Pathogenesis of onchocercal keratitis (River blindness)

Abstract

Onchocerciasis is a major cause of blindness. Although the World Health Organization has been successful in reducing onchocerciasis as a public health problem in parts of West Africa, there remain an estimated 17 million people infected with Onchocerca volvulus, the parasite that causes this disease. Ocular pathology can be manifested in any part of the eye, although disease manifestations are frequently characterized as either posterior or anterior eye disease. This review focuses on onchocerca-mediated keratitis that results from an inflammatory response in the anterior portion of the eye and summarizes what is currently known about human disease. This review also describes studies with experimental models that have been established to determine the immunological mechanisms underlying interstitial keratitis. The pathogenesis of keratitis is thought to be due to the host inflammatory response to degenerating parasites in the eye; therefore, the primary clinical symptoms of onchocercal keratitis (corneal opacification and neovascularization) are induced after injection of soluble O. volvulus antigens into the corneal stroma. Experimental approaches have demonstrated an essential role for sensitized T helper cells and shown that cytokines can regulate the severity of keratitis by controlling recruitment of inflammatory cells into the cornea. Chemokines are also important in inflammatory cell recruitment to the cornea, and their role in onchocerciasis is being examined. Further understanding of the molecular basis of the development of onchocercal keratitis may lead to novel approaches to immunologically based intervention.

FIG. 1

River blindness in a 29-year-old man from Cote d’Ivoire. Note the corneal opacification in the right eye. This individual also had corneal neovascularization and severe conjunctivitis. (Photograph by Eric Pearlman.)

FIG. 2

Cytokine expression by peripheral blood mononuclear cells from O. volvulus-infected patients with (Dis+) or without (Dis−) ocular disease. Cells were stimulated with O. volvulus antigens, and cytokine expression was determined by reverse transcription-PCR in relation to the housekeeping gene HPRT. Note the elevated IL-4, IL-5, and IL-10 expression in Dis+ individuals. The horizontal lines denote geometric means. Reprinted from reference with permission of the publisher.

FIG. 3

Corneal opacification and neovascularization in a BALB/c mouse. Animals were immunized subcutaneously and challenged intrastromally with soluble O. volvulus antigens. No inflammatory response was induced in the absence of prior immunization. Reprinted from reference with permission of the publisher.

FIG. 4

IL-4 gene knockout (IL-4^−/−) mice, which have diminished keratitis compared with immunocompetent IL-4^−/− mice, continue to express other Th2-associated cytokines (IL-5, IL-10, and IL-13). The animals were immunized subcutaneously, injected intrastromally with O. volvulus antigens, and sacrificed at the indicted times postinjection. Corneas pooled from five mice per group were processed by reverse transcription-PCR with cytokine-specific primers and compared with the housekeeping gene HPRT. IL-5 and IFN-γ were also secreted in vitro by lymphoid cells from IL-4^−/− mice. Reprinted from reference with permission of the publisher.

FIG. 5

IL-4 regulates inflammatory cell recruitment to the cornea. (A) IL-4^+/+ mice, which develop severe keratitis, have extensive stromal edema and inflammatory cell infiltration, notably by eosinophils, 1 week after intrastromal injection. Note also the presence of blood vessels. (B) In contrast, corneas from similarly treated IL-4^−/− mice did not develop keratitis, had no stromal edema, and had minimal cellular infiltration. Sections were stained with hematoxylin and eosin. Magnification, ×400. Reprinted from reference with permission of the publisher.

FIG. 6

Neutrophils infiltrate the cornea before eosinophils do. C57BL/6 mice were sacrificed at the indicated times after intrastromal injection, eyes were immersed in formalin, and adjacent 5-μm paraffin sections were immunostained with antisera to eosinophil MBP or with anti-neutrophil MAb 7/4. Reprinted from reference with permission of the publisher.

FIG. 7

The CC chemokine eotaxin contributes to eosinophil recruitment in onchocercal keratitis. Corneas from eotaxin^−/− and immunocompetent wild-type mice were immunostained with antisera to eosinophil MBP after subcutaneous and intrastromal injection of O. volvulus antigens. Data points represent individual animals from two separate experiments. Horizontal lines denote means. Adapted from reference with permission of the publisher.

FIG. 8

Proposed sequence of events for development of onchocercal keratitis based on studies with a murine model. Systemic exposure to O. volvulus (O.v.) antigens selectively induces a Th2 response, with production of IL-4 and IL-5. The presence of parasite antigens in the cornea stimulates the recruitment of neutrophils and eosinophils into the cornea. The presence of antibody (Ab) at that site probably causes degranulation of these inflammatory cells, leading to disruption of stromal function and loss of corneal clarity (refer to the text for details).