2020–2021 BCSC Basic and Clinical Science Course™

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9 Uveitis and Ocular Inflammation

Chapter 1: Basic Concepts in Immunology: Effector Cells and the Innate Immune Response

Triggers of Innate Immunity

Innate immune responses generally use direct triggering mechanisms. Four of the most important are reviewed below and include

bacteria-derived molecules

interactions between nonimmune ocular parenchymal cells and toxins or trauma

recruitment and activation of neutrophils through the activation of vascular endothelial cells

innate mechanisms for the recruitment and activation of macrophages

Table 1-1 summarizes the effector responses of the ocular innate immune system.

Table 1-1 Innate Immune Response in the Eye

Bacteria-Derived Molecules That Trigger Innate Immunity

Bacterial lipopolysaccharide

Bacterial lipopolysaccharide (LPS), also known as endotoxin, is an intrinsic component of the cell walls of most gram-negative bacteria. Among the most important triggering molecules of innate immunity, LPS consists of 3 components:

lipid A

O polysaccharide

core oligosaccharide

The exact structures of each component vary among species of bacteria, but all are recognized by the innate immune system. The primary receptors are the toll-like receptors (TLRs), principally TLR4 and TLR2, which are expressed on macrophages, neutrophils, and dendritic cells, as well as on B cells and T cells. Lipid A is the most potent component, capable of activating effector cells at concentrations of a few picograms per milliliter.

The effects of LPS include activation of monocytes and neutrophils, leading to upregulation of genes for various cytokines (IL-1, IL-6, tumor necrosis factor [TNF]); degranulation; alternative pathway complement activation; and direct impact on the vascular endothelium. LPS is the major cause of shock, fever, and other pathophysiologic responses to bacterial sepsis, making it an important cause of morbidity and mortality during gram-negative bacterial infections. Interestingly, footpad injection of LPS in rodents results in an acute anterior uveitis. This animal model is called endotoxin-induced uveitis (EIU; see Chapter 4). See Clinical Examples 1-1 and 1-2.

Other bacterial cell wall components

The bacterial cell wall and membrane are complex. They contain numerous polysaccharide, lipid, and protein structures that can initiate an innate immune response independent of adaptive immunity. Killed lysates of many types of gram-positive bacteria or mycobacteria can directly activate macrophages, making them useful as adjuvants. Some of these components have been implicated in various models for arthritis and uveitis. In many cases, the molecular mechanisms might be similar to those of LPS.

CLINICAL EXAMPLE 1-1

Lipopolysaccharide-induced uveitis Humans are intermittently exposed to low levels of LPS that the gut releases, especially during episodes of diarrhea and dysentery. Exposure to LPS may play a role in dysentery-related uveitis, arthritis, and reactive arthritis. Systemic administration of a low dose of LPS in rabbits, rats, and mice produces a mild acute uveitis. This effect occurs at doses of LPS lower than those that cause apparent systemic shock. In rabbits, a breakdown of the blood–ocular barrier occurs because of loosening of the tight junctions between the nonpigmented ciliary epithelial cells, which allows leakage of plasma proteins through uveal vessels. Rats and mice exhibit an acute neutrophilic and monocytic infiltrate in the iris and ciliary body within 24 hours.

The precise mechanism of the LPS-induced ocular effects after systemic administration is unknown. One possibility is that LPS circulates and binds to the vascular endothelium or other sites within the anterior uvea. Alternatively, LPS might cause activation of uveal macrophages or circulating leukocytes, leading them to preferentially adhere to the anterior uveal vascular endothelium. Toll-like receptor 2 (TLR2) recognizes LPS, and binding of LPS by TLR2 on macrophages results in macrophage activation and secretion of a wide array of inflammatory cytokines. Degranulation of platelets is among the first histologic changes in LPS uveitis; likely mediators are eicosanoids, platelet-activating factors, and vasoactive amines. The subsequent intraocular generation of several mediators, especially leukotriene B4, thromboxane B2, prostaglandin E2, and IL-6 correlates with the development of the cellular infiltrate and vascular leakage.

Not surprisingly, direct injection of LPS into various ocular sites can initiate a severe localized inflammatory response. For example, intravitreal injection of LPS triggers a dose-dependent neutrophilic and monocytic infiltration of the uveal tract, retina, and vitreous. Injection of LPS into the central cornea results in the development of a ring infiltrate comprised of neutrophils that migrated circumferentially from the limbus.

CLINICAL EXAMPLE 1-2

Role of bacterial toxin production in the severity of endophthalmitis As described in Clinical Example 1-1, intraocular injection of LPS is highly inflammatory and accounts for much of the enhanced pathogenicity of gram-negative infections of the eye. Using clinical isolates or bacteria genetically altered to diminish production of the various types of bacterial toxins, investigators have demonstrated that toxin elaboration in gram-positive or gram-negative endophthalmitis greatly influences inflammatory cell infiltration and retinal cytotoxicity. This effect suggests that sterilization through antibiotic therapy alone, in the absence of antitoxin therapy, may not prevent activation of innate immunity, ocular inflammation, and vision loss in eyes infected by toxin-producing strains.

Booth MC, Atkuri RV, Gilmore MS. Toxin production contributes to severity of Staphylococcus aureus endophthalmitis. In: Nussenblatt RB, Whitcup SM, Caspi RR, Gery I, eds. Advances in Ocular Immunology: Proceedings of the 6th International Symposium on the Immunology and Immunopathology of the Eye. New York, NY: Elsevier; 1994:269–272.

Jett BD, Parke DW 2nd, Booth MC, Gilmore MS. Host/parasite interactions in bacterial endophthalmitis. Zentralbl Bakteriol. 1997;285(3):341–367.

Exotoxins and other secretory products of bacteria

Certain bacteria secrete products known as exotoxins into their surrounding microenvironment. Many of these products are enzymes that, although not directly inflammatory, can cause tissue damage and subsequent inflammation and tissue destruction. Examples of these products include

collagenases

hemolysins such as streptolysin O, which can kill neutrophils by causing cytoplasmic and extracellular release of their granules

phospholipases such as the Clostridium perfringens α-toxins, which kill cells and cause necrosis by disrupting cell membranes

An intravitreal injection of a purified hemolysin BL toxin derived from Bacillus cereus can cause direct necrosis of retinal cells and retinal detachment. In animal studies, as few as 100 B cereus can produce enough toxin to cause complete loss of retinal function in 12 hours. In addition to being directly toxic, bacterial exotoxins can also be strong triggers of an innate immune response.

Callegan MC, Jett BD, Hancock LE, Gilmore MS. Role of hemolysin BL in the pathogenesis of extraintestinal Bacillus cereus infection assessed in an endophthalmitis model. Infect Immun. 1999;67(7):3357–3366.

Murphy K, Travers P, Walport M. Janeway’s Immunobiology. 8th ed. London: Garland Science; 2012.

Excerpted from BCSC 2020-2021 series: Section 9 - Uveitis and Ocular Inflammation. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.

2020–2021 BCSC Basic and Clinical Science Course™

9 Uveitis and Ocular Inflammation

Chapter 1: Basic Concepts in Immunology: Effector Cells and the Innate Immune Response

Triggers of Innate Immunity

Table 1-1 Innate Immune Response in the Eye

Bacteria-Derived Molecules That Trigger Innate Immunity

Bacterial lipopolysaccharide

Other bacterial cell wall components

CLINICAL EXAMPLE 1-1

CLINICAL EXAMPLE 1-2

Exotoxins and other secretory products of bacteria

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