Regulatory T Cells in Psoriasis

12.1 Introduction 194

12.1.1 Psoriasis as a T Cell-Mediated Autoimmune Disease 194

12.2 T Cell Activation 196

12.3 T Regulatory Cells 197

12.3.1 Identifying Treg Cells 197

12.4 T Regulatory Cells in Psoriasis 199

12.4.1 Numbers 200

12.4.2 Activity 200

12.4.3 Tissue 203

12.4.4 Measuring Treg Cells in Skin 203

12.5 Therapy and the Treg Population: The Example of Alefacept . . . 205

12.6 Conclusions and Implications 206

References 207

Abstract. Psoriasis is a chronic autoimmune disease in which T lymphocytes are thought to be central in the pathogenesis. Recently, a T cell subset population was identified, whose role is to suppress inflammatory responses triggered by T effector cells. T cells in this new population are referred to as T regulatory cells. We studied their number and activity in psoriatic lesions and found that they are both numerically and functionally deficient in their ability to suppress the abnormally persistent psoriatic immune response. This deficiency may shed more light on the complex pathophysiology of psoriasis.

12.1 Introduction

Psoriasis is a common cutaneous disease affecting as many as 2% of the population in the world. Though there have been differing viewpoints regarding the pathogenesis of psoriasis over the preceding decades, common consensus holds that it is an autoimmune disease, and likely the most common autoimmune disease. Though an etiology of psoriasis still has not been determined, activated T cells appear to be central in promoting both disease onset and maintenance. This determination arrives from several observations:

1. T cells are seen to appear in nonlesional skin before there is evidence of keratinocyte proliferation; these T cells are usually of the memory (CD45RO+) subtype.

2. Therapy specifically directed against T cells may be remittive in disease.

3. T cells are critical to maintain lesions.

Why T cells remain in a persistently activated state and target normal biologic structure, i.e., keratinocytes, remains unclear, though we can postulate that any of several factors may play a role, perhaps in concert. There may be an overactivity of antigen presentation by antigen presenting cells (APCs) which interact with naive T cells through receptor pairing and interaction, such as LFA3-ICAM-1, B-7-CD28, etc. APCs may be elaborating stimulatory cytokines such as IL-12, IL-23 TNF-a, or IL-15, activating T cells and driving a differentiation toward the type I or pro-inflammatory phenotype. There may be an abnormal basement membrane zone in prelesional psoriatic skin that is hyperstimulatory. Furthermore, we may postulate that in individuals with psoriasis, there is an intrinsic defect in the ability of elements in the immune system whose function it is to restrain and terminate brisk responses, therefore leading to a persistent and chronically abnormal immune response. These elements of the immune system include what are now recognized to be T regulatory (Treg) cells.

12.1.1 Psoriasis as a T Cell-Mediated Autoimmune Disease

Evidence of psoriasis as a T cell-mediated autoimmune disease is fairly recent, as earlier research had focused on the epidermal hyperplasia as the more primary phenomenon. However, even before antibodies were available to phenotype different types of leukocytes, it was observed that the dermis of psoriasis vulgaris lesions contained numerous mononu-clear cells, and that these cells appeared in early lesions before obvious epidermal changes were apparent (Braun-Falco and Schmoekel 1977). We now recognize these cells as T cells, and in fact, the earliest appearing T cells are CD45RO+ memory T cells (Vissers et al 2004); the CD45RO memory (effector) population actually undergoes proliferation within the psoriatic lesion (Morganroth et al. 1991). Phenotypic analysis of infiltrating T cells reveals that a majority of the infiltrate in the dermis is CD4+, whereas most of the epidermal T cells are CD8+ (cyototoxic T cells) (Krueger 2002). By both analysis of surface markers and measures of cytokines produced, it is apparent that the majority of these infiltrating T cells are type I, or prinflammatory and produce cytokines such IFN-y, TNF-a, IL-8 and IL-2 as opposed to more anti-inflammatory or humoral cytokines, such as IL-4, IL-5, IL-10, or IL-13. (Szabo et al. 1998; Austin et al. 1999; Lew et al. 2004) Over time, both through serendipity and by design, it has been observed that agents that either inhibit T cell activity (such as steroids or cyclosporine), or that were directly toxic to these cells (DAB389IL-2, UV light) were associated with clearance of psoriasis. As such, it is now the current consensus that pathogenic T effector cells mediate both the initiation and maintenance of chronic psoriatic plaques.

Several have noticed that the basement membrane of the epidermis in patients with psoriasis is ultrastructrally different than that of phenotyp-ically normal individuals (Heng et al. 1986). Concordantly, uninvolved and involved skin of patients with psoriasis exhibits increased basement membrane zone expression of the EDA splice variant of fibronectin, a form that is associated with hyperplasia, such as in wounds, fetal tissue, and cancer (Bata-Csorgo et al. 1998; Ting et al. 2000). Functionally, psoriatic basal keratinocytes containing resting stem cells exposed to fibronectin undergo more rapid induction of cell cycle entry and cell spreading if the cells are derived from psoriatic uninvolved vs normal skin, particularly in combination with psoriatic T cell lymphokines (Bata Csorgo et al. 1995; Chen et al. 2001; Szeli et al. 2004). This is, it appears, central in the pathogenesis of psoriasis is the interplay of activated T cells, antigen-presenting cells, and an abnormally primed hyperplastic

Natural Treatments For Psoriasis

Natural Treatments For Psoriasis

Do You Suffer From the Itching and Scaling of Psoriasis? Or the Chronic Agony of Psoriatic Arthritis? If so you are not ALONE! A whopping three percent of the world’s populations suffer from either condition! An incredible 56 million working hours are lost every year by psoriasis sufferers according to the National Psoriasis Foundation.

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