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Lichenoid Tissue Reaction/Interface Dermatitis: Clinical and Histological Perspectives

  • Richard D. Sontheimer
    Correspondence
    Department of Dermatology, University of Oklahoma Health Sciences Center, 619 NE, 13th Street, Oklahoma City, Oklahoma 73104, USA
    Affiliations
    Department of Dermatology, Richard and Adeline Fleischaker Chair in Dermatology Research, University of Oklahoma Health Sciences Center, Adjunct Investigator, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
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      A number of uncommon, clinically diverse and poorly understood inflammatory skin diseases are linked by the presence of a set of histopathological elements that have traditionally been referred to as the “lichenoid tissue reaction/interface dermatitis” (LTR/IFD). The prototypic skin disease in this category is lichen planus. However, the LTR/IFD can also be seen in skin disorders associated with systemic illnesses (lupus erythematosus, dermatomyositis), and the skin changes of potentially fatal disorders such as graft-versus-host disease, Stevens–Johnson syndrome, and toxic epidermal necrolysis. It has been traditionally felt that cytotoxic T-lymphocytes represent the final effector cell type for the epidermal basal cell layer injury pattern that is common to LTR/IFD disorders. Recent work has suggested that a number of different LTR/IFD skin disorders share a common inflammatory signaling pathway involving the actions of plasmacytoid dendritic cell-derived IFN-α. This signaling pathway appears to amplify cytotoxic T cell injury to the epidermal basal cell compartment. This review will summarize the work implicating this pathway as well as the other cellular and molecular mechanisms that are thought to be responsible for the prototypic LTR/IFD disorder, lichen planus. It is hoped that a better understanding of the immunological commonalities shared by various LTR/IFD disorders will lead to more effective safer treatment options for these illnesses.

      Abbreviations

      APC
      antigen-presenting cell
      LE
      lupus erythematosus
      LTR/IFD
      lichenoid tissue reaction/interface dermatitis
      MHC
      major histocompatibility complex
      TNF
      tumor necrosis factor

      Introduction

      The programmatic theme for the 2007 Montagna Symposium on the Biology of Skin was “Keratinocyte-T Cell Interactions”. Jan P. Dutz, MD, chaired the symposium session that was entitled “Lichenoid Tissue Reaction”. This article represents a summary of the introductory presentation given by the author at that session.
      Recent work has suggested that a number of different lichenoid tissue reaction/interface dermatitis (LTR/IFD) clinical disorders may share a common immunopathogenesis involving plasmacytoid dendritic cell-mediated type I interferon signaling (
      • Blomberg S.
      • Eloranta M.L.
      • Cederblad B.
      • Nordlin K.
      • Alm G.V.
      • Ronnblom L.
      Presence of cutaneous interferon-alpha producing cells in patients with systemic lupus erythematosus.
      ;
      • Farkas L.
      • Beiske K.
      • Lund-Johansen F.
      • Brandtzaeg P.
      • Jahnsen F.L.
      Plasmacytoid dendritic cells (natural interferon-alpha/beta-producing cells) accumulate in cutaneous lupus erythematosus lesions.
      ;
      • Meller S.
      • Winterberg F.
      • Gilliet M.
      • Muller A.
      • Lauceviciute I.
      • Rieker J.
      • et al.
      Ultraviolet radiation-induced injury, chemokines, and leukocyte recruitment: an amplification cycle triggering cutaneous lupus erythematosus.
      ;
      • Wenzel J.
      • Scheler M.
      • Bieber T.
      • Tuting T.
      Evidence for a role of type I interferons in the pathogenesis of dermatomyositis.
      ,
      • Wenzel J.
      • Uerlich M.
      • Worrenkamper E.
      • Freutel S.
      • Bieber T.
      • Tuting T.
      Scarring skin lesions of discoid lupus erythematosus are characterized by high numbers of skin-homing cytotoxic lymphocytes associated with strong expression of the type I interferon-induced protein MxA.
      ,
      • Wenzel J.
      • Worenkamper E.
      • Freutel S.
      • Henze S.
      • Haller O.
      • Bieber T.
      • et al.
      Enhanced type I interferon signalling promotes Th1-biased inflammation in cutaneous lupus erythematosus.
      ,
      • Wenzel J.
      • Scheler M.
      • Proelss J.
      • Bieber T.
      • Tuting T.
      Type I interferon-associated cytotoxic inflammation in lichen planus.
      ,
      • Wenzel J.
      • Schmidt R.
      • Proelss J.
      • Zahn S.
      • Bieber T.
      • Tuting T.
      Type I interferon-associated skin recruitment of CXCR3+ lymphocytes in dermatomyositis.
      ;
      • Scheler M.
      • Wenzel J.
      • Tuting T.
      • Takikawa O.
      • Bieber T.
      • von B.D.
      Indoleamine 2,3-dioxygenase (IDO): the antagonist of type I interferon-driven skin inflammation?.
      ). The program for the LTR/IFD session of the 2007 Montagna Symposium was designed to further explore the hypothesis that certain immunological effector mechanisms might be common to a variety of clinical disorders that share elements of the LTR/IFD. In their elegant discussion of immunological command and control in the skin,
      • Schroder J.M.
      • Reich K.
      • Kabashima K.
      • Liu F.T.
      • Romani N.
      • Metz M.
      • et al.
      Who is really in control of skin immunity under physiological circumstances—lymphocytes, dendritic cells or keratinocytes?.
      ) voiced a supporting sentiment for this hypothesis: “… the lichenoid reaction pattern, which is seen in such different conditions as drug reactions, skin manifestations of collagen vascular diseases, chronic cutaneous graft-versus-host disease and lichen planus predict a cutaneous immune program from a provoking stimulus.” Exploration of this hypothesis might result in the development of new, safer therapeutic approaches for this debilitating, disabling, and sometimes-fatal group of skin disorders. It was the Montagna Symposium program co-chairs’ hope that a session focused on the LTR/IFD might lead to new approaches to better understand and treat this diverse group of cutaneous disorders.
      This article will review the body of knowledge relating to the etiopathogenesis of the prototypic LTR/IFD disorder, lichen planus, up until several years ago when the hypothesis that plasmacytoid dendritic cell production of IFN-α is a driving force in the LTR/IFD was put forward.

