Tetsuo Shiohara

Current understanding of cytomegalovirus infection in immunocompetent individuals

Human cytomegalovirus (CMV) is a member of the herpes family of viruses. After primary infection, it undergoes latency/persistence. Significant progress has been made in the last few years in detecting CMV. The most available approach to the diagnosis of CMV infection is the direct detection of CMV antigen in nuclei of peripheral blood leukocytes, an assay known as pp65 direct antigenemia test. CMV infection is well controlled in the immunocompetent hosts; however, there are various immunological changes in immune function during and after recovery from CMV infections. Characteristic changes in lymphocyte subsets occur during CMV infection, mainly involving expansion and activation of CD8+ T lymphocytes and NK cells. On the other hand, CMV has an array of immune escape strategies for establishing a life long latent state: CMV inhibits major histocompatibility complex (MHC) class I expression within infected cells and impairs IFN-gamma-induced MHC class II-dependent antigen presentation by macrophages; it can also encode proteins that can interfere with the presentation of viral peptide antigens to T cells. While cutaneous manifestations of CMV seen in immunocompromised patients have been extensively reported, those in adult immunocompetent individuals have received relatively little attention: in this setting the primary CMV infection appears as CMV mononucleosis. At the time of occurrence of the mononucleosis syndrome, a variety of extracutaneous and cutaneous manifestations occur. These clinical symptoms are not the direct consequence of proliferation of CMV in given tissues but indicative of the immunological response toward CMV. The incidence of the appearance of eruptions in CMV mononucleosis is variable. Certain drugs given in the early stage of this disease play an important role in the development of eruption, just as with the ampicillin rashes in the Epstein-Barr virus mononucleosis. Although the mechanism by which drugs trigger the development of rashes in patients with CMV mononucleosis is unknown, it is assumed that CMV is likely to be a potential amplifier of drug rashes induced by activation of drug-specific T cells. By improving methods for detection of CMV, we can recognize that many types of eruptions other than CMV mononucleosis could be induced by primary infection or reactivation of CMV.

Pathophysiology of fixed drug eruption: the role of skin-resident T cells.

Purpose of reviewFixed drug eruption is a distinct variant of drug-induced dermatoses characterized by their relapse in the same location after the administration of the causative drug. We have recently shown that intraepidermal CD8+ T cells phenotypically resembling effector memory T cells are greatly enriched in the resting lesions of FDE. Although effector memory T cells have been implicated as the mediators of protection in epithelial tissues, our observation raises an alternative possibility that improper, enhanced or uncontrolled activation of intraepidermal T cells could contribute to severe tissue injury. Until recently, however, their detrimental effects on epithelial tissues have rarely been examined. The focus of this review is on how intra-epidermal T cells originally evolved to protect tissue integrity can exert an opposite action that is deleterious to the host. Recent findingsBecause those T cells residing in the lesions, upon activation, can rapidly produce large amounts of IFN-γε followed by localized epidermal injury, their activation is probably essential for the initiation of deleterious inflammatory responses in the lesions. The activity of these potent effector T cells is therefore carefully controlled to prevent unwanted tissue injury under physiological conditions. A complex interplay of stop and go signals to the skin-resident T cells provides a delicate balance between cell death and survival, thereby determining the degree and outcome of inflammation generated in response to pathogens or antigens. SummaryThis consideration may provide important insights into the way in which skin-resident T cells maintain immunological homeostasis in the skin.

Preferential expression of αEβ7 integrin (CD103) on CD8+ T cells in the psoriatic epidermis: regulation by interleukins 4 and 12 and transforming growth factor-β

Summary Background u2003Intraepidermal T lymphocytes are a critical element for sustaining the lesional pathology of psoriasis. Integrin αEβ7 (CD103), a ligand for E‐cadherin, may play a role in the localization of pathogenic T cells within the epidermis of psoriatic lesions. However, little information is available regarding αEβ7 expression on intraepidermal T cells in psoriasis.

Virus-induced immune dysregulation as a triggering factor for the development of drug rashes and autoimmune diseases: with emphasis on EB virus, human herpesvirus 6 and hepatitis C virus.

