基础知识：对于隐形眼镜与细菌性角膜炎关系的概述

1. Bacterial keratitis （细菌性角膜炎）

    - Cornea, 角膜 (the clear dome covering the colored part of the eye) 

    - Bioburden 或许会因为隐形眼镜的佩戴而增长。

    - 常见病理反应：microbial keratitis (MK) and corneal inflammatory events (CIEs)

    - the most common cause of infection (microbial keratitis; MK) remains the Gram-negative bacterium Pseudomonas aeruginosa (绿脓杆菌，又称铜绿假单胞菌，广泛分布于自然界及正常人皮肤、肠道和呼吸道，革兰氏阴性菌、好氧、呈长棒形的细菌，只有单向的运动性。)

        -  it has extracellular virulence factors that it can use to initiate and maintain infection

2. Contact lenses (silicone hydrogel)

    - Immune cells cannot interact with silicone directly

        - But can interact with antigens on these lenses. These antigens could be due to tear film deposits, microbial contamination, or components of care systems used with these lenses.

    - Inflammatory reactions associated with silicone hydrogel contact lens wear are not caused by an allergic reaction to silicone alone.

    - illness caused by microbial colonization of contact lenses:

        - contact lens-induced acute red eye (CLARE)

        - contact lens-induced peripheral ulceration

        - infiltrative keratitis (IK)

        - asymptomatic infiltrative keratitis (AIK)

    - P. aeruginosa is a major causative agent of MK, CLARE, CPU and AIK

3.为什么MK会对角膜产生损伤

    - 绿脓杆菌产生 proteases （蛋白质酶）, to either invade or kill corneal cells

    - 绿脓杆菌 coordinate expression of virulence factors via quorum-sensing （群体感应, population density biosensor mechanisms）

        - quorum, i.e., a certain density of bacteria

    - excessive activation of the host defense system 人体的免疫反应

        P. aeruginosa can activate several pathways of the immune system during MK,  often involves receptors on the corneal epithelial cells called toll-like receptors (TLRs).

    - These TLRs （参与非特异性免疫（天然免疫）的一类重要蛋白质分子，也是连接非特异性免疫和特异性免疫的桥梁。TLR是单个的跨膜非催化性蛋白质，可以识别来源于微生物的具有保守结构的分子。当微生物突破机体的物理屏障，如皮肤、粘膜等时，TLR可以识别它们并激活机体产生免疫细胞应答。）can recognize lipopolysaccharide 脂多糖 or flagella 鞭毛 from P. aeruginosa and activate the corneal epithelial cells to produce inflammatory mediators like cytokines 细胞因子and chemokines （趋化因子，细胞因子的一种， leukocyte recruitment）

    - They recruit white blood cells, predominantly polymorphonuclear leukocytes （中性，嗜酸性，嗜碱性粒细胞）, in order to phagocytose 吞噬 and kill the P. aeruginosa. 

    - However, continued recruitment and presence of polymorphonuclear neutrophils (PMNs) and other white blood cells in the corneal tissue lead to the destruction of corneal cells and tissue components. 

    - This can ultimately lead to scarring and vision loss.

4. Virulence factors

    - exoenzymes S (gene called exoS), U (exoU)

        - P. aeruginosa strains can usually be distinguished by the presence of either genes to exoS or exoU, which encode the toxins exoenzyme S and exotoxin U respectively.

            - ExoS protein is both a GTPase-activating protein and an ADP-ribosyltransferase and both these activities lead to rearrangement of the cytoskeleton protein actin and ultimately cell death.

            - ExoU is an intracellular phospholipase and causes rapid cell death.

    - elastase (lasB), alkaline protease (aprA), protease IV (prpL)

        - Elastase (LasB) breaks down elastin, fibrin, and collagen, which are critical for the mechanical properties of connective tissue. It has also shown to degrade host immunological factors IgG, IgA, IFNγ, TNFα.

        -  Alkaline protease is known to degrade fibrin, complement molecules C1q, and C3, and in conjunction with LasB, cytokines IFNγ, TNFα.

        - Protease IV degrades important host immunological proteins such as complement and IgG, compromises the integrity of structural proteins such as elastin, causing tissue damage and facilitating bacterial infection.

            - Protease IV degrades the iron binding proteins lactoferrin and transferrin which enables P. aeruginosa to scavenge iron from the host

            - Protease IV has been shown to be a key virulence factor for P. aeruginosa in ocular infections

关于免疫反应引发的详细过程

1. Corneal infection with P. aeruginosais 

    - extensive recruitment of inflammatory cells with PMNs being the most predominant cell type seen in the cornea.

        - PMNs are believed to be essential for the elimination of bacteria and to promote wound healing; however, the persistence of these cells may contribute to corneal damage.

2. The first step of the reaction

    - The initial inflammatory cascade is most likely mediated by the innate immune system, i.e., not dependent on antibody production.

    - The adaptive antibody-associated immune system probably plays a smaller role in the initial inflammatory response during keratitis, but is likely to increase in importance as the infection develops.

3. The second step of the reaction

    -  During the course of the inflammatory response, migrating and resident white blood cells, including polymorphonuclear leukocytes, macrophages, dentritic cells, and T cells, are the major mediators of the inflammatory response

    - the activation of TLRs of dendritic cells is a major influence on the progression from an innate to adaptive immune response.

        - This interaction occurs between pattern-recognition receptors (such as TLRs) on host cells and pathogen-associated molecular patterns (PAMPs) of microorganisms.

    - Apart from the chemokines directly associated with recruitment of PMNs, several other cytokines or chemokines have been shown to play major roles in the inflammatory response associated with Pseudomonas aeruginosa keratitis, and these include IL-1β, IL-6,IL-10, IL-18 and interferon (IFN)γ.

        - IL-1β may be the master mediator of the inflammatory response; after its appearance other mediators are generated.

            - IL-1β appears early in the infection. Blocking IL-1β reduces corneal inflammation during keratitis.

        - IL-6 may be involved in down-regulating corneal inflammation and the resolution of disease.

    - IL-1β and IL-6 are initially produced by the corneal epithelial cells

        * A peripheral blood mononuclear cell (PBMC) is any peripheral blood cell having a round nucleus. These cells consist of lymphocytes (T cells, B cells, NK cells) and monocytes, whereas erythrocytes and platelets have no nuclei, and granulocytes (neutrophils, basophils, and eosinophils) have multi-lobed nuclei.

4. 关于Th1和Th2的作用

    - the Th1 response is associated with susceptibility of the cornea to perforation following infection with P. aeruginosa, whereas the Th2 response is associated with resistance to perforation. Th1 cells produce IFN-γ, whereas Th2 cells produce IL-4, IL-5 and IL-13, among numerous other cytokines.

    - The Th1 response seems to assist in the continued recruitment of PMNs to the cornea, and it is these PMNs that mediate perforation.