      Definitions, Nomenclature, And Classification

      A number of clinically diverse, poorly understood, and relatively uncommon inflammatory skin diseases are linked together by the presence of a pattern of common histopathological elements that traditionally has been referred to as the “lichenoid tissue reaction” (LTR) (
      • Pinkus M.D.
      Lichenoid tissue reactions. A speculative review of the clinical spectrum of epidermal basal cell damage with special reference to erythema dyschromicum perstans.
      ). These elements include a pattern of epidermal basal cell morphological change that has been variously described as being “liquefactive/hydropic/vacuolar” (Figure 1). In the LTR, this characteristic pattern of epidermal basal cell injury/degeneration is intimately associated with a band-like array of mononuclear inflammatory cells in the papillary and mid-dermis consisting of activated T cells, macrophages, and dendritic cells (Figure 1). Prototypic skin diseases in this category are lichen planus and cutaneous lupus erythematosus (LE), which are illustrated in Figures 2 and 3.
      Figure thumbnail gr1
      Figure 1Histopathology of LTR/IFD. (a) Histopathology of normal human skin compared with a cell-rich LTR/IFD disorder, (b) lichen planus, and cell-poor LTR/IFD disorder, (c) subacute cutaneous lupus erythematosus. Bars=25μm.
      Figure thumbnail gr2
      Figure 2Examples of clinical varieties of a cell-rich LTR/IFD disorder, lichen planus. (ac) Most common clinical form of cutaneous lichen planus, lichen planus rubra. Note the fine basket weave pattern of scale in the image in panel c. This characteristic change is referred to as Wickham's striae. Panel d illustrates the linear white network on the buccal mucosa that is characteristic of oral lichen planus. Panel e illustrates erosive lichen planus of the vaginal orifice with the characteristic associated debilitating scarring.
      Figure thumbnail gr3
      Figure 3Examples of clinical varieties of cell-poor LTR/IFD clinical disorders. (a) Acute cutaneous LE. Note in the characteristic symmetrical erythema and scale over the malar eminences. (b) Annular/polycyclic type of subacute cutaneous LE. (c) Cutaneous dermatomyositis. Note the violaceous scaling erythema over the posterior aspect of the neck that extended to the posterior shoulders (the shawl sign). (d) Cutaneous dermatomyositis. Note the violaceous erythema preferentially targeting the skin over the knuckles.
      Lichenoid tissue reaction/interface dermatitis skin diseases have traditionally been subdivided into those clinical disorders that display a high-density (“cell-rich”) inflammatory infiltrate and those that display a low-density (“cell-poor”) infiltrate (
      • Romero R.W.
      • Nesbitt Jr, L.T.
      • Reed R.J.
      Unusual variant of lupus erythematosus on lichen planus. Clinical, histopathologic and immunofluorescence studies.
      ;
      • Sontheimer R.D.
      • Gilliam J.N.
      Immunologically mediated epidermal cell injury [Review].
      ). Clinical examples of a cell-rich LTR include lichen planus and its variants, lichenoid drug reactions, lichen nitidus, lichen striatus, and some forms of autoimmune connective tissue skin disease such as discoid LE. Examples of a cell-poor LTR/IFD include virus- and drug-induced morbilliform exanthems, other forms of autoimmune connective tissue skin diseases (acute cutaneous LE, subacute cutaneous LE, cutaneous dermatomyositis), acute graft-versus-host skin disease, and erythema multiforme.
      More modern workers have begun to refer to this histological pattern as an “interface dermatitis” (IFD) rather than as an LTR (
      • Hurwitz R.M.
      • Rivera H.P.
      • Gooch M.H.
      • Slama T.G.
      • Handt A.
      • Weiss J.
      Toxic shock syndrome or toxic epidermal necrolysis? Case reports showing clinical similarity and histologic separation.
      ;
      • Fitzpatrick J.E.
      New histopathologic findings in drug eruptions.
      ;
      • Crowson A.N.
      • Magro C.M.
      Idiopathic perniosis and its mimics: a clinical and histological study of 38 cases.
      ). Some modern workers have defined “interface dermatitis” more broadly—“The term interface dermatitis refers to the finding in a skin biopsy of an inflammatory infiltrate that abuts or obscures the dermal epidermal junction” (
      • Crowson A.N.
      • Magro C.M.
      • Mihm Jr, M.
      Interface dermatitis.
      ). These workers feel that the term “LTR” should be reserved for the cell-rich subset of IFD diseases such as lichen planus (that is, the designation “lichenoid”) (see Figure 1b). However, the designation “LTR” for this group of diseases remains in use (
      • Teraki Y.
      • Shiohara T.
      Spontaneous tolerance to terbinafine-induced lichenoid drug eruption.
      ;
      • Tilly J.J.
      • Drolet B.A.
      • Esterly N.B.
      Lichenoid eruptions in children.
      ;
      • DeRossi S.S.
      • Ciarrocca K.N.
      Lichen planus, lichenoid drug reactions, and lichenoid mucositis.
      ;
      • Shiohara T.
      • Mizukawa Y.
      The immunological basis of lichenoid tissue reaction.
      ). There were 107 publications in the PubMed database under the search term “lichenoid tissue reaction” as of October 24, 2007, whereas there were 1,440 publications listed under the rather unique search term “lichenoid”. There were 195 PubMed publications under the search term “interface dermatitis”. Thus, to be as inclusive as possible, the terms LTR and IFD will be used synonymously in this review and referred to under the designation “LTR/IFD”.

      Examples Of Clinically Severe Ltr/ifd Skin Diseases

      The cell-rich and cell-poor LTR/IFD diseases are a diverse group of clinical disorders. Table 1 presents a comprehensive listing of such disorders. This list was compiled from several recent reviews of this subject (
      • Shiohara T.
      • Kano Y.
      Lichen planus and lichenoid dermatoses.
      ;
      • Crowson A.N.
      • Magro C.M.
      • Mihm Jr, M.
      Interface dermatitis.
      ). With respect to clinical diversity, some of these disorders represent fulminant, potentially fatal mucocutaneous illnesses (for example, erythema multiforme major (synonym: Stevens–Johnson syndrome)). Others are associated with potentially fatal patterns of systemic autoimmunity (for example, lupus-specific skin diseases, cutaneous dermatomyositis). Some represent highly symptomatic and potentially disfiguring and/or disabling dermatoses (for example, erosive lichen planus). And still others represent banal self-limited dermatoses (for example, lichen nitidus, lichen striatus). Table 2 provides a categorization of traditional LTR/IFD diseases on the basis of clinical severity and association with systemic involvement.
      Table 1Classification of LTR/IFD skin disorders listed alphabetically within subgroups
      Lymphocyte-rich LTR/IFD
       Autoimmune connective tissue diseases
        Discoid lupus erythematosus (LE)
       Fixed drug eruption
       Keratosis lichenoides chronica
       Lichen nitidus
       Lichen planus
       Lichen striatus
       Lichenoid drug reactions
       Lichenoid and granulomatous dermatitis
       Lichenoid graft-versus-host disease
       Lichenoid mycosis fungoides
      Lymphocyte-poor LTR/IFD
       Acute graft-versus-host skin disease
       Autoimmune connective tissue skin diseases
        LE
         Acute cutaneous LE
         Subacute cutaneous LE
        Dermatomyositis
        Mixed connective tissue disease
       Erythema multiforme
        Erythema multiforme minor
        Erythema multiform major (synonym: Stevens–Johnson syndrome)
       Interface dermatitis of HIV infection
       Morbilliform exanthems
        Virus-induced
        Drug-induced
       Paraneoplastic pemphigus
       Pityriasis lichenoides
      Table 2A classification of traditional LTR/IFD skin diseases according to clinical severity and quality-of-life impact
      Minimally-symptomatic, self-limited dermatoses
       Lichenoid actinic keratosis
       Lichen planus group
        Lichen nitidis
        Lichen striatus
      Significantly symptomatic but self-limited dermatoses
       Fixed drug eruption
       Lichen planus group
       Lichen planus rubra
      Severely symptomatic, potentially disfiguring/disabling, difficult-to-treat dermatoses
       Lichen planus group
        Erosive lichen planus (synonyms: orovaginalvulvar lichen planus; vulvovaginal-gingival syndrome)
      Dermatoses associated with potentially disabling or life-threatening systemic diseases
       Acute graft-versus-host disease
       Dermatomyositis
       LE-specific skin diseases
        ACLE
        SCLE
        Discoid LE
       Paraneoplastic pemphigus
      Life-threatening dermatoses
       Erythema multiforme major (synonym: Stevens–Johnson syndrome)
       Toxic epidermal necrolysis
      Figure 2 presents clinical photos of various clinical subtypes of lichen planus. Representative cell-poor LTR/IFD skin disorders are illustrated in Figure 3.

      Unconventional Ltr/ifd Cutaneous Disorders

      There are other inflammatory skin diseases that display subtle elements of the LTR/IFD that are not conventionally classified in the LTR/IFD category. A case can be made that erythema dyschromicum perstans (ashy dermatosis), vitiligo, alopecia areata, lichen sclerosis atrophicus, and morphea could also be considered to be LTR/IFD clinical disorders as they can manifest subtle features of a “cell-sparse” LTR/IFD. In addition, an LTR/IFD might serve a protective function in being responsible for the involution of certain self-resolving cutaneous proliferative disorders (for example, lichenoid actinic keratosis, halo nevus, keratoacanthoma).

      Epidemiology Of Ltr/ifd Diseases

      The epidemiology of many LTR/IFD skin disorders has not been systematically examined. A number of such disorders are quite rare, making population-based epidemiological studies very difficult to perform. Table 3 presents a listing of environmental agents that have been implicated as triggers for lichen planus or lichenoid drug eruptions.
      Table 3Some environmental antigens implicated to be triggering factors in the etiopathogenesis of the lichen planus or lichenoid drug reactions
      Data in this table are compiled from the works by Shiohara and Kano (2003) and Litt (2004).
      Contactants
       Dental amalgams
        Mercury
        Copper
        Gold
       Color photography, developing chemicals
      Ingestants
       Drugs
      The third edition of Jerome Litt's Pocketbook of Drug Eruptions and Interactions lists a total of 114 individual drugs that have been implicated as triggers for lichen planus or lichenoid drug eruptions (Litt, 2004). Listed above are some of the more common drug classes that can induce a lichenoid drug eruption.
        Angiotensin-converting enzyme inhibitors
        Antimalarials
        Calcium channel blockers
        Gold
        Nonsteroidal anti-inflammatory drugs
      Injections
       Hepatitis B vaccines
      Infections
        Hepatitis B
        Hepatitis C
        Human herpes virus-7
      1 Data in this table are compiled from the works by
      • Shiohara T.
      • Kano Y.
      Lichen planus and lichenoid dermatoses.
      ) and
      • Litt J.Z.
      ).
      2 The third edition of Jerome Litt's Pocketbook of Drug Eruptions and Interactions lists a total of 114 individual drugs that have been implicated as triggers for lichen planus or lichenoid drug eruptions (
      • Litt J.Z.
      ). Listed above are some of the more common drug classes that can induce a lichenoid drug eruption.

