Pathogenesis of trachoma
In a community with endemic or hyperendemic trachoma, individuals from early childhood are exposed to repeated ocular re-infection with C. trachomatis. There is evidence that this results in partial immunity as follows:
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Active trachoma (grades TF or TI) with shedding of viable chlamydiae from the conjunctiva is primarily a childhood disease. Adults with trachoma rarely shed significant amounts of viable chlamydiae from the eye, although a proportion of those with the scarring sequelae of the disease nevertheless carry chlamydial antigen or nucleic acid in the eye [Ward et al., 1990].
The duration of disease and infection in active trachoma decreases markedly during childhood. Thus in one study in The Gambia where individuals were monitored for trachoma and for ocular chlamydial infection bi-weekly over a six month period, it was found that the estimated median duration of disease was 13.2 weeks in 0-4-year-old subjects but only 1.7 weeks in those age 15 and over. More rapid disease resolution was found to be the main source of reduction in the prevalence of active trachoma and ocular C. trachomatis infection with age. Interestingly disease incidence reduced to a less marked extent [Bailey et al., 1999], suggesting that the key factor was increasing host immunity . In experimental animal models, repeated chlamydial infection also leads to more rapid disease resolution and there is good evidence that adaptive cell mediated immune responses, primarily those involving interferon gamma secreting T-helper 1 cells, are protective [see: Main.ArchiveImmunolindex].
The serious sequelae of trachoma result from conjunctival scarring [see: trachoma in pictures]. Although a severe primary childhood infection may result in conjunctival scarring, the evidence is that re-infection is the most important factor [see: role of repeatedInfection]. It is a paradox that increasing age, which brings increasing exposure to infection and increasing immunity, also increases the likelihood of severe sequelae . There are several considerations here:
There is little if any evidence that trachoma or genital tract strains of C. trachomatis vary significantly in their ability to cause severe disease
There is evidence that ocular chlamydial load is an important determinant of chronic severe disease in trachoma. In 6/10 families where siblings were infected, the duration of infection differed significantly between the siblings, suggesting that host variation played a significant role [Bobo et al., 1997]. Thus those individuals whose immune response is inappropriate for restricting chlamydial replication are most likely to develop severe disease.
Socio-economic factors are key determinants of severe trachoma [see: trachoma transmission] presumably because poverty and poor hygiene increase the likelihood of a high chlamydial load. In Tanzania, for example, familial cattle ownership, facial cleanliness and living less than two hours from a source of clean water were associated with reduced severity of trachoma [Hsieh et al., 2000]. However malnutrition [which is often accompanied by some degree of immunosuppression] does NOT appear to be a major determinant of severe trachoma, even though malnutrition and trachoma commonly occur together [Fine & West, 1997].
There is increasing evidence that host genetic factors affecting the cellular immune response to trachoma agents may be important in determining disease severity [see also: host genotypic factors]. In The Gambia, although there is some evidence that HLA-A*6802-restricted individuals suffer more severe disease, which would be expected to directly or indirectly involve CD8+ cytotoxic or interferon gamma secreting T cells, initial studies have not been able to demonstrate this [Mahdi et al., 2001]. In Oman, DNA typing of HLA class II DR beta genes [associated with antigen presentation to CD4+ T-helper cells of the cell mediated immune system] showed a significant increase in HLA DR16 (relative risk = 3.8) and a significant decrease in HLA DR53 (relative risk = 0.05) in individuals with severe trachoma. This is consistent with reports of an HLA DR2 association with leprosy and tuberculosis, diseases also caused by a [facultative] intracellular micro-organism. Similarly, resistance to leprosy is associated with HLA DR53 as observed here for blinding trachoma. It is postulated that HLA DR2 or subtypes in association with HLA DQ 1 may enable an intracellular micro-organism to enter the cell or are involved in presentation of peptides derived from intracellular micro-organisms to T lymphocytes, thereby initiating a damaging delayed hypersensitivity or anti-self cellular immune response [White et al., 1997]. Clear evidence of the importance of the cellular immune response and of the host genetic constitution came from a study of trachoma among leprosy patients living in a trachoma endemic area. C. trachomatis and Mycobacterium leprae share the common feature of being intracellular bacterial pathogens. Tuberculoid leprosy patients, characterized by vigorous but damaging cell mediated immunity to M. leprae had a greater conjunctival scarring due to trachoma than patients with lepromatous leprosy, which is characterized by a weak cell mediated immune response to M. leprae [Courtright et al., 1993]. Further investigation of the role of genotypic factors in different geographic settings are urgently needed.
