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Ultrastructural pathology of experimental autoimmune uveitis. Quantitative evidence of activation and possible high
P G McMenamin1, J V Forrester, R J Steptoe
1Department of Anatomy and Human Biology, University of Western Australia, Nedlands, Perth.
Background:
Experimental autoimmune uveitis (EAU) is a highly organ-specific autoimmune disease in which the target is the retinal photoreceptors. It is well recognized as a model of uveoretinitis in humans. The mechanisms that control the homing of sensitized lymphocytes and other leukocytes to the retina is unknown. The aim of this study was to investigate changes in the retinal vasculature that may be involved with aiding leukocyte-endothelial cell interactions and subsequent extravasation of leukocytes into the retina.
Experimental Design:
Lewis rats immunized with S-antigen were used to produce EAU. The retinal vasculature was assessed by morphologic (light and electron microscopy) and morphometric techniques at various stages in the generation and course of the disease (days 3, 7, 11, 14, 21, 28 and 49 postimmunization) for evidence of endothelial cell (EC) activation and leukocyte-EC interaction. Image analysis of the retinal vessels at the electron microscopic level was performed to detect alterations in the thickness and irregularity of the EC surface, both considered to be important in lymphocyte homing in the high endothelial venules (HEVs) of lymphoid tissues. Control values were obtained from normal eyes, pertussis-only treated animals, and normal lymph node HEVs.
Results:
The clinical and histopathologic changes in the eyes were consistent with previous descriptions of EAU and included perivasculitis, focal mononuclear infiltrate in the outer retina, and choroid with destruction of the photoreceptor outer segments and eventually loss of large portions of the outer retina. During the course of EAU, a significant proportion of retinal venules underwent both qualitative and quantitative morphologic changes including EC activation evident as increased cytoplasmic organelles, a 230% average increase in mean EC thickness, and a concomitant 4-fold increase in irregularity of the EC, that produced plump irregular EC with deep intercellular clefts. These alterations were maximal at day 21, however from day 11 onward, large numbers of lymphocytes and monocytes were observed adhering to or lodged in the clefts of plump EC, migrating through the EC cytoplasm, or lying beneath the EC.
Conclusions:
The characteristics acquired by the retinal venules during EAU are reminiscent of HEVs. This study suggests that tissue-specific changes in the endothelial cells of retinal venules may be responsible for the homing of S-antigen specific autoreactive lymphocytes to the target organ in this model of retinal autoimmunity.