Interleukin-17A (IL-17A) is elaborated by the T helper 17 (T(H)17) subset of T(H) cells and exhibits potent proinflammatory properties in animal models of autoimmunity, including collagen-induced arthritis, experimental autoimmune encephalomyelitis, and experimental autoimmune uveitis. To determine whether IL-17A mediates human inflammatory diseases, we investigated the efficacy and safety of AIN457, a human antibody to IL-17A, in patients with psoriasis, rheumatoid arthritis, and chronic noninfectious uveitis. Patients with chronic plaque-type psoriasis (n = 36), rheumatoid arthritis (n = 52), or chronic noninfectious uveitis (n = 16) were enrolled in clinical trials to evaluate the effects of neutralizing IL-17A by AIN457 at doses of 3 to 10 mg/kg, given intravenously. We evaluated efficacy by measuring the psoriasis area and severity index (PASI), the American College of Rheumatology 20% response (ACR20) for rheumatoid arthritis, or the number of responders for uveitis, as defined by either vision improvement or reduction in ocular inflammation or corticosteroid dose. AIN457 treatment induced clinically relevant responses of variable magnitude in patients suffering from each of these diverse immune-mediated diseases. Variable response rates may be due to heterogeneity in small patient populations, differential pathogenic roles of IL-17A in these diseases, and the different involvement or activation of IL-17A-producing cells. The rates of adverse events, including infections, were similar in the AIN457 and placebo groups. These results support a role for IL-17A in the pathophysiology of diverse inflammatory diseases including psoriasis, rheumatoid arthritis, and noninfectious uveitis.

Effects of AIN457, a Fully Human Antibody to Interleukin-17A, on Psoriasis, Rheumatoid Arthritis, and Uveitis

https://stm.sciencemag.org/content/suppl/2010/10/04/2.52.52ra72.DC1/2-52ra72_SM.pdf

Supplementary Materials for Effects of AIN457, a Fully Human Antibody to Interleukin-17A, on Psoriasis, Rheumatoid Arthritis, and Uveitis

Behcet's disease is a genetically complex disease of unknown etiology characterized by recurrent inflammatory attacks affecting the orogenital mucosa, eyes and skin. We performed a genome-wide association study with 311,459 SNPs in 1,215 individuals with Behcet's disease (cases) and 1,278 healthy controls from Turkey. We confirmed the known association of Behcet's disease with HLA-B*51 and identified a second, independent association within the MHC Class I region. We also identified an association at IL10 (rs1518111, P = 1.88 x 10(-8)). Using a meta-analysis with an additional five cohorts from Turkey, the Middle East, Europe and Asia, comprising a total of 2,430 cases and 2,660 controls, we identified associations at IL10 (rs1518111, P = 3.54 x 10(-18), odds ratio = 1.45, 95% CI 1.34-1.58) and the IL23R-IL12RB2 locus (rs924080, P = 6.69 x 10(-9), OR = 1.28, 95% CI 1.18-1.39). The disease-associated IL10 variant (the rs1518111 A allele) was associated with diminished mRNA expression and low protein production.

Genome-wide association study identifies variants in the MHC class I, IL10, and IL23R-IL12RB2 regions associated with Behcet's disease

Autoimmune and inflammatory uveitis are a group of potentially blinding intraocular inflammatory diseases that arise without a known infectious trigger and are often associated with immunological responses to unique retinal proteins. In the United States, about 10% of the cases of severe visual handicap are attributed to this group of disorders. As I discuss here, experimental models of ocular autoimmunity targeting retinal proteins have brought about a better understanding of the basic immunological mechanisms involved in the pathogenesis of uveitis and are serving as templates for the development of novel therapies.

/pdf/a-look-at-autoimmunity-and-inflammation-in-the-eye-rfbe54h39d.pdf

A look at autoimmunity and inflammation in the eye

Autoreactive effector CD4+ T cells have been associated with the pathogenesis of autoimmune disorders. Early studies implicated the interferon (IFN)-γ-producing T helper (Th)1 subset of CD4+ cells as the causal agents in the pathogenesis of autoimmunity. However, further studies have suggested a more complex story. In models thought to be driven by Th1 cells, mice lacking the hallmark Th1 cytokine IFN-γ were not protected but tended to have enhanced susceptibility to disease. Identification of the IL-17-producing CD4+ effector cell lineage (Th17) has helped shed light on this issue. Th17 effector cells are induced in parallel to Th1, and, like Th1, polarized Th17 cells have the capacity to cause inflammation and autoimmune disease. This, together with the finding that deficiency of the Th17-related cytokine IL-23 but not the Th1-related cytokine IL-12 causes resistance, led to the notion that Th17 cells are the chief contributors to autoimmune tissue inflammation. Nevertheless, mice lacking IL-17 are not protected from disease and display elevated numbers of IFN-γ-producing CD4+ T cells, and, in some cases, lack of IFN-γ does confer resistance. Recent studies report overlapping as well as differential roles of these cells in tissue inflammation, which suggests the existence of a more complex relationship between these two effector T-cell subsets than has hitherto been suspected. This review will attempt to bring together current information regarding interaction, balance, and collaborative potential between the Th1 and Th17 effector lineages.

