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Pathogenic Mechanisms of Uveitis Brian C. Gilger, DVM, MS, Dipl. ACVO, Professor of Ophthalmology Department of Clinical Sciences, College of Veterinary Medicine North Carolina State University, Raleigh, NC General Features of Ocular Immunology and Uveitis The two components of the anterior uvea, the iris and the ciliary body, contain heavily pigmented connective, vascular, and muscle tissue. The iris functions as a shutter that responds to prevailing light conditions, and the ciliary body produces aqueous humor through active secretion and ultrafiltration of plasma. Both the iris and ciliary body have many blood vessels within their connective tissue, and the inner aspect of both structures is lined by a double layer of epithelium. The layer of epithelium closest to the connective tissue is pigmented, and the boundary layer closest to the vitreous is nonpigmented. The choroid, or posterior part of the uvea, functions as the primary vascular supply of the horse retina. It lies between the sclera and the retina and contains the tapetum, the fibrous reflective layer. The uveal tract contains most of the blood supply of the eye and is in direct contact with peripheral vasculature. Therefore diseases of the systemic circulation (e.g., septicemia and bacteremia) will also affect the uveal blood circulation. There is a barrier between this blood circulation and the internal aspects of the eye, called the blood-ocular barrier. The blood-ocular barrier consists of the blood-aqueous barrier (i.e., tight junctions between the nonpigmented epithelial cells of the ciliary body and nonfenestratediridalblood vessels) and the blood-retinal barrier (i.e., tight junctions between the cells of the retinal pigmented epithelium [RPE] and nonfenestrated retinal vessels). These semipermeable barriers normally prevent large molecules and cells from entering the eye and help the intraocular fluids remain clear. The blood-ocular barrier also limits the immune response to the internal aspects of the eye, causing the eye to be considered an immune-privileged site. In cases of trauma or inflammation, these barriers can be disrupted, allowing blood products and cells to enter the eye. Flare, cell accumulations, and haze in the aqueous or vitreous are clinically observable signs of the disruption of the blood-ocular barrier that occurs in uveitis. Disruption of the barrier enables activation of various host immune responses, including production of antibodies to self-antigens not normally recognized by the animals's own immune system, as well as production of antibodies to foreign antigens inside the eye. The inner eye is devoid of immune cells, and the eye maintains an immunosuppressive environment through, for example, factors expressed in the vitreous such as transforming growth factor β (TGF-β). The eye has long been recognized as an immune-privileged organ. Immune privilege in the eye was originally ascribed to its separation from the systemic immune system by the blood-ocular barrier, lack of lymphatics, and the presence of limited numbers of resident leukocytes. More recent work, however, has demonstrated that ocular privilege is a far more active process than this. In uveitis, leucocytes are able to enter the inner eye due to a bread-down of the blood ocular barrier, and cause damage to the inner ocular tissues. From: Caspi R. Immune mechanisms of uveitis, NIH In equine recurrent uveitis,analysis of the infiltrating cells revealed that the majority of cells are lymphocytes. These cells are predominantly CD4-positive T cells that secrete proinflammatory cytokines such as interleukin 2 (IL-2) and interferon γ (IFN-γ). The IFNγ-producing phenotype is named TH1 helper cell. TH cells are involved in activating and directing other immune cells and are particularly important in the immune system. They are essential in determining B-cell antibody class switching, in the activation and growth of cytotoxic T cells, and in maximizing activity of macrophages. Until recently, this cell type of IFN-γ-producing TH1 effector cells was considered the main pathogenic pathway in autoimmune diseases. TH17 cells are a newly identified subset of CD4+ Thelper cells producing IL-17. They are found at interfaces between the external environment and the internal environment, such as the skin and