Recent physiopathological insights in cutaneous lymphocytic infiltrates

ARTICLE

The spectrum of cutaneous lymphocytic infiltrates (CLI) includes a wide variety of clinicopathological entities either of benign or malignant nature, sharing in common the infiltration of dermis and/or of epidermis as the main histopathological feature [1, 2]. In some cases, these clinicopathological entities have been causally related to identified stimuli such as drug intake [3, 4], vaccination [3] or infection with the human immunodeficiency virus (HIV) [5], while etiological factors remain unknown in other entities such as in Jessner's infiltrate [6]. Although the delineation of the clinical and evolutive patterns at one hand, and of histopathological and immunohistochemical features on the other hand, lead to a subclassification of different types of CLI [7-9], the clonality status of CLI and the physiopathological mechanisms underlying these disorders have only been extensively investigated in recent years [10]. Indeed, the emerging development of new techniques has allowed the analysis of clonality in both T cell and B cell infiltrates, thus providing new clues in the field of the natural history of these disorders [11, 12], whereas functional studies recently helped to elucidate the pathogenesis of benign conditions mimicking lymphoid malignancies such as HIV-related CD8 cutaneous pseudolymphomas [13]. Finally, important results concerning the skin-homing and the survival of lymphoid cells infiltrating CLI have been recently obtained, leading to a reappraisal of the physiopathological mechanisms underlying these clinical conditions. This review will focus on the recent insights provided by molecular and functional studies investigating the mechanisms involved in the recruitment and in the expansion of B and/or T lymphocytes in benign CLI, although some results obtained from patients affected with malignant cutaneous lymphocytic infiltrates are also discussed. Since patients affected with particular types of CLI are more prone to further development of cutaneous lymphoid malignancy [14], the studies analyzing the clonality status in both conditions are also discussed.

Classification of benign cutaneous lymphocytic infiltrates

The classification of CLI has been established on the basis of the clinical features and of the histopathological findings ­ mostly the structure of the lymphocytic infiltrate, and membership of the predominant infiltrating cellular subset either to the T or to the B lineage. The main clinicopathological entities which have been delineated are listed in Table I, and have been subdivided into two major groups : predominant T CLI on the one hand, and B CLI on the other hand [7-9, 15]. However, particular types of CLI such as lymphocytoma cutis, which is characterized by the presence of germinal centers, are associated with a mixed B/T lymphocytic infiltrate [16]. Immunophenotypic studies of the cutaneous infiltrate have provided help in this classification, showing evidence that most predominant T CLI are of the CD4 phenotype [1], while CD8 lymphocytes are predominant in actinic reticuloid, a chronic dermatitis associated with photosensitivity [17, 18], and in HIV-related cutaneous pseudolymphoma, a recently described entity related to the infiltration of both dermis and epidermis by CD8 HIV-specific cytotoxic T lymphocytes [5, 13, 19, 20]. These latter entities indicate that although most CLI are idiopathic, etiological factors have been unambiguously identified in some cases. Thus, drug-related cutaneous reactions may be either of the T lineage [4], or more rarely exhibiting a predominantly B phenotype [21, 22], and cases of CLI due to contact hypersensitivity have also been reported [23]. Infection with Borrelia is sometimes associated with cutaneous B cell infiltrates with germinal centers emerging during the chronic phase of the disease [24].

The clonality status of CLI

Recently, the development of the polymerase chain reaction (PCR) has provided a new tool allowing the sensitive detection of clonally rearranged genes coding for TCR and immunoglobulin chains [25]. Thus, PCR-based assays have been shown to detect TCR/Ig clonal rearrangement as representing less than 1% of all rearrangements and they are now considered as the reference methods for the routine analysis of the clonality status in cutaneous lymphocytic infiltrates [11, 26]. Indeed, the studies performed in CLI have provided new clues in the knowledge of the natural history of some skin diseases known as precursors of cutaneous lymphomas. Molecular assays have shown the clonal T cell nature of lymphomatoid papulosis (LyP), which is characterized by a spontaneously regressing lymphoinfiltrative skin lesions, exhibiting histopathological features undistinguishable from lymphoid malignancy, thus questioning the neoplastic or the benign nature of LyP [27]. Furthermore, a recent analysis of TCR junctional DNA sequences in lesions of LyP and of cutaneous T cell lymphoma (CTCL) occurring in one patient revealed that these different cutaneous diseases may derive from an identical T cell clone [28]. More recently, investigations of the clonality status of the T cell infiltrate underlying plaque type parapsoriasis lesions have shown evidence of monoclonality in some cases [29], possibly suggesting that an initiating molecular event conferring a selective advantage to a T cell clone, might be followed by secondary promoting abnormalities leading to further development of mycosis fungoides, which is defined as an epidermotropic CTCL, and is now known to correspond to a clonal proliferation of CD4 lymphocytes [11, 12, 30]. Interestingly, monoclonal rearrangements of TCR genes have also been reported in pityriasis lichenoides et varioliformis acuta [31], which is not associated with a malignant potential, illustrating that the detection of T/B cell monoclonality in CLI is not synonymous with a high risk of cutaneous lymphoid malignancy. This latter notion has been reinforced by the results of highly sensitive PCR-based investigations showing T cell monoclonality in a small proportion of cutaneous benign inflammatory disorders analyzed [12]. Interestingly, studies of clonality have also shown the T cell clonal nature of a subset of cutaneous chronic disorders called "chronic dermatitis" or "clonal lymphoid hyperplasia of the skin", and follow-up studies are currently ongoing to determine whether patients affected with these clonal benign CLI are prone or not to further development of cutaneous lymphoma [12].

