Th17 lymphocyte

Subgroup of T-helper lymphocytes (Th cells), which, independent of the known differentiation pathways of Th1 and Th2 cells, have their own differentiation path with their own cytokine pattern. 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 particular inflammatory pattern is responsible for the infiltration of the skin by neutrophil granulocytes and the reactive proliferation of keratinocytes and dermal vessels.

The crucial 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, IL-17A and IL-17F show the highest sequence homology. They seem to be responsible for the proinflammatory effect in psoriasis and rheumatoid arthritis. Increased levels 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 therapy of psoriasis since 2009) blocks the Th-17 immune response. It binds to the subunit p40 of Il-23, which is at the same time part of the cytokine IL-12 produced by the Th1 cells. Thus, this biologic blocks the function of 2 cytokines simultaneously in a dual approach.

Apparently, however, the selective blockade of Il-23 is sufficient for a good antisporial effect. The biologics Guselkumab, Tildrakizumab and BI 655066, which are currently undergoing clinical trials, pursue exactly this therapeutic approach. Another therapeutic approach which 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 of this biologics class is Secukinumab (Cosentyx®) which has been approved in the meantime and has a very good antipsoriatic effect. 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 target cells, resulting in enhanced granulocytopoiesis and neutrophil granulocyte activation and attraction. In addition, IL-17 induces the expression of several proinflammatory mediators, such as IL-1, IL-6, PGE2, cyclooxygenase 2, and matrix metalloproteinases.

IL-17 further 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.