      Etiopathogenesis Of Ltr/ifd

      The abstract of a recent authorative review of the immunological basis of the LTR/IFD begins with the following sentence: “An autoimmune attack by T cells on the epidermis is the primary pathological event in the lichenoid tissue reaction” (
      • Shiohara T.
      • Mizukawa Y.
      The immunological basis of lichenoid tissue reaction.
      ). It has been traditionally felt that cytotoxic T-lymphocytes represent the major effector cell type for the epidermal basal cell layer injury pattern that is common to LTR/IF disorders. These conclusions are based primarily upon the histopathological findings of human LTR/IFD diseases and experimental studies in animal models (animal models of LTR/IFD will be addressed separately in these symposium proceedings by Dr Jan Dutz).
      In some LTR disorders, the antigen being targeted by activated T cells is known (for example, alloantigens in graft-versus-host skin disease). In others, the targeted antigen is thought to be an autoantigen (for example, Ro/SSA and La/SS-B in neonatal LE and subacute cutaneous LE). However, in most LTR/IFD disorders, the targeted antigen is unknown, with cross-reactivity between environmental antigens (for example, viral, drug, chemical) and self-antigens being suspected. A number of infectious agents, drugs, and other chemicals have been implicated as environmental triggers for lichen planus and lichenoid drug eruptions (Table 3).
      For lichen planus, separate research data sets exist for the oral (
      • Sugerman P.B.
      • Savage N.W.
      • Walsh L.J.
      • Zhao Z.Z.
      • Zhou X.J.
      • Khan A.
      • et al.
      The pathogenesis of oral lichen planus [Review].
      ;
      • Lodi G.
      • Scully C.
      • Carrozzo M.
      • Griffiths M.
      • Sugerman P.B.
      • Thongprasom K.
      Current controversies in oral lichen planus: report of an international consensus meeting. Part 1. Viral infections and etiopathogenesis.
      ) and cutaneous (
      • Shiohara T.
      • Mizukawa Y.
      The immunological basis of lichenoid tissue reaction.
      ) manifestations of this disease. Recent progress in understanding the cellular immunopathogenesis of oral lichen planus has been especially notable (
      • Sugerman P.B.
      • Savage N.W.
      • Walsh L.J.
      • Zhao Z.Z.
      • Zhou X.J.
      • Khan A.
      • et al.
      The pathogenesis of oral lichen planus [Review].
      ;
      • Lodi G.
      • Scully C.
      • Carrozzo M.
      • Griffiths M.
      • Sugerman P.B.
      • Thongprasom K.
      Current controversies in oral lichen planus: report of an international consensus meeting. Part 1. Viral infections and etiopathogenesis.
      ;
      • Bascones-Ilundain C.
      • Gonzalez-Moles M.A.
      • Esparza-Gomez G.
      • Gil-Montoya J.A.
      • Bascones-Martinez A.
      Importance of apoptotic mechanisms in inflammatory infiltrate of oral lichen planus lesions.
      ,
      • Bascones-Ilundain C.
      • Gonzalez-Moles M.A.
      • Esparza G.
      • Gil-Montoya J.A.
      • Bascones-Martinez A.
      Significance of liquefaction degeneration in oral lichen planus: a study of its relationship with apoptosis and cell cycle arrest markers.
      ;
      • Bai J.
      • Zhang Y.
      • Lin M.
      • Zeng X.
      • Wang Z.
      • Shen J.
      • et al.
      Interleukin-18 gene polymorphisms and haplotypes in patients with oral lichen planus: a study in an ethnic Chinese cohort.
      ;
      • Gustafson J.
      • Eklund C.
      • Wallstrom M.
      • Zellin G.
      • Magnusson B.
      • Hasseus B.
      Langerin-expressing and CD83-expressing cells in oral lichen planus lesions.
      ). It is generally felt that the etiopathogenetic mechanisms of tissue-injury in the oral mucosal and skin compartments are fundamentally the same except for the differences that might be predicted on the basis of differences in anatomical location and environmental exposure.
      It is beyond the scope of this presentation to review all of the previous work that has been done to unravel the etiopathogenesis of even the major human LTR/IFD skin disorders listed in Tables 1 and 2. Therefore, the focus here will be on lichen planus, the prototypic LTR/IFD clinical disorder. Even this is a rather broad subject. For more in-depth discussion of the primary observations relating to the etiopathogenesis of lichen planus, the reader is referred to other more in-depth treatments of this subject (
      • Pinkus M.D.
      Lichenoid tissue reactions. A speculative review of the clinical spectrum of epidermal basal cell damage with special reference to erythema dyschromicum perstans.
      ;
      • Sontheimer R.D.
      • Gilliam J.N.
      Immunologically mediated epidermal cell injury [Review].
      ;
      • Shiohara T.
      • Moriya N.
      • Tsuchiya K.
      • Nagashima M.
      • Narimatsu H.
      Lichenoid tissue reactioin induced by local transfer of Ia-reacive T-cell clones.
      ,
      • Shiohara T.
      • Moriya N.
      • Mochizuki T.
      • Nagashima M.
      Lichenoid tissue reaction (LTR) induced by local transfer of Ia-reactive T-cell clones. II. LTR by epidermal invasion of cytotoxic lymphokine-producing autoreactive T cells.
      ,
      • Shiohara T.
      • Moriya N.
      • Gotoh C.
      • Saizawa K.
      • Nagashima M.
      Lichenoid tissue reaction induced by local transfer of Ia-reactive T-cell clones. III. Role of Ia+ keratinocytes in the epidermotropic migration of the T cells.
      ,
      • Shiohara T.
      • Moriya N.
      • Tanaka Y.
      • Arai Y.
      • Hayakawa J.
      • Chiba M.
      • et al.
      Immunopathologic study of lichenoid skin diseases: correlation between HLA-DR-positive keratinocytes or Langerhans cells and epidermotropic T cells.
      ,
      • Shiohara T.
      • Nickoloff B.J.
      • Moriya N.
      • Gotoh C.
      • Nagashima M.
      In vivo effects of interferon-gamma and anti-interferon-gamma antibody on the experimentally induced lichenoid tissue reaction.
      ,
      • Shiohara T.
      • Moriya N.
      • Nagashima M.
      Induction and control of lichenoid tissue reactions.
      ;
      • Oliver G.F.
      • Winkelmann R.K.
      • Muller S.A.
      Lichenoid dermatitis: a clinicopathologic and immunopathologic review of sixty-two cases.
      ;
      • Bleicher P.A.
      • Dover J.S.
      • Arndt K.A.
      Lichenoid dermatoses and related disorders. I. Lichen planus and lichenoid drug-induced eruptions.
      ;
      • Bratel J.
      • Dahlgren U.
      • Simark M.C.
      • Jontell M.
      The frequency of different T-cell receptor V-families in oral lichen planus and lichenoid contact lesions: an immunohistochemical study.
      ;
      • Sugerman P.B.
      • Savage N.W.
      • Walsh L.J.
      • Zhao Z.Z.
      • Zhou X.J.
      • Khan A.
      • et al.
      The pathogenesis of oral lichen planus [Review].
      ;
      • Lodi G.
      • Scully C.
      • Carrozzo M.
      • Griffiths M.
      • Sugerman P.B.
      • Thongprasom K.
      Current controversies in oral lichen planus: report of an international consensus meeting. Part 1. Viral infections and etiopathogenesis.
      ;
      • Shiohara T.
      • Mizukawa Y.
      The immunological basis of lichenoid tissue reaction.
      ). This review will address some of the modern currents of thought in this area.

