Th17 lymphocyte

Subgroup of T helper lymphocytes (Th cells) that have their own differentiation pathway with their own cytokine pattern, independent of the known differentiation pathways of Th1 and Th2 cells. In addition to interleukin 17, Th17 cells produce a number of other cytokines(interleukin-6, interleukin-17A, interleukin-17F, interleukin-21, interleukin-22, interleukin-23, TNF-alpha, GM-CSF). Activated Th17 lymphocytes specifically express the transcription factor ROR-gamma-T.

Due to their broad inflammatory potency, they have an essential function in the pathogenesis of autoimmune diseases.

A Th-17 accentuated inflammatory pattern dominates in psoriasis and rheumatoid arthritis. This specific inflammatory pattern is responsible for the infiltration of the skin by neutrophil granulocytes and for the reactive proliferation of keratinocytes and dermal vessels.

The decisive factors for the differentiation of IL-17 producing cells are the cytokines IL-6 and TGF-beta. It has now been established that IL-17 is not just a single cytokine, but an entire cytokine family with 6 members.

This consists of the cytokines IL-17A - F. IL-17A, IL-17E and -IL-17F are produced by T cells, with IL-17A and IL-17F showing the highest sequence homology. They appear to be responsible for the pro-inflammatory effect in psoriasis and rheumatoid arthritis. Increased concentrations of IL-17 have been detected in the synovial fluid of patients with rheumatoid arthritis.

The importance of the Th17 cytokine family results from the large number of biologics already available or still in development that modulate the cytokine pattern of Th17 cells. For example, the biologic ustekinumab (approved for the treatment of psoriasis since 2009) blocks the Th-17 immune response. It binds to the p40 subunit of Il-23, which is also part of the cytokine IL-12 produced by the Th1 cells. This biologic thus blocks the function of 2 cytokines simultaneously in a dual approach.

However, the selective blockade of Il-23 is apparently sufficient for a good anti-sporiatic effect. The biologics guselkumab, tildrakizumab and BI 655066, which are currently undergoing clinical trials, follow exactly this therapeutic approach. Another therapeutic approach that emphasizes the importance of the Th-17 cell is the direct blockade of the cytokine IL-17A or the blockade of its receptor (IL-17RA). The first antibody in this class of biologics is secukinumab (Cosentyx®), which has now been approved and has very good antipsoriatic effects. The anti-Il17A antibody Ixekizumab is similarly effective. The monoclonal antibody brodalumab binds the soluble IL-17 receptor and thus prevents the signal transmission of IL-17A and IL-17F.

The IL-17 receptor(IL-17R) is expressed by myeloid cells, B and T lymphocytes, epithelial and endothelial cells and fibroblasts, among others. IL-17 induces the expression of G-CSF, IL-8 and IL-6 in the target cells and thus causes increased granulocytopoiesis as well as the activation and attraction of neutrophil granulocytes. IL-17 also induces the expression of various pro-inflammatory mediators, such as IL-1, IL-6, PGE2, cyclooxygenase 2 and matrix metalloproteinases.

IL-17 also stimulates osteoclastogenesis, inhibits proteoglycan synthesis and induces proteoglycan degradation. IL-17 exerts its pathogenic effects in arthritis partly synergistically with, but independently of TNF-a and IL-1.

Th17 cells are so named because they form the cytokine Il-17.

1. Griffiths CE et al (2015) Comparison of ixekizumab with etanercept or placebo in moderate to severe psoriasis (UNCOVER-2 and UNCOVER-3): results from two phase 3 randomised trials. Lancet 386(9993):541-551.
2. Volc S et al (2016) Pathophysiological basis of systemic therapies in psoriasis. J Dtsch Dermatol 14:557-557
3. Weaver CT et al (2007) IL-17 family cytokines and the expanding diversity of effector T cell lineages. Annu Rev Immunol 25:821-852.