IL-17 and Other New Agents
John Y. M. Koo, Ethan C. Levin, Argentina Leon, Jashin J. Wu, Alice B. Gottlieb in Moderate to Severe Psoriasis, 2014
Psoriasis was once thought to be a disease primarily mediated by the Th1 axis [1]. In 2005, Th17 cells were recognized as a distinct subtype of helper T cells (see Chapter 13) and were linked to autoimmune inflammation in murine models [2,3]. Th17 cells are defined by their ability to secrete interleukin-17 (IL-17) cytokines. These proinflammatory cytokines have increased expression in psoriatic skin and are now recognized as playing a critical role in the pathogenesis of psoriasis (Figure 16.1) [4–13]. IL-17 cytokines as well as their cell surface receptors represent promising therapeutic targets [10]. Other proinflammatory cytokines secreted by Th17 cells thought to be key players in the pathogenesis of psoriasis include tumor necrosis factor-α (TNF-α) and IL-22 (for more information on TNF-α, see Chapters 11, 12, and 14). In the skin, IL-22 primarily targets epithelial cells leading to epidermal hyperplasia [14]. Stimulation of keratinocytes with IL-22 induces proliferation and inhibits terminal differentiation. In addition, expression of antimicrobial proteins (e.g., defensins) is increased. Recently, a new subset of cells was described known as Th22 cells, which also secrete IL-22 but lack the ability to secrete IL-17 [15]. This section will focus on the role of IL-17 in the pathogenesis of psoriasis and will summarize the clinical trials data for medications that target the IL-17 inflammatory pathway.
Multifaceted Role of Th17 Cells in Psoriatic Disease
Siba P. Raychaudhuri, Smriti K. Raychaudhuri, Debasis Bagchi in Psoriasis and Psoriatic Arthritis, 2017
In 2005, the discovery of CD3+/CD4+ Th17 cells changed the paradigm for understanding autoinflammatory disease processes [7,8]. Th17 cells are a distinct form of CD4+ T cells that by either induction or activation can produce a completely distinct cytokine repertoire. These cells respond to the interleukin 1 receptor 1 (IL-1R1) and interleukin 23 receptor (IL-23R) signaling pathways. It has been postulated that transforming growth factor β (TGFβ), IL-1, IL-6, and IL-23 induce retinoic acid orphan receptors (RORγt and RORα), which result in the upregulation of IL-23R and eventual differentiation of naïve CD4+ T cells into Th17 cells. This has been eloquently summarized in a model for the development of Th17 cells, consisting of three overlapping steps: differentiation, amplification, and stabilization [9]. In particular, TGFβ and IL-6 induce differentiation, IL-21 expressed by developing Th17 cells mediates amplification, and IL-23 expands and stabilizes previously differentiated Th17 cells (also summarized in Table 6.1) [9].
Basics of Allergy
Pudupakkam K Vedanthan, Harold S Nelson, Shripad N Agashe, PA Mahesh, Rohit Katial in Textbook of Allergy for the Clinician, 2021
T cell phenotype: Activated T and B cells in the lymph node downregulate CCR7, begin to express receptors for chemokines that are preferentially expressed in the peripheral tissue and migrate to the site of pathogen entry. CD4 T cells (also called Th0) differentiate into T helper 1 cells (Th1), T helper 2 cells (Th2), and T helper 17 (Th17) cells, whereas CD8 T cells differentiate into cytotoxic T cells (Tables 1.3 and 1.4). Under specific circumstances cytotoxic CD8 T cells can differentiate into Tc1 and Tc2 cells, whose cytokine production profile is similar to that Th1 and Th2 cells. The differentiation of Th1, Th2 and Th17 cells is induced by IL-12, IL-4, and IL6, IL1 (in humans) and TGFb (in mice) respectively (Glimcher 2001). The foregoing cytokines are typically secreted by the antigen-presenting cell and/or other accessory cells. For Th1 differentiation IL-12 signaling via STAT-4 is essential, which activates the master Th1 regulator—T-bet, a transcription factor that induces sustained production of Th1 cytokines and also blocks Th2 differentiation. IL-4 signaling via STAT-6 and other signaling molecules, induces the master Th2 switch—GATA-3. GATA-3 stimulates Th2 cytokine production and inhibits Th1 differentiation (Table 1.4). IL6 stimulated STAT3 in the presence of TGFb induces RORgT, the master regulator of Th17. Th1 cells are primarily induced by and play a critical role in the defense against intracellular pathogens. Th2 cells are induced by extracellular pathogens/antigens. Th17 cells are induced by pathogens but are involved in autoimmunity in addition to defense against pathogens.