      Epidermal basal layer target cells

      One approach to considering the etiopathogenetic elements of LTR/IFD is to divide this reaction pattern into its two major component compartments. The compartment that is the focus of injury is the epidermal basal cell layer. The compartment that most authorities feel is responsible for this injury pattern is the dermal mononuclear cell inflammatory infiltrate.
      Whereas other epidermal compartment histological changes are regularly seen in LTR/IFD disorders such as lichen planus (for example, orthokeratotic hyperkeratosis, focal hypergranulosis, irregular acanthosis), the hallmark epidermal change is damage to and disarray of the cells that comprise the epidermal basal layer (Figures 1 and 4). In 1973,
      • Pinkus M.D.
      Lichenoid tissue reactions. A speculative review of the clinical spectrum of epidermal basal cell damage with special reference to erythema dyschromicum perstans.
      ) stated, “Lichenoid tissue reaction is defined as one exhibiting epidermal basal cell damage and the chain of histobiological events resulting from such damage. It is not essential whether damage to the basal cells is primary or is itself due to a preceding event in the dermis. The cascade of events resulting from damage to the germinal basal cells is predictable from a general knowledge of epidermal biology.”
      Figure thumbnail gr4
      Figure 4The epidermal basal layer of normal human skin. This is a 1-μm-thick section of Epon-embedded normal human skin stained with methylene blue-Azure II-Basic fuchsin. As can be seen, the epidermal basal layer is morphologically diverse (broken line rectangles). It contains epidermal stem cells that are differentiating into daughter transient amplifying cells that subsequently differentiate into basal keratinocytes. It is possible that epidermal stem cells, transient amplifying cells, and basal keratinocytes could display varying surface autoantigens that could be targeted by LTR/IFD effector cells. In addition, the epidermal basal layer contains melanocytes and, in some anatomical skin regions, Merkel cells. Both of these cell types have been assumed to be innocent bystanders in the LTR/IFD. Dendrites from suprabasal epidermal Langerhans cells are intermixed with the cellular components of the epidermal basal layer. The constituent cell types of normal human dermis are surrounded by the solid line figure. These cells include dermal microvascular endothelial cells, pericytes, dendritic cells, macrophages, mast cells, and fibroblasts. Bar=25μm.

      Keratinocyte necrosis in the LTR/IFD disorders

      Epidermal basal cell degeneration seen in the LTR/IFD has been variously described morphologically with the following synonymous qualifying terms: hydropic, liquefactive/liquefaction, vacuolar. These descriptive terms correspond to Virchow's basic concept of “cloudy swelling”. Cloudy swelling is a phenomenon that results from rapid cytoplasmic swelling (oncosis). Oncosis leads to plasma membrane rupture and organelle breakdown typical of cell necrosis (
      • Krysko D.V.
      • Vanden Berghe T.
      • D’Herde K.
      • Vandenabeele P.
      Apoptosis and necrosis: detection, discrimination and phagocytosis.
      ) Cellular necrosis can be induced in human epidermal cells as well as other cell types by a number of mechanisms, most prominent being injury by toxins and oxidative stress. More recently, it has been suggested that different cellular stimuli including cytokines, ribonucleotides, ATP depletion, and ischemia can induce cellular necrosis that follows a sequential process that is suggestive of a cell death program (
      • Vanden Berghe T.
      • Declercq W.
      • Vandenabeele P.
      NADPH oxidases: new players in TNF-induced necrotic cell death.
      ).
      Whereas there are many markers for cellular apoptosis, there are virtually no positive markers for cellular necrosis. Traditionally, necrosis has been characterized predominantly in negative terms by the absence of markers of apoptosis. However, it has recently been suggested that it might be possible to actively distinguish apoptosis from necrosis using a combination of analytical techniques (
      • Krysko D.V.
      • Vanden Berghe T.
      • D’Herde K.
      • Vandenabeele P.
      Apoptosis and necrosis: detection, discrimination and phagocytosis.
      ). To the author's knowledge, this approach has not previously been applied to any LTR/IFD disorder.
      It has traditionally been assumed that the primary epidermal basal cell layer target in the LTR/IFD is the basal keratinocyte. As keratinocytes constitute more than 90% of the epidermal basal layer, the extensive pattern of epidermal basal layer damage seen in some LTR/IFD disorders such as lichen planus demands that basaloid keratinocytes be involved. However, other cell types residing in the basal layer such as the melanocyte might also be targeted (Figure 4). In some LTR/IFD skin diseases such as a discoid LE, a permanent vitiligo-like leukoderma can be seen to occur in the central inactive areas of lesions.
      A role for the Merkel cell as a target of the LTR/IFD has not been addressed. Whether epidermal basal layer stem cells might be preferentially targeted in the LTR/IFD has also not been addressed. The bodies of epidermal Langerhans cells reside in a suprabasilar position; however, their dendrites extend into the epidermal basal layer. Interestingly, Langerhans cells have been confirmed to be increased in number in some LTR/IFD skin lesions such as lichen planus (
      • Santoro A.
      • Majorana A.
      • Roversi L.
      • Gentili F.
      • Marrelli S.
      • Vermi W.
      • et al.
      Recruitment of dendritic cells in oral lichen planus.
      ) and decreased in others such as cutaneous LE (
      • Sontheimer R.D.
      • Bergstresser P.R.
      Epidermal Langerhans cell involvement in cutaneous lupus erythematosus.
      ).

      Keratinocyte apoptosis in LTR/IFD disorders

      Because of the prominent cloudy swelling changes noted in epidermal basal cells in various LTR/IFD disorders, previous workers assumed that the LTR/IFD-associated immune effector cells were inducing necrotic degeneration of epidermal basal cells. However, with the growth in understanding of the process of programmed cell death (apoptosis), it is now recognized that some epidermal basal cells in a number of LTR/IFD disorders are also undergoing apoptotic death (for example, lichen planus, cutaneous LE, cutaneous dermatomyositis, acute and lichenoid graft-versus-host skin disease). However, it is clear that the epidermal basal layer damage in LTR is not the sole result of primary apoptosis (
      • Bascones-Ilundain C.
      • Gonzalez-Moles M.A.
      • Esparza G.
      • Gil-Montoya J.A.
      • Bascones-Martinez A.
      Significance of liquefaction degeneration in oral lichen planus: a study of its relationship with apoptosis and cell cycle arrest markers.
      ).
      Markers of apoptosis are associated with terminal keratinocyte differentiation. It has been stated that terminal keratinocyte differentiation seems to be a special form of apoptosis (
      • Boehm I.
      Apoptosis in physiological and pathological skin: implications for therapy.
      ). However, there are both human in vivo and in vitro studies that suggest that epidermal keratinocytes have active defense mechanisms to retard conventional UVB-induced and cytokine-induced apoptosis. It has been reported that only a minority of keratinocytes in suprabasal and mid-epidermal layers of intact human skin undergo apoptosis after exposure to two minimal erythema doses of UV radiation (
      • Norris D.A.
      • Middleton M.H.
      • Whang K.
      • Schleicher M.
      • Mcgovern T.
      • Bennion S.D.
      • et al.
      Human keratinocytes maintain reversible anti-apoptotic defenses in vivo and in vitro.
      ). Epidermal basal cells were completely resistant to apoptosis. In addition, this study demonstrated that primary and secondary cultures of human epidermal keratinocytes as well as epidermal keratinocyte lines were relatively resistant to UVB-induced apoptosis and cytokine-induced apoptosis compared with many other cell types.
      It has recently been suggested that expression of anti-apoptotic molecules in oral lichen planus might counteract the pro-apoptotic assault and rescue the epithelium from rampant cell death and resulting clinical ulceration (
      • Karatsaidis A.
      • Hayashi K.
      • Schreurs O.
      • Helgeland K.
      • Schenck K.
      Survival signalling in keratinocytes of erythematous oral lichen planus.
      ). In this study, biopsies from active lichen planus oral mucosal lesions and healthy control oral mucosal epithelium were examined by immunohistochemistry for both pro-and anti-apoptotic molecules. Both the pro-apoptotic Fas-associated death domain protein and the antiapoptotic molecules I kappa B kinase (p-IKK), NF-κB/p50, FLICE inhibitory protein (L), inhibitor of apoptosis (cIAP-1) and cIAP-2 markers were strongly upregulated in lichen planus lesional biopsies compared with normal oral mucosal biopsies. However, there were no significant differences in the staining patterns for active caspase-3 and caspase-8.
      In addressing basal cell abnormalities in a recent authoritative review on oral lichen planus, emphasis was placed almost entirely on apoptosis as a causative mechanism (
      • Lodi G.
      • Scully C.
      • Carrozzo M.
      • Griffiths M.
      • Sugerman P.B.
      • Thongprasom K.
      Current controversies in oral lichen planus: report of an international consensus meeting. Part 1. Viral infections and etiopathogenesis.
      ). However, the primary morphological changes seen in the epidermal basal layer is one of necrosis-associated cloudy swelling. Future studies need to more systematically address the relationship between basal cell apoptosis and necrosis as a basis for clinical differences in LTR/IFD skin diseases. This will become possible as molecular tools become available to discriminate between apoptotic and necrotic pathways of cell death.

