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What can psoriasis teach us about the genetic basis of cutaneous T-cell lymphoma?

Psoriasis is a germ-line polygenic disorder in which major histocompatibility complex class I appears to play a major role, whereas cutaneous T-cell lymphoma (CTCL) is likely influenced by germline variation but appears to be driven largely by somatic mutations; though familial cases of CTCL have been identified, the rarity of the disorder makes it difficult to apply the large case-control sampling strategy that has led recently to the identification of multiple susceptibility loci in psoriasis and other immune-mediated disorders. While underlying genetic variation may play a role in contributing to the spectrum of phenotypic variation in CTCL, current knowledge suggests that this disease is best understood in terms of somatic mutations occurring in pathogenic T-cell clones, resulting in a further host immune response. Whether germ-line or somatic, alterations in various components of nuclear factor-κB signaling may prove to be an important final common pathway in both disorders. Cutaneous T-cell lymphoma is a heterogeneous group of extranodal non-Hodgkin lymphomas (NHLs) targeted to the skin,1 with mycosis fungoides (MF) and Sézary syndrome (SS) being most familiar to dermatologists. Mycosis fungoides and psoriasis are both mediated by skin-homing T cells. While the 2 disorders are readily distinguished histologically, they can occasionally be confused clinically, leading to worsening of MF after anti–tumor necrosis factor (TNF) treatment.2 In both disorders, there is clonal expansion of skin-homing memory T cells and a milieu that encourages polyclonal T-cell activation.3 However, there are important differences. In psoriasis, expansion of pathogenic T cells tends to be oligoclonal and may be due to chronic antigen stimulation originating in the tonsils,4 whereas in MF, clonal expansion is accompanied by genomic instability affecting genes involved in cell survival and apoptosis.5 Furthermore, in CTCL there is a nonclonal population of cytotoxic CD8+ T cells and possibly natural killer cells that is thought to be involved in controlling the malignant T-cell clone,6 whereas most pathogenic schema for psoriasis lack such a population. Moreover, in MF, CD8+ T cells are found in both the dermis and epidermis, where as in psoriasis, they are largely confined to the epidermis.3 The potential importance of antigenic stimulation in maintaining the malignant clone in MF has been emphasized7 but remains incompletely understood. While the classic Pautrier microabscess indeed represents a clustering of epidermal T cells around epidermal Langerhans cells, these are immature antigen-presenting cells with strong phagocytic function but weak major histocompatibility complex (MHC) class II expression and costimulatory activity. Suggestive of a role for antigen-dependent MHC–T-cell receptor (TCR) engagement, MF is an HLA-associated disorder, and immature antigen-presenting cells derived from extracorporeal photopheresis support long-term proliferation and survival of CTCL cells in a contactand TCR-dependent manner.8 However, most studies have not directly addressed the role of MHC class II in supporting proliferation or blocking apoptosis through the use of class II– blocking antibodies. Indeed, there is recent evidence that reduced signaling through the TCR is important for CTCL cell survival.9 Psoriasis and CTCL also manifest prominent differences in the cytokine milieu, with psoriasis being dominated by a mixture of Th1, Th17, and Th22 cells,10,11 whereas MF is Th2 dominant,6 as is atopic dermatits.12 Correspondingly, the innate immune response of the epidermis in psoriasis features much higher expression of the interleukin (IL)-17 target gene DEFB4 (encoding human β-defensin-2) than does either atopic dermatitis or MF.13,14 In this article, we will explore the role of genetics as a tool to better understand the pathogenesis of MF and SS. After briefly reviewing the genetic epidemiology of MF (see also an article by Hodak on familial MF in this issue), we will focus on psoriasis as a prototypical polygenic immune-mediated disorder, contrast the germ-line genetics of psoriasis to the prominently somatic cell genetics of MF, and consider how recent discoveries in psoriasis genetics might serve to define pathways relevant to both disorders.