Interleukin-17 promotes the production of underglycosylated IgA1 in DAKIKI cells
Published in Renal Failure, 2018
Jia-Ru Lin, Ji Wen, Hui Zhang, Li Wang, Fang-Fang Gou, Man Yang, Jun-Ming Fan
Th17 cells are a type of T helper cell with the main function of secreting interleukin 17 (IL-17), which is a newly discovered cytokine implicated in inflammation regulation. At the same time, Th17 cells play a significant role in the development of autoimmune diseases including rheumatoid arthritis and multiple sclerosis. Matsumoto et al. observed increased levels of IL-17 excretion in the urine of patients with minimal-change nephrotic syndrome (MCNS) and IgAN when compared to non-nephrotic patients and healthy controls. In MCNS, the daily urinary IL-17 (uIL-17) excretion was increased, and there was a positive correlation between urinary protein excretion and daily uIL-17 excretion. IL-17 was also shown to stimulate the release of a number of pro-inflammatory cytokines from peripheral blood monocytes (PBM) in IgAN patients [5,6]. However, the molecular mechanisms mediating IL-17 involvement in the immune-related pathogenesis of IgAN have not been fully elucidated.
Pregnancy immune tolerance at the maternal-fetal interface
Published in International Reviews of Immunology, 2020
Xiaopeng Li, Jiayi Zhou, Min Fang, Bolan Yu
Th17 cells are a subpopulation of T helper cells, which produce IL-17 with specific roles in host defense against certain pathogens and in organ specific autoimmunity.92,93 IL-17 has pro-inflammatory properties inducing various cells to express cytokines such as IL-6, IL-8, GM-CSF, G-CSF, chemokines CXCL1, CXCL10 and metalloproteinases.94 Th17 cells-mediated local inflammation responses contribute to anti-pathogen defense like Bacteroides species,95Klebsiella pneumoniae and Candida albicans.96 Extensive inflammation affects the pregnancy tolerance, so the Th17 cells must be balanced by other cell types. The CD56brightCD27+ decidual NK cell subsets promote immune tolerance and successful pregnancy by dampening inflammatory Th17 cells depending on INF-γ secretion.97 Th17-related cytokines could promote the expression of depressive and anxiety symptoms during pregnancy. Regulation of Th17 cell proportion by immunological therapy might be a new strategy for happy and healthy pregnancy.98–100
Immune-related adverse events are clustered into distinct subtypes by T-cell profiling before and early after anti-PD-1 treatment
Published in OncoImmunology, 2020
Kyung Hwan Kim, Joon Young Hur, Jinhyun Cho, Bo Mi Ku, Jiae Koh, June Young Koh, Jong-Mu Sun, Se-Hoon Lee, Jin Seok Ahn, Keunchil Park, Myung-Ju Ahn, Eui-Cheol Shin
The Th17-related subgroup was characterized by a high baseline Th17 to Th1 ratio. The role of Th17 cells has been demonstrated in multiple autoimmune diseases.12,18 Th17 cells secrete a highly inflammatory cytokine, IL-17A, which plays protective roles in host defense against bacterial and fungal pathogens at epithelial and mucosal barriers. Dysregulated production of IL-17A can result in autoimmunity and tissue damage. In addition, previous studies have suggested that the balance between Th17 and Th1 is associated with autoimmune disease.19,20 Recently, an IL-17A blocking antibody was developed and introduced for the treatment of psoriasis,21 psoriatic arthritis,22 and ankylosing spondylitis.23 Intriguingly, IL-17A blocking antibody was also tried in the management anti-PD-1-induced irAEs.24,25
Related Knowledge Centers
- Cd4
- Interleukin 17
- Interleukin 23
- Interleukin 6
- Regulatory T Cell
- T Helper Cell
- Transforming Growth Factor Beta
- Interleukin 21
- Stat3
- Rar-Related Orphan Receptor Gamma