lining of the GI tract. Numerous immune regulatory functions have been reported for the IL-17 family of cytokines, presumably due to their induction of many immune signaling molecules. Most notably, IL-17 is involved in inducing and mediating proinflammatory responses. IL-17 induces the production of many other cytokines, chemokines, and prostaglandins from many cell types. The increased expression of chemokines attracts other cells, including neutrophils but not eosinophils. To date, it is not known if a certain percentage of ERU cases are caused through TH17 cells. The efferent phase of Uveitis: the mechanisms of tissue damage It is likely that specific and the nonspecific cells penetrate the eye at random in small numbers; however, only autoantigen specific cells (see below) - probably upon recognition of their specific antigen in situ - are able to subsequently cause recruitment of massive numbers of inflammatory host leukocytes and induce uveitis. 2 The phenomenon of "nonspecific" inflammatory cell recruitment is a critical step in uveitis development. Lymphocytes, monocytes and neutrophils are recruited to the site, with mononuclear cells accounting for the majority of the infiltrate. Cell recruitment is dependent on local production of lymphokines and chemokines by the first infiltrating T cells, that result in induction of adhesion molecules on retinal vascular endothelium and further production of chemoattractants from the tissue, and establish a chemotactic gradient for leukocytes. The recruited cells then amplify this process by contributing their own products, thus fueling an escalating inflammatory cascade. Degranulation of mast cells that occurs at the time of disease onset helps to break down the blood-retinal barrier. This facilitates the entry of cells into the eye, and the exit of tissue breakdown products and soluble mediators into the circulation, thus fueling the progression of the autoimmune process. An important part of the tissue damage in the eye is mediated by active oxygen products, such as nitric oxide, peroxide, and other products. The oxidative and other tissue damage mechanisms are redundant, and no single pathway by itself is critical for pathogenesis. Autoantigens and Uveitis Uveitis is a clinically heterogeneous disease. Although the antigenic triggers of autoimmune uveitis are still under discussion, there is a large body of evidence implicating responses to retinal antigens in the etiology and/or progression of the disease. Current concepts to explain the origin and perpetuation of autoimmune diseases include molecular mimicry, bystander activation, and epitope spreading. These mechanisms do not exclude each other but could appear together and even interact. Epitope spreading is defined as the diversification of epitope specificity from the initial focused, dominant, epitope-specific immune response, directed against a self or foreign protein to cryptic epitopes on that protein (intramolecular spreading) or other proteins (intermolecular spreading). The immune response consists of an initial magnification phase and a later downregulatory phase to return the immune system to homeostasis. In most autoimmune diseases, several autoantigens participate in the pathogenesis, and epitope spreading is accountable for disease induction, progression, and inflammatory relapses. The shifts in immunoreactivity could account for the remitting/relapsing character of ERU. Different target antigens may be important for a given individual, depending on the MHC background. Genetic background and antigens encountered influence the direction and extent of epitope reactivity and probably play an important role in the heterogeneous clinical manifestations of disease. In many autoimmune diseases, epitope spreading is suspected to occur as a result of an immune response against endogenous target antigens first and secondary to the release of self-antigen during the chronic autoimmune response. The formation of new antibodies may 3 determine a different clinical picture. For example, the transformation of anterior uveitis to posterior uveitis may be an excellent example of the effects of epitope spreading. Through tissue damage, cryptic or hidden epitopes on the same molecule will be suddenly presented to the immune system. The end result is that every target antigen generally contains several