Ocular pathogens establish long-term infections by direct infection of the eye or indirectly following dissemination of infection from elsewhere in the host. These pathogens survive or evade the host immune response, damage the eye and affect sight.
Herpes simplex virus type 1 (HSV-1) is associated with a range of eye diseases known as herpes simplex virus ophthalmia (HSVO). It causes conjunctivitis and lesions in the skin surrounding the eye, and ophthalmologists commonly describe this as primary HSVO. It also causes corneal ulceration, vascularization of the cornea, uveitis and glaucoma, and consequent loss of vision. Ophthalmologists describe this as recurrent HSVO. Studies of patients with HSVO
have shown that the terms primary and recurrent are inaccurate and misleading. It has therefore been proposed that HSVO should be described by its clinical features.
A life-long infection is established by HSV-1 in the sensory ganglia where it remains isolated from the host immune system. Occasional forays along nerves to the eye produce active HSVO, and HSV-1 can be isolated from the eyes for about a week. This suggests that host defense mechanisms terminate the active phase. Active corneal disease can however last for months; HSV-1 can survive for long periods in the cornea and has been isolated from corneas during quiescence. Patients with HSVO develop humoral and cellular immune responses to HSV.
Experimental infections in animals have shown that different clinical forms of HSVO result from differences in genetic factors of host animals and also differences between strains of HSV-1. The ability of HSV-1 to cause severe corneal disease, to establish latent infection in the eye and to multiply in isolated trigeminal ganglia infected in vitro differs in different strains of mice. Susceptibility to corneal disease is determined by alleles of the immunoglobulin heavy-chain locus. Paradoxically, the major functional immunological difference is that susceptible mice have a much higher proportion of T helper lymphocytes in the corneal periphery than resistant mice. Different strains of HSV-1 produce different forms of HSVO. Strains isolated from patients with conjunctivitis caused conjunctivitis and strains from patients with corneal disease caused corneal disease. Strains isolated from patients with chronic stromal disease produced larger amounts of soluble precursor glycoprotein D than strains isolated from patients with other forms of HSVO.
Studies in rabbits and mice showed that previous ocular or dermal infection, immunization with inactivated virus, subunit vaccines and human hyperimmune gamma globulin all conferred a degree of protective immunity against subsequent ocular infection. Immunization of mice with HSV glycoprotein D prevented the development of stromal keratitis and corneal vascularization, and spread of infection to the trigeminal ganglia and the central nervous system. These protective effects were associated with raised levels of neutralizing antibodies and complement-dependent cytolysis.
Chlamydia trachomatis is an obligate intracellular bacterium which infects mucosal epithelia. Serovars A, B, Ba and C cause trachoma, an important cause of preventable blindness in developing countries. Infection is transmitted directly from eye to eye. In contrast, serovars D to K are a common cause of genital infection in developed countries and occasionally infect eyes, but they do not cause trachoma.
Patients with trachoma have immune responses to the agent. Tears and blood contain antibodies which reduce the infectivity of C. trachomatis. Skin-testing for cell-mediated responses produced negative results in children with trachoma in The Gambia, but adults with severe trachoma in South Africa had positive reactions. Immunohistochemical studies of conjunctival biopsies obtained from patients with trachoma show that the inflammatory cell infiltrate contains B and T lymphocytes and that epithelial cells have MHC class II antigens (HI.A-DR) as well as class I on their surfaces.
When strains of C. trachomatis isolated from patients with trachoma were inoculated into the eyes of blind human volunteers and nonhuman primates, they did not produce trachoma. They produced disease resembling that found in developed countries. Studies in animals (subhuman primates infected with C. trachomatis; guinea pigs infected with guinea pig inclusion conjunctivitis agent, a strain of C. psittaci) showed that antibodies and cell-mediated responses developed during infection and terminated infection. Features of trachoma, i.e. chronic conjunctivitis, corneal vascularization, scarring of the palpebral conjunctivae and subsequent distortion of the eye-lids developed after repeated episodes of infection. In guinea pigs, repeated ocular infection produced partial microbiological immunity which comprised two components. The short-term local component increased the amount of agent required to initiate reinfection and was probably mediated by secretory IgA in the eye. The long-term systemic component limited the growth of the agent following reinfection and was probably mediated by T lymphocytes. It paralleled the delayed-type hypersensitivity skin reaction to the agent, was associated with tissue damage and was suppressed by cyclosporine.
Staphylococcus aureus causes acute and chronic conjunctivitis, corneal ulcers and blepharitis. Patients with staphylococcal eye diseases were skin-tested with staphylococcal antigens to see if hypersensitivity reactions played a role in the disease process. Patients with corneal disease were more likely to have enhanced delayed-type skin responses to killed whole cells of S. aureus and S. epidermidis than those with blepharitis. Experimental infections in rabbits have demonstrated that immune responses contribute to pathology. Ocular infection only produced corneal disease and blepharitis when it was preceded by immunization with staphylococcal antigens.
Mycobacterium leprae causes leprosy, which is common in many developing countries. It is divided into four clinical forms. Patients with lepromatous leprosy have disseminated infection associated with poor cellular immune responses. They often develop major ocular complications and blindness. The mechanisms which protect the front surface of the eye are compromised because of damage to the facial and trigeminal nerves caused by M. leprae. This leads to lid abnormalities and abolition of the blink and corneal reflexes, which render the eye more susceptible to secondary infection. The iris is damaged by acute and chronic iritis. Acute iritis is part of .1 generalized reaction, known as the 'lepra' reaction, which is caused by the deposition of immune com plexes in the iris. Acute iritis is similar to other forms of acute nonleprous iritis, and can lead to glaucoma and cataract. Chronic iritis is caused by M. leprae growing in the iris, causing iris atrophy. This is the commonest cause of visual impairment.
Onchocerciasis or river blindness is caused by the filarial nematode Onchocerca volvulus, which is transmitted by several species of blackflies of the genus Similium. Infected blackflies transmit larvae to humans by biting them. Larvae migrate to subcutaneous tissues where they become mature adults. Gravid females produce large numbers of microfilariae which migrate throughout the body. Over a period of many years, microfilariae migrate into the ocular tissues and die, causing small inflammatory lesions which leave scars. The accumulation of small scars in the cornea and the retina cause blindness. Live microfilariae are difficult to sec in the cornea because they do not stimulate an inflammatory response. In contrast, dead microfilariae evoke punctate keratitis; small lesions which consist of dead microfilariae surrounded by lymphocytes, eosinophils and local edema.
Drugs which kill microfilariae cause a marked inflammatory response known as the 'Mazotti reaction' and concurrent treatment with anti-inflammatory drugs is required to reduce the severity of this reaction. The drugs suramin and diethylcarbamizine cause severe reactions, increasing corneal and retinal lesions and damaging the optic nerve, causing blindness. Ivermectin is currently being tested on patients and it has significant advantages over the other two drugs. In clinical trials, the number of microfilariae in the anterior chamber of the eye was reduced.
patients had the same or improved visual acuity and the Mazotti reaction was less marked. Ivermectin does not enter the eye, so that ocular tissues are spared the damaging and potentially blinding reaction to dead microfilariae.
See also: Adenovirus, infection and immunity; Chlamydia, infection and immunity; Eye, autoimmune disease; Herpes simplex virus, infection and immunity; Mycobacteria, infection and immunity; Onchocerciasis; Paramyxoviruses, infection and immunity; Picornavirus, infection and immunity; Staphylococcus, infection and immunity.
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