Update on the Pathophysiology of Psoriasis

Implicating Dysregulation of Immunity

Our present appreciation of the pathogenesis of psoriasis is based on the history of trial-and-error therapies; serendipitous discoveries; and the current immune targeting drugs used in a variety of chronic inflammatory conditions, including rheumatoid arthritis, ankylosing spondylitis, and inflammatory bowel disease. Before the mid-1980s, research focused on the hyperproliferative epidermal cells as the primary pathology because a markedly thickened epidermis was indeed demonstrated on histologic specimens. Altered cell-cycle kinetics were thought to be the culprit behind the hyperkeratotic plaques. Thus, initial treatments centered on oncologic and antimitotic therapies used to arrest keratinocyte proliferation with agents such as arsenic, ammoniated mercury, and methotrexate.⁴

However, a paradigm shift from targeting epidermal keratinocytes to immunocyte populations was recognized when a patient receiving cyclosporine to prevent transplant rejection noted clearing of psoriatic lesions in the 1980s.⁵ Cyclosporine was observed to inhibit messenger RNA transcription of T-cell cytokines, thereby implicating immunologic dysregulation, specifically T-cell hyperactivity, in the pathogenesis of psoriasis.⁶ However, the concentrations of oral cyclosporine reached in the epidermis exerted direct effects on keratinocyte proliferation and lymphocyte function in these patients.⁷ Thus, the question was raised as to whether the keratinocytes or the lymphocytes drove the psoriatic plaques. The use of an IL-2 diphtheria toxin-fusion protein, denileukin diftitox, specific for activated T cells with high-affinity IL-2 receptors and nonreactive with keratinocytes, distinguished which cell type was responsible. This targeted T-cell toxin provided clinical and histological clearing of psoriatic plaques. Thus, T lymphocytes rather than keratinocytes were recognized as the definitive driver behind the psoriatic plaques.⁸

Additional studies have demonstrated that treatments that induce prolonged clearing of psoriatic lesions without continuous therapy, such as psoralen plus UVA irradiation, decreased the numbers of T cells in plaques by at least 90%.⁹ However, treatments that require continual therapy for satisfactory clinical results, such as cyclosporine and etretinate, simply suppress T-cell activity and proliferation.^10,11 Further evidence has linked cellular immunity with the pathogenesis of psoriasis, defining it as a T_H1-type disease. Natural killer T cells were shown to be involved through the use of a severe combined immunodeficient mouse model. They were injected into prepsoriatic skin grafted on immunodeficient mice, creating a psoriatic plaque with an immune response showing cytokines from T_H1 cells rather than T_H2 cells.¹² When psoriatic plaques were treated topically with the toll-like receptor 7 agonist imiquimod, aggravation and spreading of the plaques were noted. The exacerbation of psoriasis was accompanied by an induction of lesional T_H1-type interferon produced by plasmacytoid dendritic cell (DC) precursors. Plasmacytoid DCs were observed to compose up to 16% of the total dermal infiltrate in psoriatic skin lesions based on their coexpression of BDCA2 and CD123.¹³ Additionally, cancer patients being treated with interferon alfa experienced induction of psoriasis.¹⁴ Moreover, patients being treated for warts with intralesional interferon alfa developed psoriatic plaques in neighboring prior asymptomatic skin.¹⁵ Patients with psoriasis who were treated with interferon gamma, a T_H1 cytokine type, also developed new plaques correlating with the sites of injection.¹⁶

Intralesional T Lymphocytes

Psoriatic lesions contain a host of innate immunocytes, such as APCs, NK cells, and neutrophils, as well as adaptive T cells and an inflammatory infiltrate. These cells include CD4 and CD8 subtypes in which the CD8⁺ cells predominate in the epidermis, while CD4⁺ cells show preference for the dermis.¹⁷ There are 2 groups of CD8⁺ cells: one group migrates to the epidermis, expressing the integrin CD103, while the other group is found in the dermis but may be headed to or from the epidermis. The CD8⁺ cells residing in the epidermis that express the integrin CD103 are capable of interacting with E-cadherin, which enables these cells to travel to the epidermis and bind resident cells. Immunophenotyping reveals that these mature T cells represent chiefly activated memory cells, including CD2⁺, CD3⁺, CD5⁺, CLA, CD28, and CD45RO⁺.¹⁸ Many of these cells express activation markers such as HLA-DR, CD25, and CD27, in addition to the T-cell receptor (TCR).

