Project 8 Uveitis

The role of interleukin (IL)-10 in the pathogenesis of autoimmune uveitis in mice and man

Summary

Intraocular inflammation (uveitis) is a common cause of blindness. Etiologically, uveitis can be divided into infectious and autoimmune forms, with some associations between both forms, as in the case of HLA-B27 positive uveitis. Since there is a release of self antigens during every infection, the body prevents the development of subsequent autoimmune reactions by peripheral tolerance mechanisms including regulatory cell populations and cytokines such as interleukin (IL)-10. Failure of this network may explain the known association between autoimmune disorders and preceding infections. Our preliminary work in the murine model of human uveitis, experimental autoimmune uveitis (EAU), has shown that pre-exposure with bacterial products (analogous to a preceding infection) in form of complete freund´s adjuvant (CFA) ameliorates EAU. This protective feature critically depends on IL-10 and is associated with an expansion of myeloid derived suppressor cells (MDSC). The aim of this project now is to elucidate the mechanisms of this protective effect, particularly the role of MDSC and the cellular source of IL-10. Based on these findings we want to explore the hypothesis that dysregulation of IL-10 production, especially during infections, predisposes to subsequent autoimmune uveitis. Our initial findings support that in the EAU model, uveitis develops in IL-10 deficient mice after pre-exposure with bacterial products followed by EAU induction, but not in wild-type mice that are protected through bacteria-induced IL-10. In addition to peripheral MDSC, resident macrophages in the retina are present as microglia and aquire an activated state during EAU. The contribution of this population to immunoregulation of EAU via IL-10 will be analyzed. Local delivery by intravitreal application of IL-10 will be evaluated in EAU as a novel therapeutical means for uveitis, enabling a local immunosuppression without potential systemic side-effect due to the pleiotropic profile of this cytokine. Finally, secretion patterns of IL-10 in serum and peripheral blood monocytes and lymphocytes as putative markers of susceptibility for developing uveitis will be examined in patients with HLA-B27 positive uveitis.

Publications

Cursiefen C, Bock F, Clahsen T, Regenfuss B, Reis A, Steven P, Heindl LM, Bosch JJ, Hos D, Eming S, Grajewski R, Heiligenhaus A, Fauser S, Austin J, Langmann T. [New Therapeutic Approaches in Inflammatory Diseases of the Eye – Targeting Lymphangiogenesis and Cellular Immunity: Research Unit FOR 2240 Presents Itself]. Klin Monbl Augenheilkd. 2017 May;234(5):679-685.

Cursiefen C, Heiligenhaus A. [“Translational Research in Ophthalmology is Important!”]. Klin Monbl Augenheilkd. 2017 May;234(5):650-651.

Grajewski RS, Barahmand Pour N, Burian K, Caramoy A, Kirchhof B, Cursiefen C, Heindl LM. Analysis of the impact of allergy and atopy on new onset of uveitis. Acta Ophthalmol. 2017 May;95(3):e236-e241.

Böhm MR, Tappeiner C, Breitbach MA, Zurek-Imhoff B, Heinz C, Heiligenhaus A. Ocular Hypotony in Patients With Juvenile Idiopathic Arthritis-Associated Uveitis. Am J Ophthalmol. 2017 Jan;173:45-55.

Tappeiner C, Mesquida M, Adán A, Anton J, Ramanan AV, Carreno E, Mackensen F, Kotaniemi K, de Boer JH, Bou R, de Vicuña CG, Heiligenhaus A. Evidence for Tocilizumab as a Treatment Option in Refractory Uveitis Associated with Juvenile Idiopathic Arthritis. J Rheumatol. 2016 Dec;43(12):2183-2188.

Walscheid K, Weinhage T, Foell D, Heinz C, Kasper M, Heiligenhaus A. Phenotypic changes of peripheral blood mononuclear cells upon corticosteroid treatment in idiopathic intermediate uveitis. Clin Immunol. 2016 Oct 28. pii: S1521-6616(16)30534-4. [Epub ahead of print]

Jaffe GJ, Dick AD, Brézin AP, Nguyen QD, Thorne JE, Kestelyn P, Barisani-Asenbauer T, Franco P, Heiligenhaus A, Scales D, Chu DS, Camez A, Kwatra NV, Song AP, Kron M, Tari S, Suhler EB. Adalimumab in Patients with Active Noninfectious Uveitis. N Engl J Med. 2016 Sep 8;375(10):932-43.

Tappeiner C, Schenck S, Niewerth M, Heiligenhaus A, Minden K, Klotsche J. Impact of Antiinflammatory Treatment on the Onset of Uveitis in Juvenile Idiopathic Arthritis: Longitudinal Analysis From a Nationwide Pediatric Rheumatology Database. Arthritis Care Res (Hoboken). 2016 Jan;68(1):46-54.

Walscheid K, Heiligenhaus A, Holzinger D, Roth J, Heinz C, Tappeiner C, Kasper M, Foell D. Elevated S100A8/A9 and S100A12 Serum Levels Reflect Intraocular Inflammation in Juvenile Idiopathic Arthritis-Associated Uveitis: Results From a Pilot Study. Invest Ophthalmol Vis Sci. 2015 Dec;56(13):7653-60.