https://nyaspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1749-6632.2009.05133.x

Th1 and Th17 cells

PURPOSE. Behcet disease (BD) is a systemic inflammatory dis- ease presumably caused by an autoimmune response. The interleukin (IL)-23/IL-17 pathway has been demonstrated to be involved in the development and maintenance of certain in- flammatory diseases. This study was designed to investigate the role of IL-23 and IL-17 in BD. METHODS. IL-23p19 mRNA in peripheral blood mononuclear cells (PBMCs) was examined using RT-PCR. The levels of IL-23, IL-17, and IFN- in sera or PBMCs were detected by ELISA. Flow cytometry was used to evaluate the frequencies of IL-17- producing and IFN--producing T cells and the expression of CD45RO. RESULTS. Results showed that the expression of IL-23p19 mRNA, IL-23, IL-17, and IFN- was markedly elevated in BD patients with active uveitis. The frequencies of IL-17-produc- ing and IFN--producing T cells from PBMCs were significantly upregulated in BD patients with active uveitis. The increased IL-17 (3.10% 0.53%) in BD patients with active uveitis was primarily produced by CD45RO memory T cells. Recombi- nant (r) IL-23 could upregulate IL-17 production by poly- clonally stimulated PBMCs, whereas interferon (IFN)- down- regulated IL-17 production. CONCLUSIONS. These findings reveal that the levels of IL-23, IL-17, and IFN- are elevated in BD patients with active uveitis, and they suggest that the IL-23/IL-17 pathway together with IFN- is associated with the active intraocular inflammation in BD patients. (Invest Ophthalmol Vis Sci. 2008;49:3058 -3064)

Upregulated IL-23 and IL-17 in Behçet patients with active uveitis.

Inhibitory effect of Cyclosporin A and corticosteroids on the production of IFN-gamma and IL-17 by T cells in Vogt-Koyanagi-Harada syndrome.

SUMO4 gene polymorphisms in Chinese Han patients with Behcet's disease.

Association of the CTLA-4 gene with Vogt-Koyanagi-Harada syndrome.

Backgroud/aims: Leptin has recently been found to play an important role in the development of autoimmune diseases. Our study is designed to investigate the expression and possible role of leptin in the pathogenesis of Vogt–Koyanagi–Harada (VKH) disease, one of the common types of autoimmune uveitis in China. Methods: Leptin levels in serums of 20 active, 16 inactive VKH patients and 20 healthy controls were measured using ELISA. Peripheral blood mononuclear cells (PBMCs) separated from active VKH patients and healthy controls were cultured with recombinant human leptin, and cell proliferation was assayed by [3H]-TdR incorporation. Cytokine levels in the supernatant of PBMCs cultured in mixed lymphocyte reaction (MLR) upon stimulation with leptin were assayed by ELISA. Results: Our results showed that leptin was significantly increased in the serum of active VKH patients compared with that in inactive VKH patients and healthy controls. Leptin levels in active VKH patients remained markedly higher when divided by body mass index (BMI). PBMCs cultured with leptin induced a marked cell proliferation and profound secretion of IFN-γ and IL-17. Conclusion: These findings suggest that leptin may be involved in the development of VKH disease possibly by promoting an immune response.

https://bjo.bmj.com/content/bjophthalmol/92/4/557.full.pdf

Xiaomin Lin

Papers

Upregulated IL-23 and IL-17 in Behçet patients with active uveitis.

Inhibitory effect of Cyclosporin A and corticosteroids on the production of IFN-gamma and IL-17 by T cells in Vogt-Koyanagi-Harada syndrome.

SUMO4 gene polymorphisms in Chinese Han patients with Behcet's disease.

Association of the CTLA-4 gene with Vogt-Koyanagi-Harada syndrome.

Leptin increases in Vogt-Koyanagi-Harada (VKH) disease and promotes cell proliferation and inflammatory cytokine secretion