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Originally published In Press as doi:10.1167/iovs.08-3345 on June 3, 2009
 (Investigative Ophthalmology and Visual Science. 2009;50:5310-5317.)
© 2009 by The Association for Research in Vision and Ophthalmology, Inc.
doi:10.1167/iovs.08-3345
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Tumor Necrosis Factor-{alpha} in Ocular Mucous Membrane Pemphigoid and Its Effect on Conjunctival Fibroblasts

Valerie P. J. Saw,1,2 Robin J. C. Dart,1 Grazyna Galatowicz,1 Julie T. Daniels,1 John K. G. Dart,1,2 and Virginia L. Calder1

From the 1Department of Ocular Biology and Therapeutics, University College London Institute of Ophthalmology, London, United Kingdom; and 2the Moorfields Eye Hospital, London, United Kingdom.

Corresponding author: Valerie P. J. Saw, Moorfields Eye Hospital, 162 City Road London EC1V 2PD, UK; v.saw{at}ucl.ac.uk.

Purpose. First, to determine whether tumor necrosis factor-(TNF)-{alpha} is expressed in the conjunctiva of ocular mucous membrane pemphigoid (MMP) and the consequences of systemic immunosuppressive treatment on this expression. Second, to investigate the in vitro effects of TNF{alpha} on human conjunctival fibroblasts.

Methods. The expression of TNF{alpha} in conjunctival tissues of patients with actively inflamed ocular MMP (n = 10), patients with clinically noninflamed ocular MMP after systemic immunosuppressive treatment (n = 10), and normal subjects (n = 10) was studied by immunohistochemistry. The effect of TNF{alpha} on functional assays of human conjunctival fibroblast activity were investigated, including migration, collagen lattice contraction, matrix metalloproteinase (mmp), and tissue inhibitor of matrix metalloproteinase (timp) secretion, proliferation, and surface expression of HLA-DR, ICAM, CD80, CD86, CD40, CD40-ligand.

Results. In active ocular MMP, TNF{alpha} is expressed by a large number of stromal infiltrating cells (234 cells/mm2), and although the level of stromal TNF{alpha} expression is significantly reduced after immunosuppressive treatment (90 cells/mm2), these levels are still significantly elevated compared with normal conjunctiva (10 cells/mm2, P < 0.05). TNF{alpha} stimulates increased migration by conjunctival fibroblasts (P < 0.001), increased production of mmp-9 (P = 0.01), decreased production of timp-2 (P = 0.01) and timp-4 (P = 0.04), and upregulated expression of CD40 and ICAM (P = 0.04). No significant effects of TNF{alpha} on fibroblast proliferation or collagen lattice contraction were detected.

Conclusions. Increased conjunctival expression of TNF{alpha} in ocular MMP suggests that systemic TNF{alpha} antagonists are likely to be effective in controlling severe disease unresponsive to conventional systemic immunosuppression. Residual TNF{alpha} expression persists in clinically noninflamed disease. TNF{alpha} appears to have profibrotic and proinflammatory effects on human conjunctival fibroblasts.






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