Although severe scarring trachoma in adults is not associated with shedding of viable C. trachomatis, it does from several studies appear to be associated with the carriage of chlamydial antigen or nucleic acid [see for example: Ward, et al., 1990]. Chronic carriage of chlamydial antigen will induce an inflammatory cytokine response [see: role of cytokines] which, in turn, may increase the likelihood of persistent infection [see: clinical significance of persistent infection]. Some cytokines stimulate fibrosis leading to scarring [see: inflammation & repair].
Bailey, R., Duong, T., Carpenter, R., Whittle, H. & Mabey, D. (1999). The duration of human ocular Chlamydia trachomatis infection is age dependent. Epidemiology and Infection 123, 479 - 486.
Bailey, R. & Mabey, D. (1997). Comment: HLA and trachoma. British Journal of Ophthalmology 81, 425 - 426.
Bobo, L., Novak, N., Mkocha, H., Vitale, S., West, S. & Quinn, T. C. (1996). Evidence for a predominant proinflammatory conjunctival cytokine response in individuals with trachoma. Infection and Immunity 64, 3273 - 3279. Full Article.
Bobo, L. D., Novak, N., Munoz, B., Hsieh, Y. H., Quinn, T. C. & West S. (1997). Severe disease in children with trachoma is associated with persistent Chlamydia trachomatis infection. Journal of Infectious Diseases 176, 1524-1530.
Courtright, P., Lewallen, S. Howe, R. (1993). Cell-mediated immunity in trachomatous scarring. Evidence from a leprosy population. Ophthalmology 100, 98 - 104.
el-Asrar, A. M., Geboes, K., al-Kharashi, S. A., Al-Mosallam, A. A., Missotten, L., Paemen, L. & Opdenakker G. (2000). Expression of gelatinase B in trachomatous conjunctivitis. British Journal of Ophthalmology 84, 85-91.
el-Asrar, A. M., Geboes, K., Tabbara, K. F., al-Kharashi, S. A., Missotten, L. & Desmet, V. (1998). Immunopathogenesis of conjunctival scarring in trachoma. Eye. 12, 453 - 460.
Fine, D. & West, S. (1997). Absence of a relationship between malnutrition and trachoma in preschool children. Ophthalmic Epidemiology 4, 83 - 88.
Ghaem-Maghami, S., Bailey, R. L., Mabey, D. C., Hay, P. E., Mahdi, O. S., Joof, H. M., Whittle, H. C., Ward, M. E. & Lewis, D. J. (1997). [[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9393782&dopt=Abstract]]Characterization of B-cell responses to Chlamydia trachomatis antigens in humans with trachoma. Infection and Immunity 65, 4958 - 4964. Full article.
Guzey, M., Ozardali, I., Basar, E., Aslan, G., Satici, A. & Karadede S. (2000). A survey of trachoma: the histopathology and the mechanism of progressive cicatrization of eyelid tissues. Ophthalmologica 214, 277 - 284.
Hsieh, Y. H., Bobo, L. D., Quinn, T. O. & West, S. K. (2000). Risk factors for trachoma: 6-year follow-up of children aged 1 and 2 years. American Journal of Epidemiology 152, 204 -211.
Mahdi, O. S., Whittle, H. C., Joof, H., Mabey, D. C. & Bailey, R. L. (2001). Failure to detect HLA-A*6802-restricted CD8+ T cells specific for Chlamydia trachomatis antigens in subjects from trachoma-endemic communities. Clinical and Experimental Immunology 123, 68-72.
Mozzato-Chamay, N., Mahdi, O. S., Jallow, O., Mabey, D. C., Bailey R. L. & Conway DJ (2000). Polymorphisms in candidate genes and risk of scarring trachoma in a Chlamydia trachomatis - endemic population. Journal of Infectious Diseases 182, 1545 - 1548.
Peeling, R. W., Bailey, R. L., Conway D. J., Holland, M. J., Campbell, A. E., Jallow, O., Whittle, H. C. & Mabey DC (1998). Antibody response to the 60-kDa chlamydial heat-shock protein is associated with scarring trachoma. Journal of Infectious Diseases 177, 256 - 259.
White AG, Bogh J, Leheny W, Kuchipudi P, Varghese M, al Riyami H, al Hashmi S, Daar AS (1997). HLA antigens in Omanis with blinding trachoma: markers for disease susceptibility and resistance. British Journal of Ophthalmology 81, 431 - 434.
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