Tappeiner C, Klotsche J, Schenck S, Niewerth M, Minden K, Heiligenhaus A. Temporal change in prevalence and complications of uveitis associated with juvenile idiopathic arthritis:data from a cross-sectional analysis of a prospective nationwide study. Clin Exp Rheumatol. 2015 Nov-Dec;33(6):936-44.

Tappeiner C, Miserocchi E, Bodaghi B, Kotaniemi K, Mackensen F, Gerloni V, Quartier P, Lutz T, Heiligenhaus A. Abatacept in the treatment of severe, longstanding, and refractory uveitis associated with juvenile idiopathic arthritis. J Rheumatol. 2015 Apr;42(4):706-11.

Grajewski RS, Caramoy A, Frank KF, Rubbert-Roth A, Fätkenheuer G, Kirchhof B, Cursiefen C, Heindl LM. Spectrum of Uveitis in A German Tertiary Center: Review of 474 Consecutive Patients. Ocul Immunol Inflamm. 2015 Mar 11:1-7.

Krawczyk A, Dirks M, Kasper M, Buch A, Dittmer U, Giebel B, Wildschütz L, Busch M, Goergens A, Schneweis KE, Eis-Hübinger AM, Sodeik B, Heiligenhaus A, Roggendorf M, Bauer D. Prevention of herpes simplex virus induced stromal keratitis by a glycoprotein B-specific monoclonal antibody. PLoS One. 2015 Jan 14;10(1):e0116800.

Thanos S, Böhm MR, Meyer zu Hörste M, Prokosch-Willing V, Hennig M, Bauer D, Heiligenhaus A. Role of crystallins in ocular neuroprotection and axonal regeneration. Prog Retin Eye Res. 2014 Sep;42:145-61.

Schlereth SL, Neuser B, Caramoy A, Grajewski RS, Koch KR, Schrödl F, Cursiefen C, Heindl LM. Enrichment of lymphatic vessel endothelial hyaluronan receptor 1 (LYVE1)-positive macrophages around blood vessels in the normal human sclera. Invest Ophthalmol Vis Sci. 2014;10;55(2):865-72.

Busch M, Bauer D, Hennig M, Wasmuth S, Thanos S, Heiligenhaus A. Effects of systemic and intravitreal TNF-a inhibition in experimental autoimmune uveoretinitiis. Invest Ophthalmol Vis Sci 2013; 54: 39-46.

Grajewski RS, Li J, Wasmuth S, Hennig M, Bauer D, Heiligenhaus A. Intravitreal treatment with antisense oligonucleotides targeting tumor necrosis factor alpha in murine herpes simplex virus type 1 retinitis. Graefes Arch Clin Exp Ophthalmol 2012; 250 (2): 231-8.

Hennig M, Bauer D, Wasmuth S, Busch M, Walscheid K, Thanos S, Heiligenhaus A. Everolimus improves experimental autoimmune uveoretinitis. Exp Eye Res 2012;105: 43-52.

Bauer D, Wasmuth S, Hennig M, Baehler H, Steuhl KP, and Heiligenhaus A. Amniotic membrane transplantation induces apoptosis in T lymphocytes in murine corneas with experimental herpetic stromal keratitis. Invest Ophthalmol Vis Sci 2009;50:3188-3198.

Grajewski RS, Hansen AM, Agarwal RK, Kronenberg M, Sidobre S, Su SB, Silver PB, Tsuji M, Franck RW, Lawton AP, Chan CC, Caspi RR. Activation of invariant NKT cells ameliorates experimental ocular autoimmunity by a mechanism involving innate IFN-gamma production and dampening of the adaptive Th1 and Th17 responses. J Immunol. 2008 Oct 1;181(7):4791-7.

Heiligenhaus A, Niewerth M, Ganser G, Heinz C, Minden K, German Uveitis in Childhood Study Group.Prevalence and complications of uveitis in juvenile idiopathic arthritis in a population-based nation-wide study in Germany: suggested modification of the current screening guidelines. Rheumatology 2007;46:1015-1019.

Grajewski RS, Silver PB, Agarwal RK, Su SB, Chan CC, Liou GI and Caspi RR. Endogenous expression of IRBP can be dispensable for generation of natural CD4+CD25+ regulatory T cells that protect from IRBP-induced retinal autoimmunity. J Exp Med. 2006; 203(4): 851-56.

Heiligenhaus A, Li HF, Yang Y, Wasmuth S, Steuhl KP, Bauer D. Transplantation of amniotic membrane in murine herpes stromal keratitis modulates matrix metalloproteinases in the cornea. Invest Ophthalmol Vis Sci 2005; 46: 4079-4085.

Avichezer D, Grajewski RS, Chan CC, Mattapallil MJ, Silver PB, Raber JA, Liou GI, Wiggert B, Lewis GM, Donoso LA, Caspi RR. An immunologically privileged retinal antigen elicits tolerance: major role for central selection mechanisms. J Exp Med. 2003; 198(11): 1665-76.