      Dermal mononuclear inflammatory cells

      There are two cell types found in the dermis of lichen planus lesions that relate directly to the epidermal basal layer injury—melanophages and colloid bodies (synonyms: hyaline, cytoid, or Civatte bodies). Melanophages are dermal phagocytic cells of the macrophage lineage that have engulfed large amounts of melanin pigment released from epidermal basal layer keratinocytes and melanocytes that have been damaged by the LTR/IFD. Colloid bodies are thought to represent injured basal layer keratinocytes that have undergone amyloid degeneration.
      The dermal mononuclear cell inflammatory infiltrate holds the most interest with respect to inciting injury in the epidermal compartment. There are three major bone marrow-derived inflammatory cell types in the LTR/IFD: T lymphocytes, macrophages, dendritic cells.

      T cells

      The vast majority of lymphoid cells infiltrating the epidermis and dermis in both oral and cutaneous lichen planus are T cells. Infiltrating T cells in lichen planus demonstrate a mixed phenotype of activated CD4/CD8 cells. There is an enrichment of CD45RO memory T cells that display a Th1 cytokine bias. IL-17 and IL-23 have recently emerged as key proinflammatory cytokines in psoriasis (
      • Zheng Y.
      • Danilenko D.M.
      • Valdez P.
      • Kasman I.
      • Eastham-Anderson J.
      • Wu J.
      • et al.
      Interleukin-22, a T(H)17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis.
      ). Studies of IL-17 and IL-23 expression in lichen planus skin lesions have yet to be reported. However, it has been suggested that an LTR/IFD-related disorder, graft-versus-host disease, cannot be induced with T cells from IL-17-deficient animals (
      • Nakae S.
      • Komiyama Y.
      • Nambu A.
      • Sudo K.
      • Iwase M.
      • Homma I.
      • et al.
      Antigen-specific T cell sensitization is impaired in IL-17-deficient mice, causing suppression of allergic cellular and humoral responses.
      ).
      In the majority of studies, CD8 T cells have outnumbered CD4 T cells in both oral and cutaneous lichen planus lesions (
      • Sugerman P.B.
      • Savage N.W.
      • Walsh L.J.
      • Zhao Z.Z.
      • Zhou X.J.
      • Khan A.
      • et al.
      The pathogenesis of oral lichen planus [Review].
      ;
      • Lodi G.
      • Scully C.
      • Carrozzo M.
      • Griffiths M.
      • Sugerman P.B.
      • Thongprasom K.
      Current controversies in oral lichen planus: report of an international consensus meeting. Part 1. Viral infections and etiopathogenesis.
      ). HLA class I-restricted cytotoxic T cell lines and clones have been isolated from lichen planus lesions. In addition, restricted T cell receptor V-beta gene expression, especially V-beta 22 and V-beta 23, have been observed in T cells infiltrating oral lichen planus lesions, suggesting in situ antigen-specific oligoclonal T cell expansion (
      • Lodi G.
      • Scully C.
      • Carrozzo M.
      • Griffiths M.
      • Sugerman P.B.
      • Thongprasom K.
      Current controversies in oral lichen planus: report of an international consensus meeting. Part 1. Viral infections and etiopathogenesis.
      ). Perforin- and granzyme-expressing CD8 T cells have been suggested to play a primary role in keratinocyte apoptosis in both oral and cutaneous lichen planus (
      • Shimizu M.
      • Higaki Y.
      • Higaki M.
      • Kawashima M.
      The role of granzyme B-expressing CD8-positive T cells in apoptosis of keratinocytes in lichen planus.
      ;
      • Kastelan M.
      • Prpic M.L.
      • Gruber F.
      • Zamolo G.
      • Zauhar G.
      • Coklo M.
      • et al.
      The role of perforin-mediated apoptosis in lichen planus lesions.
      ;
      • Prpic M.L.
      • Kastelan M.
      • Gruber F.
      • Laskarin G.
      • Sotosek T.V.
      • Strbo N.
      • et al.
      Perforin expression in peripheral blood lymphocytes and skin-infiltrating cells in patients with lichen planus.
      ;
      • Santoro A.
      • Majorana A.
      • Bardellini E.
      • Gentili F.
      • Festa S.
      • Sapelli P.
      • et al.
      Cytotoxic molecule expression and epithelial cell apoptosis in oral and cutaneous lichen planus.
      ).
      Recent work has suggested that IFN-α is produced by an expanded plasmacytoid dendritic cell population in lichen planus skin lesions (
      • Wenzel J.
      • Scheler M.
      • Proelss J.
      • Bieber T.
      • Tuting T.
      Type I interferon-associated cytotoxic inflammation in lichen planus.
      ) and in other LTR/IDs. IFN-α then supports the local production of chemokines including IP10/CXCL10 by resident cells such as epidermal keratinocytes. These chemokines recruit CXCR3 chemokine receptor-expressing cytotoxic T cells into the inflammatory milleu of lichen planus (
      • Wenzel J.
      • Scheler M.
      • Proelss J.
      • Bieber T.
      • Tuting T.
      Type I interferon-associated cytotoxic inflammation in lichen planus.
      ,
      • Wenzel J.
      • Schmidt R.
      • Proelss J.
      • Zahn S.
      • Bieber T.
      • Tuting T.
      Type I interferon-associated skin recruitment of CXCR3+ lymphocytes in dermatomyositis.
      ;
      • Scheler M.
      • Wenzel J.
      • Tuting T.
      • Takikawa O.
      • Bieber T.
      • von B.D.
      Indoleamine 2,3-dioxygenase (IDO): the antagonist of type I interferon-driven skin inflammation?.
      ). These issues will be addressed in greater depth in other reports to be presented in these symposium proceedings.
      Systematic studies of CD4+ CD25+ regulatory T cells have yet to be reported in lichen planus. The frequencies of FOXP3(+) and GITR(+) (glucocorticoid-induced tumour necrosis factor receptor) regulatory CD4(+) CD25(+) T cells were similar in spongiotic dermatitis, psoriasis, and lichen planus in one report (
      • de Boer O.J.
      • Van der Loos C.M.
      • Teeling P.
      • van der Wal A.C.
      • Teunissen M.B.
      Immunohistochemical analysis of regulatory T cell markers FOXP3 and GITR on CD4+CD25+ T cells in normal skin and inflammatory dermatoses.
      ). Another group reported an enrichment of CD45RO, CD2, and CD25 T cells in the dermal infiltrate of lichen planus compared with psoriasis and atopic dermatitis (
      • Bovenschen H.J.
      • Seyger M.M.
      • Van De Kerkhof P.C.
      Plaque psoriasis vs atopic dermatitis and lichen planus: a comparison for lesional T-cell subsets, epidermal proliferation and differentiation.
      ). As the methodology to identify and functionally study these cells improves, their role in the pathogenesis of LTR/ID may need to be reexamined.

      Macrophages

      CD68(+) macrophages are minor component of the mononuclear cell infiltrate of lichen planus. The number and distribution of macrophages in lichen planus does not appear to differ significantly from that seen in other inflammatory skin diseases such as psoriasis and various causes of spongiotic dermatitis (
      • Deguchi M.
      • Aiba S.
      • Ohtani H.
      • Nagura H.
      • Tagami H.
      Comparison of the distribution and numbers of antigen-presenting cells among T-lymphocyte-mediated dermatoses: CD1a+, factor XIIIa+, and CD68+ cells in eczematous dermatitis, psoriasis, lichen planus and graft-versus-host disease.
      ).

