transforming-growth-factor-beta and Uveitis--Anterior

The delicate visual axis that makes precise vision possible is highly vulnerable to the destructive potential of immunogenic inflammation. Immune privilege of the eye is the experimental expression of the way in which evolution has coped with the countermanding threats to vision of ocular infections and ocular immunity and inflammation. Ocular immune privilege has five primary features that account for its existence: blood:ocular barriers, absent lymphatic drainage pathways, soluble immunomodulatory factors in aqueous humor, immunomodulatory ligands on the surface of ocular parenchymal cells, and indigenous, tolerance-promoting antigen-presenting cells (APCs). Three manifestations of ocular immune privilege that have received the most extensive study are the intraocular microenvironment, which is selectively anti-inflammatory and immunosuppressive; the prolonged acceptance of solid tissue and tumor allografts in the anterior chamber; and the induction of systemic tolerance to eye-derived antigens. Anterior chamber-associated immune deviation is known to arise when indigenous, ocular APCs capture eye-derived antigens and deliver them to the spleen where multicellular clusters of these cells, natural killer T cells, marginal zone B cells, and gammadelta T cells create an antigen-presentation environment that leads to CD4(+) and CD8(+) alpha/beta T cells, which as regulators, suppress induction and expression of T helper cell type 1 (Th1) and Th2 immune expression systems. The ways the eye influences local and systemic immune responses to ocular antigens and pathogens carry risks to and benefits for mammalian organisms. As loss of sight is a powerful, negative-selecting force, the benefits of ocular immune privilege outweigh the risks.

Topics: Antigen-Presenting Cells; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Eye; Humans; Immunity, Cellular; Receptors, Antigen, T-Cell, alpha-beta; Receptors, Antigen, T-Cell, gamma-delta; Thrombospondins; Transforming Growth Factor beta; Uveitis, Anterior

Aqueous humor (AqH) contains immunosuppressive factors, especially TGF-beta2, that contribute to the immune privileged status of the anterior chamber. However, this may not be true when the blood-ocular barrier is compromised by ocular inflammation. To determine the immunosuppressive status of AqH from murine eyes afflicted with experimental autoimmune uveitis, B10.A mice were immunized with interphotoreceptor retinoid-binding protein. AqH was collected from eyes of affected mice periodically after immunization and then evaluated for content of TGF-beta, proinflammatory cytokines, and the capacity to suppress anti-CD3-driven T cell proliferation. mRNA expression of selected cytokines in iris and ciliary body from inflamed eyes was analyzed by ribonuclease protection assay. We found that TGF-beta levels were significantly increased in AqH from EAU eyes on days 11, 17, and 28. AqH collected on day 11 (onset of disease) failed to suppress T cell proliferation and contained large amounts of locally produced IL-6 that antagonized TGF-beta. In contrast, AqH collected at 17 days (when ocular inflammation was progressively severe) re-expressed the ability to suppress T cell proliferation, in this case due to high levels of blood-derived TGF-beta1 and eye-derived TGF-beta2 in the absence of IL-6. Thus, during the onset of experimental autoimmune uveitis, the ocular microenvironment loses its immunosuppressive properties due to local production of IL-6. But as inflammation mounts, AqH IL-6 content falls, and the fluid reacquires sufficient TGF-beta eventually to suppress immunogenic inflammation. The paradoxical roles of IL-6 in antagonizing TGF-beta, while promoting TGF-beta accumulation during ocular inflammation, is discussed.

