Growth Factors , Cytokines , Cell Cycle Molecules Conjunctival Interleukin-13 Expression in Mucous Membrane Pemphigoid and Functional Effects of Interleukin-13 on Conjunctival Fibroblasts in Vitro

Interleukin-13 (IL-13) is the dominant effector cytokine of fibrosis in pulmonary and liver disease. Excessive conjunctival fibrosis in the immunobullous disease ocular mucous membrane pemphigoid (MMP) causes blindness; the pathogenesis of scarring in this disease is incompletely understood. To determine whether IL-13 is involved in conjunctival fibrosis in MMP, we studied the expression of IL-13 in ocular MMP patients before and after systemic immunosuppression and examined the effects of IL-13 on normal human conjunctival fibroblasts. We found high stromal cell expression of IL-13 in active ocular MMP by immunohistochemistry; 80% of these cells were CD3positive T cells. Following immunosuppression, in clinically uninflamed, treated, ocular MMP patients, the number of IL-13 positive cells was significantly reduced, but this was still fourfold greater than in normal conjunctiva. IL-13 stimulated collagen lattice contraction and migration, and decreased production of mmp-3 and mmp-10 by human conjunctival fibroblasts. The addition of T cell culture supernatant to IL-13 synergistically augmented fibroblast migration. IL-13 also up-regulated surface expression of HLA-DR, CD80, CD40, and CD154 by conjunctival fibroblasts, suggesting a potential mechanism for fibroblast-T cell cross talk, via which fibroblasts may actively engage in perpetuating chronic inflammation and continued fibrosis. Together, these findings suggest that IL-13 is involved in conjunctival fibrosis in MMP, and that IL-13 has both profibrotic and pro-inflammatory effects on human conjunctival fibroblasts. (Am J Pathol 2009, 175:2406–2415; DOI: 10.2353/ajpath.2009.090579) Autoimmune conjunctivitis caused by ocular mucous membrane pemphigoid (MMP), also known as ocular cicatricial pemphigoid, is a blinding disease characterized by recurrent episodes of inflammation and aggressive conjunctival fibrosis. It is part of a spectrum of immunobullous disease associated with linear deposition of IgG and IgA autoantibodies directed against epithelial basement membrane zone proteins, which most commonly involves oral and ocular mucosa. In ocular mucosa, unlike oral mucosa, scarring is a clinical hallmark of the disease. Although the mechanisms have not been clearly demonstrated, autoantibodies are thought to cause blistering by disrupting basement membrane adherence via activation of complement, neutrophils and pro-inflammatory cytokines. In the eye, blisters are infrequently seen, and the disease manifests as chronic recurrent cicatricial conjunctivitis. The functional consequences of the inflammatory lesions that heal with scarring are most evident in the eye, where patients with severe conjunctival fibrosis become blind in 30% of cases. Developing effective anti-fibrotic agents would therefore have therapeutic potential, but is challenging because the cellular and molecular mechanisms of conjunctival scarring in MMP are incompletely understood. Given that conjunctival fibrosis can still progress, despite apparent clinical control of inflammation by conventional immunosuppressive therapy, better understanding of the changes in treated tissue compared with actively inflamed tissue might assist and guide in the development of adjunctive local therapies to target conjunctival fibrosis. Interleukin-13 is a key profibrotic mediator that has been identified as the dominant effector cytokine of fibrosis in experimental models of skin, hepatic, and pulmonary fibrosis and airway remodeling in asthma. It is