      Dendritic cells

      In addition to expanded numbers in the epidermis, epidermal Langerhans cells have been observed to be present in the dermal inflammatory infiltrate of lichen planus lesions. As discussed previously, CD123(+) BDCA-2(+) plasmacytoid dendritic cells are expanded within the inflammatory infiltrate of lichen planus. It has recently been suggested that plasmacytoid dendritic cells might be differentially distributed within the inflammatory infiltrates of two other LTR/IFD skin diseases, cutaneous dermatomyositis and cutaneous LE (
      • Mcniff J.M.
      • Kaplan D.H.
      Plasmacytoid dendritic cells are present in cutaneous dermatomyositis lesions in a pattern distinct from lupus erythematosus.
      ). CD11c(+)S100(+)CD68(-) myeloid dendritic cells, DC-SIGN(+) dendritic cells, and langerin(+) epidermal Langerhans cells have also been reported to be expanded in the dermal and epidermal compartments of both oral and cutaneous lichen planus lesions (
      • Santoro A.
      • Majorana A.
      • Roversi L.
      • Gentili F.
      • Marrelli S.
      • Vermi W.
      • et al.
      Recruitment of dendritic cells in oral lichen planus.
      ;
      • Scheler M.
      • Wenzel J.
      • Tuting T.
      • Takikawa O.
      • Bieber T.
      • von B.D.
      Indoleamine 2,3-dioxygenase (IDO): the antagonist of type I interferon-driven skin inflammation?.
      ).

      NK cells

      Recent work has implicated CD94(+) CD3(-) CD56(low) CD16(+) ChemR23(+) natural killer cells as an effector cell type in oral lichen planus lesions (
      • Parolini S.
      • Santoro A.
      • Marcenaro E.
      • Luini W.
      • Massardi L.
      • Facchetti F.
      • et al.
      The role of chemerin in the colocalization of NK and dendritic cell subsets into inflamed tissues.
      ).

      Mast cells

      Increased mast cell densities have been observed in oral lichen planus (
      • Sugerman P.B.
      • Savage N.W.
      • Walsh L.J.
      • Zhao Z.Z.
      • Zhou X.J.
      • Khan A.
      • et al.
      The pathogenesis of oral lichen planus [Review].
      ;
      • Lodi G.
      • Scully C.
      • Carrozzo M.
      • Griffiths M.
      • Sugerman P.B.
      • Thongprasom K.
      Current controversies in oral lichen planus: report of an international consensus meeting. Part 1. Viral infections and etiopathogenesis.
      ). A significant percentage of such mast cells were found to be degranulated. It has been suggested that the proinflammatory milieu associated with degranulated mast cells might play a role in helping T cells breach the epidermal basement membrane in lichen planus lesions. In addition, mast cells are known to be responsive to TLR ligands.

      Cells that are typically not present in the LTR/IFD inflammatory-cell infiltrate

      Inflammatory cells that are typically absent in lichen planus include neutrophils and eosinophils. However, it cannot be excluded that neutrophils are not involved in the earliest phases of lichen planus inflammation as is the case in tuberculin-induced delayed hypersensitivity reactions. The absence of eosinophils implies dominance of Th1 cytokine pattern in lichen planus.

      Cellular dynamics and interactions

      As
      • Lodi G.
      • Scully C.
      • Carrozzo M.
      • Griffiths M.
      • Sugerman P.B.
      • Thongprasom K.
      Current controversies in oral lichen planus: report of an international consensus meeting. Part 1. Viral infections and etiopathogenesis.
      ) have pointed out, the majority of T cells within the epithelium and adjacent to damaged basal keratinocytes in oral lichen planus are activated CD8 T cells, and CD8 T cells colocalize with apoptotic keratinocytes. T cell lines and clones that can be isolated from oral lichen planus lesions are more cytotoxic against autologous lesional keratinocytes than T cell lines and clones isolated from clinically normal skin of lichen planus patients. These data suggest that CD8 lesional T cells may in part be activated by an antigen associated with major histocompatibility complex (MHC) class I on basal keratinocytes and that activated CD8 cytotoxic T cells may trigger keratinocyte apoptosis in oral lichen planus. The nature of the antigen and the key antigen-presenting cell(s) is uncertain in lichen planus.

