. -In dendritic Langerhans cells, as antigen presentation dominates phagocytosis. Neutrophil granulocytes are more effective in pathogen elimination due to the secretion

of toxic mediators such as myeloperoxidase, which is able to kill pathogens such as Acanthamoeba cysts.

4-Secreted Antimicrobial Peptides


In addition to the established antimicrobial factors such as lysozyme and lactoferrin, a broad spectrum of antimicrobial peptides was recently observed in the normal human ocular surface. -Defensin-1 to -4 were found together with liver-expressed antimicrobial peptide-1 and -2. Collectins, observed in human and mouse tear fluid and corneal epithelia, are able to inhibit invasion by Pseudomonas aeruginosa . A broad spectrum of antimicrobial peptides, including different defensins, secretory phospholipase, bactericidal permeability-increasing protein, and 37-kDa cationic antimicrobial protein, was observed in human nasolacrimal ducts .

5-Conjunctival immune response


The conjunctiva covers the sclera of the eyes, as well as the insides of the eyelids and provides nutrients to underlying and surrounding tissue. The conjunctiva is also one of the closest vascularized tissues to the cornea. As such, it provides a major source of immune components in the cornea. Not only does the conjunctiva produce IgA, like the lacrimal glands, but it also contains macrophages, neutrophilic granulocytes, mast cells, lymphocytes, and other aspects of the general mucosal immune system . Like the rest of the MALT pathway, the conjunctiva has been found to possess lymphoid follicles, as well as diffuse lymphoid tissues.

6-Lacrimal immune response


The tear film is composed of three layers: the lipid, aqueous, and mucin . the liquid layer of the tear film contains antimicrobial properties resulting from the presence of lysozymes, lactoferrins, lipocalin, and beta-lysin, which facilitate pathogen defenses such as lysis of bacterial cell walls, prevention of bacterial and viral binding, inflammation, and detoxification. Furthermore, white blood cells can be transported to the corneal surface via the tear film, and both toxic agents as well as debris can be diluted and washed away by the tear film. The tear film also contains immunoglobulins, especially IgA, which is found in concentrations significantly higher than in serum. IgA has been shown to prevent bacterial binding. Along with another immunoglobulin present in the tear film, IgG, IgA can also neutralize viruses and bind to bacteria, aiding in their detection via other pathways.
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