Adaptive and Innate Immunity in Psoriasis and Other Inflammatory Disorders

Abstract

Over the past three decades, a considerable body of evidence has highlighted T cells as pivotal culprits in the pathogenesis of psoriasis. This includes the association of psoriasis with certain MHC (HLA) alleles, oligoclonal expansion of T cells in some cases, therapeutic response to T cell-directed immunomodulation, the onset of psoriasis following bone marrow transplantation, or induction of psoriasis-like inflammation by T cells in experimental animals. There is accumulating clinical and experimental evidence suggesting that both autoimmune and autoinflammatory mechanisms lie at the core of the disease. Indeed, some studies suggested antigenic functions of structural proteins, and complexes of self-DNA with cathelicidin (LL37) or melanocytic ADAMTSL5 have been proposed more recently as actual auto-antigens in some cases of psoriasis. These findings are accompanied by various immunoregulatory mechanisms, which we increasingly understand and which connect innate and adaptive immunity. Specific adaptive autoimmune responses, together with our current view of psoriasis as a systemic inflammatory disorder, raise the question of whether psoriasis may have connections to autoimmune or autoinflammatory disorders elsewhere in the body. While such associations have been suspected for many years, compelling mechanistic evidence in support of this notion is still scant. This review sets into context the current knowledge about innate and adaptive immunological processes in psoriasis and other autoimmune or autoinflammatory diseases.

Keywords: adaptive immunity; autoimmune disease; innate immunity; psoriasis; skin—immunology.

Figure 1

Complex fine-tuning of innate and adaptive immune mechanisms determines onset, course, and activity of psoriasis. As detailed in the text, intricate interactions between components of the innate (exemplified here by dendritic cells and macrophages) with components of the adaptive immune system (exemplified here by T cells) lie at the core of the pathophysiology of psoriasis. Once established, the relative contribution and fine-tuning of various mediators of adaptive and innate immunity determine the clinical manifestation toward chronic stable vs. highly inflammatory and/or pustular psoriasis.

Figure 2

Initiation of psoriasis by antigen-dependent and antigen-independent immune mechanisms. Complexes of self-DNA with fragments of the antimicrobial peptide, cathelicidin, can stimulate plasmacytoid dendritic cells through TLR9. They can also be presented by HLA-C*06:02 molecules and specifically activate T cells through their TCR. Likewise, the melanocyte-derived ADAMTSL5 can activate pathogenic CD8+ T cells after presentation by HLA-C*06:02.

Figure 3

Differentiation of pathogenic T cells in psoriasis is embedded in a complex regulatory network. Naïve T cells can differentiate into several directions; this is mainly determined by the cytokines and transcription factors depicted here. In addition, various regulatory feedback mechanisms exist, some of which are schematically highlighted here with particular reference to Th17 cell differentiation and function.

Figure 4

Paradoxical psoriasis triggered by TNF inhibitors in predisposed individuals. Several cytokines contribute to the pathogenesis of psoriatic skin lesions, with TNFα and IL-17A playing prominent roles. However, TNFα also exerts an inhibitory effect on plasmacytoid dendritic cells. Upon therapeutic inhibition of TNFα, this inhibitory effect is abrogated and the resulting shift toward increased production of type I interferons fuels the secretion of IL-17. It is conceivable that additional mechanisms contribute to the shift of cytokines ultimately resulting in “paradoxical” psoriatic lesions.