T-Lymphocyte Stimulation

Both mature CD4⁺ and CD8⁺ T cells can respond to the peptides presented by APCs. Although the specific antigen that these T cells are reacting to has not yet been elucidated, several antigenic stimuli have been proposed, including self-proteins, microbial pathogens, and microbial superantigens. The premise that self-reactive T lymphocytes may contribute to the disease process is derived from the molecular mimicry theory in which an exuberant immune response to a pathogen produces cross-reactivity with self-antigens.¹⁹ Considering that infections have been associated with the onset of psoriasis, this theory merits consideration. However, it also has been observed that T cells can be activated without antigens or superantigens but rather with direct contact with accessory cells.²⁰ No single theory has clearly emerged. Researchers continue to search for the inciting stimulus that triggers the T lymphocyte and attempt to determine whether T cells are reacting to a self-derived or non–self-derived antigen.

T-Lymphocyte Signaling

T-cell signaling is a highly coordinated process in which T lymphocytes recognize antigens via presentation by mature APCs in the skin rather than the lymphoid tissues. Such APCs expose antigenic peptides via class I or II MHC molecules for which receptors are present on the T-cell surface. The antigen recognition complex at the T-cell and APC interface, in concert with a host of antigen-independent co-stimulatory signals, regulates T-cell signaling and is referred to as the immunologic synapse. The antigen presentation and network of co-stimulatory and adhesion molecules optimize T-cell activation, and dermal DCs release IL-12 and IL-23 to promote a T_H1 and T_H17 response, respectively. The growth factors released by these helper T cells sustain neoangiogenesis, stimulate epidermal hyperproliferation, alter epidermal differentiation, and decrease susceptibility to apoptosis that characterizes the erythematous hypertrophic scaling lesions of psoriasis.²¹ Furthermore, the cytokines produced from the immunologic response, such as tumor necrosis factor (TNF) α, IFN-γ, and IL-2, correspond to cytokines that are upregulated in psoriatic plaques.²²

Integral components of the immunologic synapse complex include co-stimulatory signals such as CD28, CD40, CD80, and CD86, as well as adhesion molecules such as cytotoxic T-lymphocyte antigen 4 and lymphocyte function-associated antigen (LFA) 1, which possess corresponding receptors on the T cell. These molecules play a key role in T-cell signaling, as their disruption has been shown to decrease T-cell responsiveness and associated inflammation. The B7 family of molecules routinely interacts with CD28 T cells to co-stimulate T-cell activation. Cytotoxic T-lymphocyte antigen 4 immunoglobulin, an antibody on the T-cell surface, targets B7 and interferes with signaling between B7 and CD28. In psoriatic patients, this blockade was demonstrated to attenuate the T-cell response and correlated with a clinical and histological decrease in psoriasiform hyperplasia.²³ Biologic therapies that disrupt the LFA-1 component of the immunologic synapse also have demonstrated efficacy in the treatment of psoriasis. Alefacept is a human LFA-3 fusion protein that binds CD2 on T cells and blocks the interaction between LFA-3 on APCs and CD2 on memory CD45RO⁺ T cells and induces apoptosis of such T cells. Efalizumab is a human monoclonal antibody to the CD11 chain of LFA-1 that blocks the interaction between LFA-1 on the T cell and intercellular adhesion molecule 1 on an APC or endothelial cell. Both alefacept and efalizumab, 2 formerly marketed biologic therapies, demonstrated remarkable clinical reduction of psoriatic lesions, and alefacept has been shown to produce disease remission for up to 18 months after discontinuation of therapy.^24-26