Editorial: Immunology of Psoriatic Disease

摘要

Psoriasis is a chronic recurrent T cell-mediated inflammatory skin disease with a strong genetic predisposition. The disease is associated with joint manifestations (psoriatic arthritis, PsA), developing in about 30% of patients, and with comorbidities such as metabolic syndrome. Genome-wide scans provided the first insight into the pathogenesis of psoriasis and showed that the HLA-C ~(*)06:02 allele in the psoriasis susceptibility locus 1 on chromosome 6 accounts for up to 50% of disease heritability. Other gene variants associated with psoriasis are involved in the IL-23/IL-17 axis, CD8 ~(+) T cells differentiation, antigen processing, NF-κB/IL-1/TNF axis, and type-I interferon response ( 1 ). The picture that emerges is that psoriasis is a complex disease with autoimmune and autoinflammatory components that involves the interplay between keratinocytes, microvascular endothelium, dendritic cells (DCs), and T cells, generating a self-sustaining inflammatory cycle around the TNF/IL-23/IL-17 axis. Epidermal CD8 ~(+) T lymphocytes producing IFNγ and IL-17 may represent a major autoimmune mechanism in disease pathogenesis ( 2 , 3 ). Many questions remain unanswered and new scenarios open up based on the increasing evidence that has been recently provided. The mechanisms leading to the initial manifestations of psoriasis remain uncertain, and the exact characterization of the autoimmune and autoinflammatory responses occurring in psoriasis patients, as well as the mechanisms linking skin with extra-cutaneous and systemic manifestations await clarification. In this Research Topic, we invited scientists to summarize the latest advances on immunological mechanisms of psoriatic disease. The topic starts with three manuscripts exploring the possible autoimmune nature of psoriasis and its extra-cutaneous manifestations. Prinz reviews the refined approach that led to the characterization of autoreactive CD8 ~(+) T cells specific for melanocyte-derived ADAMTLS5 antigens presented by HLA-C ~(*)06:02, strengthening the evidence of an autoimmune component in psoriasis pathogenesis. HLA-C appears central to the promotion of organ-specific T cell responses due to its ability to present positively charged skin self-antigens. Then, Frasca et al. describe their original research on the characterization of autoantibodies to neutrophil LL-37 antimicrobial peptide in patients presenting PsA. The authors show that autoantibodies to LL-37 are elevated in PsA synovial fluid and correlate with clinical inflammatory markers. Although antibody formation may represent a secondary effect of the priming of LL37-specific T helper cells, these findings provide new insights in the autoimmune aspects linking psoriasis and its extra-skin manifestations. In the next article, De Jesús-Gil et al. overview the translational studies showing microbial trigger of skin-homing CLA ~(+) cells. The authors provide evidence that the CLA ~(+) fraction of circulating T cells secrete IL-17A, IL-17F, and IL-9 when stimulated with Streptococcus pyogenes . In addition, they report that CLA ~(+) T cells in psoriasis patients respond to skin S. pyogenes and C. albicans extracts, suggesting a relationship between memory T cells and environmental microbes. Finally, the authors underline how CLA ~(+) T cells activated by streptococcal antigens in tonsils could migrate to the skin where they recognize keratin-derived self-antigens presenting homology with streptococcal proteins. In this context, Casciano et al. outline the conceivable sequence of T cell-mediated events of the psoriatic inflammatory cascade. These include an initial phase in which autoreactive CD8 ~(+) T cells could play a major role, a second phase involving both self-reactive and polyclonal CD4 ~(+) T amplified by the IL-23/IL-17A axis, and an antigen-independent downstream recruitment of circulating CXCR3 ~(+) T cells. In this view the egress of T cells from the skin and their recirculation through the blood could represent a link between cutaneous psoriasis and its systemic and joint manifestations. The topic proceeds with four articles addressing the complex cytokine and cellular networks in psoriasis. Sch?n and Erpenbeck uncover the importance of the IL-23/Th17 axis in the cross-talk between innate and adaptive immune responses, including new players such as IL-17-producing innate lymphoid cells and unconventional γδT cells. The authors further analyze the T cell-neutrophil-keratinocyte loop leading to the amplification of the immune responses, particularly referring to the role of neutrophil extracellular traps. These latter may modulate the immune system by reducing the activation threshold of T cells and by favoring the presentation of neutrophil autoantigens (e.g., antimicrobial peptides) to antigen presenting cells (APCs). Further exploring the cytokine network in psoriasis, Brembilla et al. review the presence and function of cytokines belonging to the IL-17 family, focusing on the role o