epitopes, each of which reacts with a T cell or antibody response of different specificity and affinity. Thus, epitope spreading in autoimmune diseases results in the detection of an increasing array of autoantibodies against various target antigens. Studies characterizing the shifting immune response of ERUdiseased horses are currently underway, but initial studies have confirmed epitope spreading in a high percentage of cases. Ocular Immunotherapy and Immunomodulation Immunotherapy is a hot topic in ophthalmology because of the recent advancements in cellular and intracytoplasmic mechanisms that control inflammation and immunology. There are many suspected ocular surface and intraocular inflammatory diseases that are thought to be mainly immune-mediated in origin or involved in the disease pathogenesis. Steroidal medications are the most frequently used “immunotherapy” medication in veterinary medicine. However, this drug is truly taking the “sledge hammer” approach to therapy, with lots of peripheral damage (i.e., side effects). Steroidal and non-steroidal therapy will be reviewed in other lectures. The newer medications are designed to be more specific in their treatment approach and thus, have fewer side effects. Most of these medications are systemically administered, although local injections, including intraocular injections, are being evaluated in humans and experimentally. The ocular penetration, both topically and via the systemic route have not been studied extensively for many drugs, but one would assume that with the blood-aqueous barrier disrupted, most blood-bourne medications should enter the eye easily. The purpose of these notes and lectures is to review existing and emerging immunomodulation drugs to better our understanding of immunotherapy of ocular disease. Corticosteroids are used as first-line treatment for many ocular inflammatory conditions. The risk of adverse effects, however, necessitates conversion to steroid-sparing immunomodulatory therapy (IMT) for disease that is recurrent, chronic, or poorly responsive to treatment. Immunomodulatory agents include the broad categories of antimetabolites (azathioprine, methotrexate, mycophenolatemofetil), alkylating agents (cyclophosphamide, chlorambucil), T-cell inhibitors (cyclosporine, tacrolimus, sirolimus), cytokine or cytokine receptor inhibitors (Etanercept, infliximab, adalimumab, and anakinra), immunosuppressive cytokines (IL-10, TGF), and oral tolerance. 4 TABLE OF IMMUNOMODULATING DRUGS Drug Trade name MolWt Use in Vet ophthalmology Dose* Azasan® Imuran® 277.264 NGE, uveitis, chorioretinitis Methotrexate Rheumatrex® 454.45 Chemotherapy Mycophenolatemofetil CellCept® 433.50 NYR Dog: 2 mg/kg PO qd x 2 wks; then 1 mg/kg qod, then 1 mg/kg once weekly for 30d.49 Dog: 2.5 mg/m2 PO qd Cat: 2.5 mg/m2 PO 2-3x weekly.49 Various Alkylating Agents Cyclophosphamide Cytoxan® 279.1 Uveitis Chlorambucil Leukeran® 304.2 Chemotherapy Neoral®, Atopia®, Optimmune®, Restasis® FK-506; Fujimycin; Prograf®) 1202.61 KCS, uveitis, VKH, IMMK See text 804.024 KCS Rapamycin 804.024 NYR Topical: 0.02% Human: 0.050.1mg/kg/day IV; 0.50.75 mg/kg/day P)(maintain trough blood concentrations @ 10-20 ng/ml) Various Antimetabolites Azathioprine T-cell Inhibitors Cyclosporine Tacrolimus Sirolimus Cytokine or Cytokine Receptor Inhibitors Etanercept Enbrel® 75 kDa NYR Infliximab Adalimumab Remicade® Humira® 149 kDa 148 kDa NYR NYR Anakinra Kineret® 17.3 kDa NYR 18.5 kDa Various NYR NYR Immunosuppressive Cytokines IL-10 Not commercial Not commercial TGF Dog: 2.2 mg/kg PO or IV for 4 consecutive days each wk. Cat: 2.5 mg PO 4 consecutive days each wk.49 Dog: 0.1-0.2 mg/kg PO qd or qod Cat: 0.w mg/kg PO q24-48 hours.49 Human: 25-50mg SQ 12 times/ week Human: IV q8 weeks Human: 40 mg SQ q 2 weeks Human: 1-2 mg/kg/day SQ Unknown Unknown 5 Oral Tolerance S-antigen; IRBP Not commercial NA NYR Unknown *Please check accuracy of all doses prior to therapy. NYR – Not yet reported. References 1. English RE, Gilger BC. Ocular Immunology. In: Gelatt KN, Gilger BC, Kern TJ. Veterinary Ophthalmology 5th Edition, Blackwell (in press). 2. Gilger BC, Deeg CA. Equine recurrent uveitis. Ed.: Gilger BC. Equine Ophthalmology Second Edition, Elsevier, Philadelphia. 2010. 3. Gilger BC, Dywer A. Equine Recurrent Uveitis. In: Gilger BC. Equine Ophthalmology, Elsevier, Philadelphia. 2005 6