The programmed cell death 1 (PD-1) surface receptor binds to two ligands, PD-L1 and PD-L2. Studies have shown that PD-1-PD-L interactions control the induction and maintenance of peripheral T cell tolerance and indicate a previously unknown function for PD-L1 on nonhematopoietic cells in protecting tissues from autoimmune attack. PD-1 and its ligands have also been exploited by a variety of microorganisms to attenuate antimicrobial immunity and facilitate chronic infection. Here we examine the functions of PD-1 and its ligands in regulating antimicrobial and self-reactive T cell responses and discuss the therapeutic potential of manipulating this pathway.

The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection

Summary: Our understanding of the role of T cells in human disease is undergoing revision as a result of the discovery of T-helper 17 (Th17) cells, a unique CD4+ T-cell subset characterized by production of interleukin-17 (IL-17) IL-17 is a highly inflammatory cytokine with robust effects on stromal cells in many tissues Recent data in humans and mice suggest that Th17 cells play an important role in the pathogenesis of a diverse group of immune-mediated diseases, including psoriasis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, and asthma Initial reports also propose a role for Th17 cells in tumorigenesis and transplant rejection Important differences, as well as many similarities, are emerging when the biology of Th17 cells in the mouse is compared with corresponding phenomena in humans As our understanding of human Th17 biology grows, the mechanisms underlying many diseases are becoming more apparent, resulting in a new appreciation for both previously known and more recently discovered cytokines, chemokines, and feedback mechanisms Given the strong association between excessive Th17 activity and human disease, new therapeutic approaches targeting Th17 cells are highly promising, but the potential safety of such treatments may be limited by the role of these cells in normal host defenses against infection

/pdf/th17-cells-in-human-disease-dzxnhjc66r.pdf

Th17 cells in human disease

Tumors arise from normal cells of the body through genetic mutation. Although such genetic mutation often leads to the expression of abnormal antigens, the immune system fails to respond effectively to these antigens; that is, it is tolerant of these antigens. This acquired state of tolerance must be overcome for cancer immunotherapy to succeed. Indoleamine 2,3-dioxygenase (IDO) is one molecular mechanism that contributes to tumor-induced tolerance. IDO helps create a tolerogenic milieu in the tumor and the tumor-draining lymph nodes, both by direct suppression of T cells and enhancement of local Treg-mediated immunosuppression. It can also function as an antagonist to other activators of antitumor immunity. Therefore, strategies to block IDO might enhance the effectiveness of tumor immunotherapy.

/pdf/indoleamine-2-3-dioxygenase-and-tumor-induced-tolerance-13g93ipp1m.pdf

Indoleamine 2,3-dioxygenase and tumor-induced tolerance.

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

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.

Purpose: To address the clinical pattern and characteristics of uveitis in a tertiary center for uveitis in China and compare the similarity and difference in the distribution of uveitis entities between China and other countries Methods: A retrospective study was performed on the patients with uveitis referred to the Zhongshan Ophthalmic Center from January 1996 to December 2003 The clinical data including category, etiology, gender, and the age of the patients at uveitis presentation were analyzed and compared with studies published previously from other countries Results: There were 902 male and 850 female patients in our series The mean age of these patients at uveitis presentation was 338 ± 165 years Anterior uveitis (800, 456%) was the most common anatomical entity, followed by panuveitis (727, 415%), posterior uveitis (119, 68%), and intermediate uveitis (106, 61%) Further classification with the etiology criteria revealed 16 entities in anterior uveitis, with idiopathic anterior uveiti

Clinical Patterns and Characteristics of Uveitis in a Tertiary Center for Uveitis in China

Background Vogt-Koyanagi-Harada (VKH) disease is a systemic refractory autoimmune disease. IL-23 has been thought to play a critical role in autoimmune disease through inducing the development of IL-17–producing CD4 + T cells. Objective To investigate the expression of IL-23 and IL-17 and the influence of IL-23 on IL-17 production in patients with VKH disease. Methods Blood samples were taken from 25 patients with VKH disease and 16 healthy controls. Peripheral blood mononuclear cells (PBMCs) were subjected to analysis of IL-23p19 mRNA and IL-23 protein expression using RT-PCR and ELISA, respectively. The IL-17 levels in the supernatants of PBMCs and CD4 + T cells cultured in the absence or presence of recombinant (r)IL-23, rIL-12, or anti–IFN-γ were determined by ELISA. Results The patients with VKH disease with active uveitis showed an elevated level of IL-23p19 mRNA in PBMCs, higher IL-23 in the serum and supernatants of PBMCs, and increased production of IL-17 by polyclonally stimulated PBMCs and CD4 + T cells. Recombinant IL-23 significantly enhanced IL-17 production, whereas rIL-12 and IFN-γ inhibited IL-17 production. More importantly, IL-17 production was significantly increased in patients with active uveitis in the presence of rIL-23. Both rIL-23 and rIL-12 enhanced IFN-γ production. Conclusion The results suggest that IL-23–stimulated production of IL-17 by CD4 + T cells may be responsible for the development of uveitis seen in patients with VKH disease. Clinical implications This study provides a new insight into the mechanism involved in the development of VKH disease.

