Association of Pathogenic Th17 Cells with the Disease Severity and Its Potential Implication for Biological Treatment Selection in Psoriasis Patients

Abstract

Psoriasis is an inflammatory autoimmune disease characterized by cutaneous lesions in plaques. It has been proposed that the immune response has a key role in the disease progression. Particularly, the Th17 cells through IL-17 can contribute to maintain the inflammatory process. The pathogenic Th17 phenotype has been described in human diseases and associated with high severity in inflammatory experimental models. However, it is not clear if the pathogenic phenotype could be present in the skin and peripheral blood as well as its possible association to severity in psoriasis. In the lesional skin, we found high infiltration of Th17 cells and the pathogenic phenotype, finding a correlation between the frequency of Th17 cells and the Psoriasis Area and Severity Index (PASI) score. In peripheral blood, we observed a pool of Th17 lymphocytes with potential to acquire pathogenic features. Interestingly, the percentage of pathogenic Th17 cells (CD4+ RORγt+ IFN-γ+) correlates with disease severity. Moreover, we distinguished three groups of patients based on their IL-17/IFN-γ production by Th17 lymphocytes, which seems to be related with a dynamic or stable potential to express these cytokines. Remarkably, we evaluated the cytokine production by Th17 cells as an immunological marker for the adequate selection of biologic therapy. We found that patients analyzed by this immunological approach and treated with antibodies against IL-17 and TNFα showed great improvement depicted by reduction in PASI and Dermatology Life Quality Index (DLQI) score as well as the percentage of Body Surface Area (BSA). Altogether, our results highlight the importance of the assessment of the pathogenic phenotype in Th17 cells as an immune personalized analysis with the potential to support the therapy choice in the clinical practice.

Skin Barrier Dysregulation in Psoriasis

“…Th17 cells also have noninflammatory, homeostatic functions, and so are separated into pathogenic and beneficial subtypes [ 136 ]. Unsurprisingly, pathogenic type Th17 cells are the subtype enriched in psoriatic lesions and peripheral blood [ 137 ]. Therapies specifically targeting pathogenic Th17 cells may, therefore, remove a promoter of psoriatic inflammation without removing homeostatic Th17 responses.…”

Proximal and Distal Regions of Pathogenic Th17 Related Chromatin Loci Are Sequentially Accessible During Pathogenicity of Th17

“…Effector cytokine expression in pathogenic or regulatory Th17 was particularly important for their functions. Ifng , Tnf , and Csf2 were prominently expressed by pathogenic Th17, while Il17a , Il17f , Il10 and Il21 were substantially expressed by regulatory Th17 ( 5 , 48 , 49 ). Consistently, obvious DNA accessibility differences at their gene loci were also identified, suggesting that these specific ChARs in the two Th17 subgroups might closely associate with their effector function ( Figure S1C ).…”

“…The effector genes in pathogenic Th17 are related to their pathogenicity in EAE. They include Ifng , Tnf , Csf2 , Ccl20 , and Ccl5 , which are much similar to the effector genes of pro-inflammatory Th1 cells ( 5 , 46 – 49 ). Their blockade can efficiently ameliorate the autoimmune responses ( 50 – 52 ).…”

Minimal Physiologically-Based Pharmacokinetic (mPBPK) Metamodeling of Target Engagement in Skin Informs Anti-IL17A Drug Development in Psoriasis

“…The model assumes that the production of IL-17A remains constant throughout the course of treatment. However, since many biomarkers, including Th17 cells ( Aguilar-Flores et al, 2020 ), IL-17 signature genes ( Chiricozzi et al, 2016 ), and serum IL-17 ( Chen et al, 2013 ) are positively correlated with disease severity, this assumption may not hold true, especially upon long-term treatment. In the TE-based MBMA, results from a small number of secukinumab and ixekizumab Phase 2 studies deviated notably from the overall PASI75/90-TE relationship.…”