Topics: Adjuvants, Immunologic; Animals; Aqueous Humor; Autoimmune Diseases; CD3 Complex; Cells, Cultured; Ciliary Body; Female; Immune Sera; Immunosuppressive Agents; Inflammation Mediators; Interleukin-6; Iris; Lymphocyte Activation; Mice; Mice, Inbred A; Mice, Inbred BALB C; Mice, Inbred C57BL; RNA, Messenger; T-Lymphocytes; Transforming Growth Factor beta; Uveitis, Anterior

Topics: Animals; Animals, Genetically Modified; Antigen Presentation; Arthritis, Psoriatic; Arthritis, Reactive; Autoimmune Diseases; CD4-Positive T-Lymphocytes; Crohn Disease; Cystine; Dimerization; Fibrillins; Genetic Predisposition to Disease; Histocompatibility Antigens Class I; HLA-B27 Antigen; Humans; Lung; Lymphocyte Activation; Marfan Syndrome; Mice; Microfilament Proteins; Models, Immunological; Organ Specificity; Protein Conformation; Rats; Sacroiliac Joint; Spondylitis, Ankylosing; Stress, Mechanical; Transforming Growth Factor beta; Uveitis, Anterior

To determine the immunosuppressive status of aqueous humor (AqH) from mouse eyes afflicted with endotoxin-induced uveitis (EIU) and to identify the relevant cytokines responsible for immunomodulatory activity within EIU AqH.. Bacterial lipopolysaccharide (LPS) was injected into hind footpads of C3H/HeN mice; and AqH, collected at 6, 12, 24, and 48 hours, was evaluated for content of transforming growth factor (TGF)-beta, tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, and interferon (IFN)-gamma and capacity to suppress anti-CD3-driven T-cell proliferation. Cytokine mRNA expression in iris-ciliary body (I/CB) was analyzed by RNase protection assays.. During 6 to 24 hours after LPS injection, total TGF-beta levels in AqH increased even though the fluid lost its capacity to suppress T-cell activation. At this time, AqH contained high levels of IL-6, and I/CB contained high levels of IL-6 mRNA. When IL-6 was neutralized with specific antibodies, inflamed AqH reacquired its capacity to suppress T-cell activation, which correlated with high levels of TGF-beta. Coinjection of IL-6 plus antigen into the anterior chamber of the eye of normal mice prevented antigen-specific anterior chamber-associated immune deviation (ACAID).. LPS-induced intraocular inflammation is associated with local production of IL-6, which robs AqH of its immunosuppressive activity, perhaps by antagonizing TGF-beta. The fact that IL-6 antagonized ACAID induction in normal eyes suggests that strategies to suppress the intraocular synthesis of IL-6 may reduce inflammation and restore ocular immune privilege.

Topics: Animals; Anterior Chamber; Aqueous Humor; Blood-Aqueous Barrier; Cytokines; Female; Hypersensitivity, Delayed; Interleukin-6; Lipopolysaccharides; Lymphocyte Activation; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Salmonella typhimurium; T-Lymphocytes; Transforming Growth Factor beta; Uveitis, Anterior

Transforming growth factor beta-1 (TGF beta-1) can modulate inflammation. Endotoxin-induced uveitis (EIU) is characterized by acute ocular inflammation related to the release of cytokines, including interleukin (IL)-6. The authors investigated the effect of TGF beta-1 on EIU in mice.. Three independent experiments were performed. Endotoxin-induced uveitis was induced in C3H/HeN mice by an injection of 200 micrograms of lipopolysaccharide (LPS). Two micrograms of TGF beta-1 in 0.1 ml phosphate-buffered saline (PBS) or 0.1 ml PBS alone was administered intraperitoneally at 8 hours after LPS injection. Twenty-four hours after LPS injection, the aqueous humor of the right eyes was collected for leukocyte count, protein concentration, and IL-6 assay. Left eyes were processed for routine histology.. TGF beta-1-treated mice showed less ocular inflammation histologically than to the animals that were given PBS. This was confirmed by decreases in leukocyte count, protein concentration, and IL-6 level in the aqueous humor.. TGF beta-1 inhibits the development of EIU. TGF beta-1 may be useful for the modulation of uveitis in humans.

Topics: Animals; Aqueous Humor; Endotoxins; Female; Leukocyte Count; Leukocytes; Mice; Mice, Inbred C3H; Salmonella typhimurium; Transforming Growth Factor beta; Uveitis, Anterior