      Unifying hypotheses relating to the immunopathogenesis of lichen planus

      Tetsuo Shiohara at Kyorin University School of Medicine in Tokyo, Japan, has maintained a career-long interest in the immunopathogenesis of LTR/IFD disorders. On the basis of his own work with experimental animal models of the LTR as well as observations relating to the human fixed drug eruption, Shiohara has proposed a unifying hypothesis concerning the immunopathogenesis of the LTR/IFD (
      • Shiohara T.
      • Kano Y.
      Lichen planus and lichenoid dermatoses.
      ;
      • Shiohara T.
      • Mizukawa Y.
      The immunological basis of lichenoid tissue reaction.
      ). Shiohara's work with murine models of the LTR was reviewed by Dr Jan Dutz at the Montagna “Lichenoid Tissue Reaction” session and will be presented elsewhere in these proceedings. I will focus here on the model devised by Shiohara et al., to explain the behavior of memory CD8 T cells in the human fixed drug eruption as a paradigm for the LTR/IFD in general.
      A fixed drug eruption typically presents as an edematous plaque on the skin that appears quickly after exposure to the triggering drug. Given time, the inflammation within a fixed drug eruption lesion subsides leaving only postinflammatory hyperpigmentation. Upon readministration of the offending drug, new fixed drug eruption lesions develop elsewhere on the skin and the older “resting” lesions characteristically again become inflamed. Presumably, drug-specific CD8 cytotoxic T cells that express certain activation markers are thought to be responsible for the LTR/IFD pattern of epidermal damage seen in a fixed drug eruption. Curiously, CD8-positive cytotoxic T cells have been shown to persist as a stable population in resting fixed drug eruption lesions between periods of clinically evident inflammation (data reviewed by
      • Shiohara T.
      • Mizukawa Y.
      The immunological basis of lichenoid tissue reaction.
      ). These “residual” CD8 T cells are intimately associated with activated macrophages/dendritic cells within “resting” fixed drug eruption lesions. A similar association of activated CD8 T cells and activating antigen-presenting cells (APCs) has been observed in the healed skin following herpes simplex virus infection. It has been suggested that these persisting activated CD8 T cells and APCs are a result of persistent, low-level viral antigen expression. Shiohara et al. have suggested that CD8 T cells that remain enriched in resting fixed drug eruption lesions could have originally evolved to prevent reactivation of viruses such as herpes simplex virus from latency. Accidental reactivation of this cytotoxic T-cell population by cross-reactive drug antigens could result in a localized LTR/IFD injury pattern seen in the fixed drug eruption (
      • Shiohara T.
      • Mizukawa Y.
      The immunological basis of lichenoid tissue reaction.
      ). Other workers including
      • Lodi G.
      • Scully C.
      • Carrozzo M.
      • Griffiths M.
      • Sugerman P.B.
      • Thongprasom K.
      Current controversies in oral lichen planus: report of an international consensus meeting. Part 1. Viral infections and etiopathogenesis.
      ) who have been focused predominately on the etiopathogenesis of oral lichen planus have presented similar unifying models. Figure 5 presents a compilation of these and related thoughts.
      Figure thumbnail gr5
      Figure 5A composite representation of unifying hypotheses for the immunopathogenesis of lichen planus (see text for discussion). Nonconsensus abbreviations: Ag, antigen; Aag, autoantigen; HSP, heat shock protein.
      This figure was adapted from a previously published figure with permission from the authors and publisher (
      • Lodi G.
      • Scully C.
      • Carrozzo M.
      • Griffiths M.
      • Sugerman P.B.
      • Thongprasom K.
      Current controversies in oral lichen planus: report of an international consensus meeting. Part 1. Viral infections and etiopathogenesis.
      ).
      At stage no. 1 of Figure 5, APCs (epidermal Langerhans cells, dermal dendritic cells) and basal keratinocytes are “activated” by viral infection, bacterial products, mechanical trauma, systemic drugs, contact sensitivity, UV light, or other unidentified agents. TLR-7 and TLR-9 signaling by plasmacytoid dendritic cells recruited into this early milieu of innate immune activation could amplify the activating effects of such stimuli via IFN-α production. Plasmacytoid dendritic cells expressing Fc receptors could also be further activated in this setting by immune complexes containing foreign (viral) or self (U1RNA, hYRNA) (
      • Kelly K.M.
      • Zhuang H.
      • Nacionales D.C.
      • Scumpia P.O.
      • Lyons R.
      • Akaogi J.
      • et al.
      “Endogenous adjuvant” activity of the RNA components of lupus autoantigens Sm/RNP and Ro 60.
      ;
      • Kelly-Scumpia K.M.
      • Nacionales D.C.
      • Scumpia P.O.
      • Weinstein J.S.
      • Narain S.
      • Moldawer L.L.
      • et al.
      In vivo adjuvant activity of the RNA component of the Sm/RNP lupus autoantigen.
      ).
      During stage no. 2a, activated APCs and keratinocytes secrete cytokines and chemokines that attract lymphocytes into the developing lichen planus lesion. Specific chemokine and chemokine receptor pairs that have recently been implicated as playing a role in the LTR/IFD (for example, CXCL-10/CXCR3) will be discussed by others in these proceedings. Activated dendritic APCs present antigen associated with MHC class II to CD4 T cells. CD40 and CD80 coexpression and IL-12 secretion by MHC class II dendritic APCs promote a Th-1 CD4 T cell response. During stage no. 2b, activated basal keratinocytes present antigen associated with MHC class I to CD8 T cells.
      At stage no. 3a, Th-1 CD4 T cells secrete IL-2 and INF-γ, which bind to their respective receptors on CD8 cytotoxic T cells (no. 3b). It is possible but not yet confirmed that the recently described Th-17 cell might play a role at this stage. Products released from activated mast cells might facilitate T cells breaching the epidermal basement membrane to enter the epidermis.
      CXCR3-expressing CD8 cytotoxic T cells are recruited from the circulation into the skin by locally elaborated chemokines such as CXCL-10. Activated antigen-specific CD8 cytotoxic T cells express FasL, secrete granzymes/perforin and/or tumor necrosis factor (TNF)-α (stage no. 4) that trigger basal cell keratinocyte apoptosis (no. 5). As discussed previously, there is evidence that basal keratinocytes in the LTR/IFD undergo necrosis as well as apoptosis. It is also possible that injured keratinocytes in this setting express heat-shock/stress-response proteins in a variant fashion (
      • Chaiyarit P.
      • Kafrawy A.H.
      • Miles D.A.
      • Zunt S.L.
      • Van Dis M.L.
      • Gregory R.L.
      Oral lichen planus: an immunohistochemical study of heat shock proteins (HSPs) and cytokeratins (CKs) and a unifying hypothesis of pathogenesis.
      ;
      • Bayramgurler D.
      • Ozkara S.K.
      • Apaydin R.
      • Ercin C.
      • Bilen N.
      Heat shock proteins 60 and 70 expression of cutaneous lichen planus: comparison with normal skin and psoriasis vulgaris.
      ). Such proteins might also be the targets of an autoimmune response.
      It has been suggested that two antigens might be required for the full development of a LTR/IFD such as lichen planus (
      • Lodi G.
      • Scully C.
      • Carrozzo M.
      • Griffiths M.
      • Sugerman P.B.
      • Thongprasom K.
      Current controversies in oral lichen planus: report of an international consensus meeting. Part 1. Viral infections and etiopathogenesis.
      ). As an example, antigen no. 1 might be an MHC class II-restricted, virus-derived polypeptide that is processed through endosomal compartments within dendritic cells. Presentation of this processed antigen by myeloid dendritic cells to CD4 Th1 cells within the milieu of dendritic cell derived to proinflammatory cytokines (for example, TNF-α, IL-1, IL-12) would result in the generation of IL-2 and IFN-γ. These latter two cytokines working in concert with locally derived, IFN-α-induced CXCL9–CXCL11 might result in the recruitment and activation of CXCR3(+) cytotoxic CD8 T cells. These cytotoxic effector T cells would then be further activated by MHC class I-restricted, cytoplasm-processed antigen no. 2 being presented by activated basaloid keratinocytes. Antigen no. 2 could be a self-antigen such as a heat shock protein induced on basaloid keratinocytes via innate immune response activation (stage no. 5). Cytotoxic and pro-apoptotic mediators/stimuli expressed by fully activated cytotoxic CD8 T cells (that is, granzyme, perforin, fas ligand) could then mediate the basal cell layer apoptosis and necrosis that is typical of lichen planus.
      It is also possible that antigen no. 1 and antigen no. 2 in Figure 5 could represent the same molecule that gains access to both the endosomal and cytosolic of antigen-presentation pathways via mechanism of crossed antigen presentation (
      • Lodi G.
      • Scully C.
      • Carrozzo M.
      • Griffiths M.
      • Sugerman P.B.
      • Thongprasom K.
      Current controversies in oral lichen planus: report of an international consensus meeting. Part 1. Viral infections and etiopathogenesis.
      ). An example might be a chemical hapten.
      Some LTR/IFD disorders such as a subacute cutaneous LE are associated with circulating Ro/SS-A and La/SS-B autoantibodies. Interestingly, Ro/SS-A and La/SS-B antigens have been shown to appear in membrane blebs of keratinocytes undergoing UV light-induced apoptotsis (
      • LeFeber W.P.
      • Norris D.A.
      • Ryan S.R.
      • Lee L.A.
      • Huff J.C.
      • Kubo M.
      • et al.
      Ultraviolet light induces binding of antibodies to selected nuclear antigens on cultured human keratinocytes.
      ;
      • Casciola-Rosen L.A.
      • Anhalt G.
      • Rosen A.
      Autoantigens targeted in systemic lupus erythematosus are clustered in two populations of surface structures on apoptotic keratinocytes.
      ) (stage no. 5). It has been proposed that a component of basal keratinocyte injury occurring in subacute cutaneous LE lesions might result from antibody-dependent cell-mediated cytotoxicity when effector cells recognize via their Fc receptors the Fc fragments of Ro/SS-A and La/SS-B autoantibody bound to their antigens on the surface of apoptotic keratinocytes (
      • Bennion S.
      • Norris D.A.
      Ultraviolet light modulation of autoantigens, epidermal cytokines and adhesion molecules as contributing factors of the pathogenesis of cutaneous LE.
      ;
      • Furukawa F.
      • Itoh T.
      • Wakita H.
      • Yagi H.
      • Tokura Y.
      • Norris D.A.
      • et al.
      Keratinocytes from patients with lupus erythematosus show enhanced cytotoxicity to ultraviolet radiation and to antibody-mediated cytotoxicity.
      ). Fc receptor expressing monocytes, dendritic cells, and NK cells would more likely serve as such effector cells in this setting compared to T cells, as T cells are relatively inefficient in expressing Fc receptors. Alternatively, Ro/SS-A and La/SS-B antibodies bound to their respective antigens on the surface of UV light-induced apoptotic keratinocytes might interfere with the physiological noninflammatory clearance of such keratinocytes by phagocytes.
      • Clancy R.M.
      • Neufing P.J.
      • Zheng P.
      • O’Mahony M.
      • Nimmerjahn F.
      • Gordon T.P.
      • et al.
      Impaired clearance of apoptotic cardiocytes is linked to anti-SSA/Ro and -SSB/La antibodies in the pathogenesis of congenital heart block.
      ), who study congenital heart block in the context of neonatal LE, have reported that the presence of maternal Ro/SS-A and La/SS-B antibodies inhibits the phagocytosis of apoptotic cardiocytes by surrounding resident cardiocytes.

      Deficient inflammation-dampening mechanisms in LTR/IFD?