Among drug-induced cutaneous pseudolymphomas, both polyclonal [4] and monoclonal patterns [32] have been reported, while the recent development of an automated method called immunoscope allowing the accurate analysis of the diversity of T cell populations [33] has been used to show the oligoclonal nature of CD8 T cells infiltrating the cutaneous lesions of HIV-infected patients presenting with a cutaneous pseudotumoral disorder [19].

The role of antigenic stimuli in CLI

The occurrence of CLI following special stimuli, such as cases occurring after the onset of drug therapy [4, 32], after vaccination [34] or during the course an infection with Borrelia, supports the hypothesis that at least some cases of CLI are causally related to an antigenic stimulation of cutaneous lymphocytes through the triggering of their specific receptor, i.e. the TCR in T cells and the surface immunoglobulins in B lymphocytes. However, demonstration of the involvement of an antigen-driven process in the skin-residing lymphocytic expansion has only rarely been provided. Thus, although the expression of membrane antigens indicating an activation in vivo of skin infiltrating T lymphocytes has been reported in drug-related pseudolymphomas [4], the fine specificity of cells infiltrating skin lesions has not been fully determined in this latter entity. Indeed, convincing results supporting the role of an antigenic stimulation in vivo in the pathogenesis of CLI have been recently provided in HIV-infected patients presenting with a severe CD8 lymphoinfiltrative disease involving the skin and the lymph nodes [19]. In vitro studies have shown evidence of the HIV-specific, HLA class I-restricted cytotoxic function of CD8 T cell lines derived from the lesional skin of these patients, strongly suggesting that HIV-derived peptides are involved in vivo in the expansion and in the activation of skin-homing CD8 T cells [19]. Interestingly, although more speculatively than in pseudolymphomas, the role of epigenetic events has also been advocated in the initial phase of cutaneous lymphoid malignancies such as mycosis fungoides (MF) [35]. Thus, the involvement of a superantigenic stimulation of Sezary cells has been raised by in vitro studies [36]. However, studies using RT-PCR-based methods for the analysis of the TCRBV repertoire in MF and Sezary syndrome (SS) did not find a biased representation of one or few BV segments [35]. Thus, it appears that the repertoire of BV segments used by Sezary cells reflects their frequency in normal CD4⁺ T cells, and that a unique antigenic or superantigenic stimulus does not underly the initial expansion phase of MF/SS.

Mechanisms of skin-homing in CLI

Memory T cells infiltrating the lesional skin in many inflammatory or malignant skin lesions express at their surface a carbohydrate epitope which is a skin homing receptor called cutaneous lymphocyte-associated antigen (CLA) [37] resulting from the modification of the glycoprotein PSGL-1 which belongs to the P-selecting family, and is expressed by all mature lymphocytes [38]. In this field, in vitro studies have shown that the dermal recruitment of memory T lymphocytes involves the interaction of CLA with E-selectin expressed at the surface of vascular endothelial cells [39, 40]. Interestingly, bacterial toxins with known superantigenic properties have been shown to induce in vitro the expression by T CD4 lymphocytes of CLA [41]. This latter study suggests a possible relationship between some particular types of stimulation of T lymphocytes that might occur in vivo in an extracutaneous site, and the skin specific tropism of the lymphocytic infiltrate. This latter hypothesis has been further supported by data obtained in vivo in HIV-related cutaneous pseudolymphoma, showing a predominant expression of CLA by CD8 lymphocytes infiltrating the skin and the lymph nodes of these patients [19]. These results are in accordance with those from other studies suggesting that the expression of CLA is an inducible process occurring in the lymph nodes during the transition of naive T cells to memory T cells [38, 42].

CONCLUSION

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