IL-23 promotes CD4+ T cells to produce IL-17 in Vogt-Koyanagi-Harada disease

PURPOSE. CD4(+)CD25(high) regulatory T (Treg) cells have been shown to be involved in the pathogenesis of autoimmune diseases. Vogt-Koyanagi-Harada (VKH) syndrome is an organ-specific autoimmune disease. This study was designed to phenotypically and functionally characterize peripheral blood CD4(+)CD25(high) Treg cells in VKH patients with active uveitis. METHODS. Blood samples were taken from 30 patients with active VKH, 19 patients with inactive VKH, and 26 healthy controls. Peripheral blood mononuclear cells were subjected to flow cytometry for analysis of phenotypes of the CD4(+)CD25(high) Treg cells. For functional analysis, CD4(+)CD25(high) Treg cells and CD4(+)CD25-T cells were separated by means of magnetic-assisted cell sorting and subsequently cocultured for 6 days. The proliferation of CD4(+)CD25-T cells was measured by [H-3] thymidine incorporation assay. The levels of IFN-gamma, IL-17, and IL-13 in the supernatants were determined by enzyme-linked immunosorbent assay. RESULTS. Significantly decreased frequencies of CD4(+)CD25(high) Treg cells and percentages of FOXP3(+) cells in these Treg cells were shown in patients with active VKH. Treg cells from patients with active VKH showed a significant deficiency in suppressing the proliferation of CD4(+)CD25-T cells and inhibiting the production of IFN-gamma and IL-13 by CD4(+)CD25-T cells. CD4(+)CD25(high) Treg cells from VKH patients or healthy controls did not markedly inhibit or promote IL-17 production. CONCLUSIONS. A significantly decreased frequency and diminished function of CD4(+)CD25(high) Treg cells is associated with active uveitis in patients with VKH syndrome. These results suggest that these dysfunctional CD4(+)CD25(high) Treg cells may play a role in the pathogenesis of uveitis in VKH syndrome.

Diminished frequency and function of CD4+CD25high regulatory T cells associated with active uveitis in Vogt-Koyanagi-Harada syndrome.

Purpose IL-23 has been shown to be involved in the pathogenesis of Behcet9s disease (BD) through promoting IL-17 production. This study examined whether IL-23R polymorphisms were associated with susceptibility to this disease in a Chinese Han population. Methods Four single-nucleotide polymorphisms (SNP), rs7517847, rs11209032, rs 1343151 and rs17375018 were genotyped in 338 BD patients and 407 age, sex and ethnically matched healthy controls using a PCR restriction fragment length polymorphism assay. Results A significantly increased prevalence of the homozygous rs17375018 GG genotype and G allele was found in BD patients compared with controls (corrected p (p c ) c c =0.024, OR 1.69, 95% CI 1.21 to 2.35; p c c =0.0016, OR 0.59, 95% CI 0.45 to 0.77). Conclusions This study, for the first time, identified a strong association of an SNP of IL-23R , rs17375018, with BD. The results also suggested that both rs11209032 AA and rs17375018 GG of IL-23R are predisposing genotypes for BD and that the AGCG haplotype may provide protection against BD.

https://ard.bmj.com/content/annrheumdis/69/7/1325.full.pdf

Hongyan Zhou

Papers

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

Clinical Patterns and Characteristics of Uveitis in a Tertiary Center for Uveitis in China

IL-23 promotes CD4+ T cells to produce IL-17 in Vogt-Koyanagi-Harada disease

Diminished frequency and function of CD4+CD25high regulatory T cells associated with active uveitis in Vogt-Koyanagi-Harada syndrome.

IL-23R gene confers susceptibility to Behcet's disease in a Chinese Han population