      As Shiohara has pointed out, many LTR/IFD disorders including lichen planus display a finite lifespan characterized by spontaneous resolution (
      • Shiohara T.
      • Mizukawa Y.
      The immunological basis of lichenoid tissue reaction.
      ). This implies that the LTR/IFD reaction pattern might represent a physiological mechanism for maintaining the integrity of epidermal basal cells that has gone awry. Genetic polymorphism of pro-inflammatory and/or anti-inflammatory components of such a protective mechanism could be at play. Polymorphism of pro-inflammatory pathways including cytokines (fir example, INF-γ, TNF-α, IL-18) have been reported in lichen planus. In addition, polymorphism of a number of anti-inflammatory pathways is possible in lichen planus. For example, variant expression of the TGF-β/Smad pathway has been reported in lichen planus (
      • Karatsaidis A.
      • Schreurs O.
      • Axell T.
      • Helgeland K.
      • Schenck K.
      Inhibition of the transforming growth factor-beta/Smad signaling pathway in the epithelium of oral lichen.
      ). In addition, low rates of apoptosis of lymphocytes infiltrating lichen planus lesions have been observed (
      • Bascones-Ilundain C.
      • Gonzalez-Moles M.A.
      • Esparza-Gomez G.
      • Gil-Montoya J.A.
      • Bascones-Martinez A.
      Importance of apoptotic mechanisms in inflammatory infiltrate of oral lichen planus lesions.
      ). Also, variant expression of cytokine inhibitors such as soluble TNF-α receptors and IL-1 receptors might also play a role. As discussed previously, preliminary studies have found no quantitative abnormalities in FOXP3(+) T regulatory cells in lichen planus.
      A number of less well-known molecules have been implicated in downregulating the inflammation of lichen planus. Examples include soluble inhibitors of cytokines (soluble TNF receptor, soluble IL-1 receptor), resolvins, and protectins (
      • Ariel A.
      • Serhan C.N.
      Resolvins and protectins in the termination program of acute inflammation.
      ;
      • Schwab J.M.
      • Chiang N.
      • Arita M.
      • Serhan C.N.
      Resolvin E1 and protectin D1 activate inflammation-resolution programmes.
      ). In addition, indoleamine 2,3-dioxygenase, which degrades tryptophan and suppresses T-cell proliferation, is induced by IFNs and other inflammatory cytokines (
      • Scheler M.
      • Wenzel J.
      • Tuting T.
      • Takikawa O.
      • Bieber T.
      • von B.D.
      Indoleamine 2,3-dioxygenase (IDO): the antagonist of type I interferon-driven skin inflammation?.
      ). Variant expression of this molecule could also play a role in faulty downregulation of INF-α-mediated inflammatory pathways. The entire field of physiological downregulation of acute and chronic inflammation deserves more attention in the context of lichen planus and other LTR/IFD disorders (
      • Wells C.A.
      • Ravasi T.
      • Hume D.A.
      Inflammation suppressor genes: please switch out all the lights.
      ;
      • Lawrence T.
      • Gilroy D.W.
      Chronic inflammation: a failure of resolution?.
      ).
      Any etiopathogenetic model of lichen planus and other LTR/IFD disorders needs to account for several consistent clinical features of this group of diseases. Nonspecific skin trauma will precipitate skin disease activity in noninvolved skin in some LTR/IFD disorders such as lichen planus and cutaneous LE (that is, the Köebner or isormorphic response). In addition, induction or exacerbation by UV light is a characteristic of some LTR/IFD disorders such as cutaneous LE and cutaneous dermatomyositis.

      Treatment

      Treatment of this diverse group of cutaneous disorders is guided by the degree of symptomatology, disability, and associated systemic illness. Banal, self-limited dermatoses such as lichen nitidus and lichen striatus are treated with topical immunomodulatories (for example, corticosteroids, calcineurin inhibitors) until they spontaneously remit. Photoavoidance and broad-spectrum sunscreen use can be of benefit to UV light-induced/exacerbated LTR/IFD disorder such as cutaneous LE and cutaneous dermatomyositis.
      Severely symptomatic, potentially disfiguring/disabling LTR/IFD disorders can be more difficult to treat. Intractable lichen planus rubra and erosive lichen planus of the genitalia can require systemic immunosuppressive/immunomodulatory therapy (for example, corticosteroids, cyclosporine, mycophenolate mofetil), with the attendant risks for significant side effects. Similar systemic treatment approaches are required for fulminant, life-threatening LTR/IFD disorders such as erythema multiforme major (Stevens–Johnson syndrome) and toxic epidermal necrolysis.
      LTR/IFD dermatoses that are associated with potentially life-threatening systemic diseases are treated empirically in a graded fashion depending upon the severity of the cutaneous and systemic manifestations. Limited forms of cutaneous LE, cutaneous dermatomyositis, and graft-versus-host skin disease can be treated with topical immunomodulatory therapy and systemic nonimmunosupressive anti-inflammatory agents such as the aminoquinoline antimalarials (hydroxychloroquine, chloroquine, quinacrine) and dapsone. When the cutaneous manifestations of these disorders are severe or are associated with significant systemic disease activity/injury, systemic immunosuppressive/immunomodulatory therapy is required (corticosteroids, methotrexate, azathioprine, mycophenolate). Because of the rarity of many of the LTR skin disorders, virtually all of the above-noted treatment modalities are carried out on an “off-label” non-FDA-indicated basis.
      In a reverse engineering approach, determining how empirically derived therapeutic agents actually work in controlling LTR/IFD inflammation could provide additional insight into the immunological mechanisms of these disorders. As an example, aminoquinoline antimalarial drugs such as hydroxychloroquine, chloroquine, and quinacrine are especially useful in controlling lupus-specific skin disease inflammation. Although antimalarials are thought to have numerous inhibitory effects on the inflammatory response, they are now known to downregulate Toll-like receptor expression due to their ability to alkalinize intracellular endosomal compartments (
      • Kalia S.
      • Dutz J.P.
      New concepts in antimalarial use and mode of action in dermatology.
      ). As has been mentioned elsewhere, Toll-like receptor signaling within plasmacytoid dendritic cells resulting in IFN-α production is thought to play a key role in the pathogenesis of LE-specific skin disease and other LTR disorders. Why antimalarial drugs are not as clinically effective in lichen planus and cutaneous dermatomyositis as they are in cutaneous LE is not clear.
      Lymphocyte function assoc. antigen (LFA-1) is expressed by T cells in the inflammatory infiltrate of all LTR/IFD skin disorders. LFA-1–intercellular adhesion molecule (ICAM-1) interaction facilitates T cells gaining access to the extravascular compartment of the skin and also facilitates T cell stimulation by APCs within the skin. Recent anecdotal observations have suggested that blocking the LFA-1–ICAM-1 costimulatory pathway might be of benefit to a number of different LTR/IFD skin disorders. One such recombinant biological drug that interferes with this costimulatory pathway, efalizumab (Raptiva), has been reported anecdotally to be of clinical benefit in multiple LTR/IFD (for example, lichen planus (
      • Cheng A.
      • Mann C.
      Oral erosive lichen planus treated with efalizumab.
      ;
      • Bohm M.
      • Luger T.A.
      Lichen planus responding to efalizumab.
      ), cutaneous LE (
      • Clayton T.H.
      • Ogden S.
      • Goodfield M.D.
      Treatment of refractory subacute cutaneous lupus erythematosus with efalizumab.
      ;
      • Usmani N.
      • Goodfield M.
      Efalizumab in the treatment of discoid lupus erythematosus.
      ), cutaneous dermatomyositis (
      • Huber A.
      • Gaffal E.
      • Bieber T.
      • Tuting T.
      • Wenzel J.
      Treatment of recalcitrant dermatomyositis with efalizumab.
      )). Systematic studies are needed to confirm the preliminary clinical observations.
      There are several small-molecule approaches on the horizon that might prove to be of clinical benefit in LTR/IFD disorders. As an example, several classes of small-molecule inhibitors of the CXCR3 receptor are currently being developed (for example, imidazole derivatives) (
      • Du X.
      • Chen X.
      • Mihalic J.T.
      • Deignan J.
      • Duquette J.
      • Li A.R.
      • et al.
      Design and optimization of imidazole derivatives as potent CXCR3 antagonists.
      ;
      • Knight R.L.
      • Allen D.R.
      • Birch H.L.
      • Chapman G.A.
      • Galvin F.C.
      • Jopling L.A.
      • et al.
      Development of CXCR3 antagonists. Part 4: discovery of 2-amino-(4-tropinyl)quinolines.
      ;
      • Li A.R.
      • Johnson M.G.
      • Liu J.
      • Chen X.
      • Du X.
      • Mihalic J.T.
      • et al.
      Optimization of the heterocyclic core of the quinazolinone-derived CXCR3 antagonists.
      ;
      • Mohan K.
      • Issekutz T.B.
      Blockade of chemokine receptor CXCR3 inhibits T cell recruitment to inflamed joints and decreases the severity of adjuvant arthritis.
      ;
      • Turner J.E.
      • Steinmetz O.M.
      • Stahl R.A.
      • Panzer U.
      Targeting of Th1-associated chemokine receptors CXCR3 and CCR5 as therapeutic strategy for inflammatory diseases.
      ;
      • Suzaki Y.
      • Hamada K.
      • Nomi T.
      • Ito T.
      • Sho M.
      • Kai Y.
      • et al.
      A small-molecule compound targeting CCR5 and CXCR3 prevents the development of asthma.
      ). These inhibitors are currently being examined in other T-cell mediated autoimmune diseases such as rheumatoid arthritis and asthma and perhaps might play a role therapeutically in LTR/IFD disorders in the future.

      Conflict Of Interest

      The author states no conflict of interest.

      ACKNOWLEDGMENTS

      My contributions to the preparation of this work was supported by The Richard and Adeline Fleischaker Chair in Dermatology Research at the University of Oklahoma Health Sciences Center. I thank Jan P Dutz, MD, for his thoughtful comments on this manuscript. I also thank Dr Neil Crowson and Dr Paul Bergstresser for providing for some of the micrographic images used in the manuscript.

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