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Pathology of trachoma

Histopathology and cytokines.

The following table summarizes differences in the histology of acute (active) trachoma and chronic scarring disease. The table has been prepared from the results of Guzey et al., 1999; 2000.

In active trachoma, the inflammatory infiltrate is organized as lymphoid follicles in the underlying stroma and cytoplasmic inclusion bodies can be seen in the conjunctival epithelia. In follicular trachoma (grade TF) there is a strong local IgA antibody response to the infecting chlamydiae and this is associated with elevated levels of antibody secreting cells with specificity for chlamydial antigens in the blood. However in the most severe cases with intense inflammation (grade TI) there is a substantial suppression of chlamydia-specific antibody secreting cells for all isotypes, including IgA. It has been suggested that this suppression may be a contributory factor leading to local tissue damage with ensuing scarring [Ghaem-Maghami et al., 1998]. This interesting observation warrants confirmation in other settings. 

In scarring trachoma there are  more marked pathological changes in the tissue of the eye lid. These include: subepithelial fibrous membrane formation, squamous cell metaplasia, loss of goblet cells, pseudogland formation in the conjunctiva, degeneration of the orbicularis oculi muscle fibres, sub-epithelial vascular dilatation and lymphocytic infiltration and localized peri-vascular amyloidosis. Accessory lachrymal glands and the ducts of glands were compromised by sub-epithelial infiltration and scarring. Contraction of the sub-epithelial fibrous tissue formed by collagen fibres and anterior surface drying are considered some of the main factors contributing to the chronic scarring and distortion of the eyelid [Guzey, et al., 1999, 2000].

The formation and remodelling of collagen fibers in trachomatous scarring suggests the likely involvement of matrix metalloproteases. In biopsies from normal conjunctiva, low levels of the metalloprotease gelatinase B were found in polymorphonuclear leukocytes only. In vernal keratoconjunctivitis and in trachomatous scarring, the matrix metalloprotease gelatinase B was additionally found in CD68+ cells of monocyte / macrophage lineage. Furthermore gelatinase B activity in the trachoma specimens, measured by zymography, was significantly greater than in vernal conjunctivitis, being particularly associated with activated macrophages with giant cell morphology. It seems likely that gelatinase B, and probably other matrix metalloproteases, play a significant role in the scarring and entropion associated with severe, blinding trachoma [el-Asrar et al., 2000].

Many of these changes are likely to be driven by inflammatory cytokines produced by the chronic inflammatory response to chlamydial antigens. Trachoma specimens show a greater number of inflammatory cells than control specimens but inflammatory cytokine expression was absent in the normal conjunctiva. In contrast, cytoplasmic IL-1 alpha and IL-1 beta expression was noted in the conjunctival epithelium in all trachoma specimens. Additionally, IL-1 alpha, IL-1 beta, TNF-alpha and PDGF were detected in macrophages infiltrating the substantia propria of the conjunctiva. B lymphocytes predominated over T lymphocytes in six trachoma biopsies, with fibrosis confined to the deep substantia propria, whereas T lymphocytes predominated over B lymphocytes in three other biopsies with more extensive fibrosis. In all trachoma biopsies helper/inducer T lymphocytes outnumbered suppressor/cytotoxic T lymphocytes. This lead to the suggestion that the upregulated local production of IL-1 alpha, IL-1 beta, TNF-alpha and PDGF might contribute to conjunctival damage and scarring in trachoma [el-Asrar et al., 1998].

A different study looked at conjunctival cytokine mRNA transcripts by RT-PCR in 50 individuals from a trachoma-endemic area. Again, there was a significant association of elevated IL-1beta, transforming growth factor beta1, and tumor necrosis factor alpha transcripts with infection, follicular inflammation, and ocular scarring. Although the t-helper-1 cellular immune response and its effector interferon-gamma have been found to have a protective role in the adaptive immune response to chlamydial infection in mice, there was no evidence that it played a protective role in trachoma. Thus, high IFN-gamma transcript levels were associated with follicles and inflammatory disease and, to a lesser extent, inflammatory scarring.  IFN-gamma transcripts were frequently present in both chlamydial infection and in disease. Transcripts of  IL-12 (p40), the cytokine which promotes the t-helper-1 cellular immune response were elevated in adults and children with follicular inflammation but not with scarring. Transcripts of IL-4, IL-5, and IL-10, which help promote t-helper-2 cellular immune responses, were not detected. 

It would appear that ocular C. trachomatis infection stimulates local cytokines which favor a strong cell-mediated and proinflammatory response in both the acute active and chronic forms of trachoma. In the presence of disease but in the absence of infection,  cytokine transcript levels were generally lower [Bobo et al., 1996]. Thus cytokines, including IFN-gamma, are produced in response to infection but appear to be often unable to clear the infection.

[MEW] March 2002

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References

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.  

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. Full Article. 

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.

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). 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.

Guzey, M., Basar, E., Ermis, S. S., Bitiren, M., Ozardali, I. & Mirzatas, C (1999). Pretarsal and marginal orbicularis oculi muscle fiber changes in trachomatous cicatricial entropion: histopathological evaluation. European Journal of Ophthalmology 9, 89 - 92.

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