Immunopathogenic mechanisms in psoriasis

Abstract

Psoriasis is a common autoimmune skin disease characterized by T cell-mediated hyperproliferation of keratinocytes. The disease has a strong but complex genetic background with a concordance of approximately 60% in monozygotic twins, and recent linkage and high resolution association studies indicate that HLA-Cw*0602 is itself a major susceptibility allele for psoriasis. Patients carrying this allele have been shown to have different clinical features and earlier age of disease onset, and patients homozygous for this allele have about 2.5 times higher disease risk than heterozygotes. Published data indicate that CD8+ T cells may play a major effector role in psoriasis. Epidermal infiltration of predominantly oligoclonal CD8+ T cells, and probably also of CD4+ T cells in the dermis, is a striking feature of chronic psoriasis lesions, indicating that these cells are responding to specific antigens. We argue that CD4+ T cells are essential for initiating and maintaining the pathogenic process of psoriasis but that cross-primed CD8+ T cells are the main effector cells responding to antigens in the HLA-Cw*0602 binding pocket of keratinocytes. It is further proposed that CD8+ T cells are involved in the control of the Th1 polarization, which is observed in psoriasis lesions, through a complex interplay between CD4+, CD8+ T cells and cross-presenting dendritic cells. It is also suggested that spontaneous remissions or fluctuations in disease activity may be determined by a balance within the lesions between effector and suppressor CD4+ and CD8+ T cells.

Fig. 1

The cytokine network in psoriasis in mainly characterized by Th1 cytokines such as IFN-γ, IL-12 and TNF-α. Major cytokine producers in the lesions are DCs, CD4+ and CD8+ T cells and keratinocytes. IFN-γ and TNF-α induce keratinocytes to produce IL-6, IL-7, IL-8, IL-12, IL-15, IL-18 and TNF-α besides multitude of other cytokines, chemokines and growth factors. IL-18 acts on DCs synergistically with IL-12, to increase the production of IFN-γ. IL-7 and IL-15 are important for the proliferation and homeostatic maintenance of the CD8+ T cells. IL-17 which is produced by activated CD4+ T cells, synergizes with IFN-γ to elicit further production of pro-inflammatory cytokines by the keratinocytes. In this way the cytokine network in psoriasis can become a self-sustaining process.

Fig. 2

It is proposed that CD8+ T cells together with TNF-α and IFN-γ increase the activation level and maturation of DCs (imDC to mDC). This results in the induction of type-1 polarized mature DCs capable of producing high levels of IL-12p70 upon a subsequent CD40 ligation. Thus, CD8+ T cells may be essential for the maintainance of the Th1 environment, and this tight control of the Th1 pattern in psoriasis can explain why a Th2 skin disease, such as atopic eczema, very rarely occurs in patients with psoriasis.

Fig. 3

Schematic presentation of the processes suggested to be involved in the generation of guttate psoriasis and chronic plaque psoriasis. In guttate psoriasis, or exacerbation of chronic plaque psoriasis after streptococcal throat infection, it is envisaged that streptococcal specific T cells, and possibly DCs carrying streptococcal antigens migrate from the tonsils into the skin where the specific T cells recognize streptococcal antigens or cross-reactive antigens derived from keratinocytes with a resulting eruption of guttate psoriasis. If effective cross-presentation does not occur, perhaps due to sufficient infiltration and activation of CD8 + suppressor T cells, the disease process is self-limited, while effective cross-presentation results in the recruitment of cross-reactive T cells that recirculate between lymph nodes and the skin lesions. This scenario predicts that oligoclonal T cells would be more pronounced in chronic plaques than in guttate lesions.