There are a considerable amount of empirical and theoretic medical literature regarding the possible role of viruses in the development of drug rashes and autoimmune diseases: under these conditions, interactions of viruses with the immune system would serve as an accelerating factor of disease pathogenesis. Recent reports have provided evidence to indicate that immune responses against infections with Epstein Barr (EB) virus and human herpesvirus 6 (HHV-6), which are lymphotropic members of the herpes virus group, not only aid the direct elimination of the virus but also contribute to a favorable milieu for the initiation or acceleration of drug rashes. Viruses that can persist for the lifetime of the host despite strong immune responses against them, such as EB virus and hepatitis C virus (HCV), would be also relevant to the pathogenesis of autoimmune diseases. HCV has been reportedly associated with a wide variety of dermatoses that, in common, show histologically the lichenoid tissue reaction. Although porokeratosis that manifests lichenoid histopathological features had long been regarded as being associated with immunosuppression, we found that HCV could act as trigger for the development of porokeratosis during states of immunosuppression. Thus, the main purpose of this review is to describe recent work on the etiology of drug rashes and autoimmune disease with special reference to viral infections.

Protective and curative effects of topically applied CX-659S, a novel diaminouracil derivative, on chronic picryl chloride-induced contact hypersensitivity responses.

Summary Backgroundu2003CX‐659S, a newly discovered anti‐inflammatory compound, exerts inhibitory effects against acute contact hypersensitivity responses (CHRs) induced by picryl chloride (PC), oxazolone and dinitrochlorobenzene. The murine model of chronic CHR induced by repeated application of PC is known to mimic many, if not all, events occurring within the lesional skin of patients with atopic dermatitis (AD).

The cytokine profile in a transient variant of angioedema with eosinophilia

Episodic angioedema with eosinophilia is characterized by recurrent angioedema, fever and weight gain with a remarkable eosinophilia. A transient type, predominantly reported in Japan, in which the disease is limited to a single attack, is usually less severe than the episodic type described in the U.S.A. and Europe, and provides an ideal disease model in which to study the mechanisms for resolution of eosinophilic inflammation. The aim of this study was to evaluate the relationship between cytokine responses and clinical course in three patients with the transient type. Serum levels of interleukin (IL) ‐5 were only marginally elevated even during an attack, unlike those in reported cases of the episodic type. Significant elevations in granulocyte‐macrophage colony‐stimulating factor levels were also noted during an attack in two cases in which it was measured. A dramatic increase in tumor necrosis factor (TNF) ‐α levels was subsequently observed in relation to resolution of clinical symptoms. No major changes in the serum levels of soluble Fas and soluble Fas ligand were found throughout the course. These results suggest that relatively lower levels of IL‐5 and a subsequent increase in TNF‐α levels are characteristic features of the transient type. The differences in clinical symptoms and course observed between the two types may be partly explained by the differences in the cytokine profiles.

Immunohistochemical Detection of Skin-Homing T Cells Expressing Fucosyltransferase VII (Fuc-TVII) In Vitro and In Situ

Although expression of cutaneous lymphocyte-associated antigen (CLA) is thought to be a specific marker of skin “homing” T cells, it has become clear that CLA is a good marker for high levels of fucosyltransferase VII (Fuc-TVII) activity but does not necessarily represent the epitope required for binding to E-selectin (Wagers et al, 1996, 1997). Therefore, expression of Fuc-TVII is an attractive candidate for identifying skin “homing” T cells. However, analyses of Fuc-TVII expression in human T cells have been performed only at the mRNA level (Nakayama et al, 2000) because of the lack of mAb. In this study Fuc-TVII was for the first time visualized in individual cells by using a novel mAb that we developed. Double immunofluorescence and immunohistochemistry demonstrated the coexpression of Fuc-TVII and CLA in cell lines in which Fuc-TVII mRNA was shown to be expressed at high levels: whereas CLA expression was seen in the cell membrane, Fuc-TVII was identified in a supra- or perinuclear location. Cytoplasmic Fuc-TVII expression was also detectable in both CD4+ and CD8+ T cells purified from peripheral blood. Fuc-TVII was also expressed at high levels in many CLA+ T cells infiltrating the skin. In these peripheral T cells, unlike in cell lines, cytoplasmic expression of Fuc-TVII was not always associated with surface CLA expression. This mAb would serve as a valuable tool for selectively identifying a novel subset of skin “homing” T cells that are not detected by the conventional method because of the lack of CLA expression.

Viral infections, allergy and autoimmunity: a complex, but fascinating link

The development of many skin diseases depends on a variable interaction of genetic and exogenous factors: genetic predisposition alone is not sufficient for the development of disease and exogenous factors often play a decisive role in triggering the outbreak of disease. Much clinical and epidemiologic evidence suggests that viral infections predispose individuals to specific disease outcomes by a variety of mechanisms that range from a direct modification of the host cell genome to virus-induced immunosuppression or immunoactivation. During the course of a viral infection profound changes take place in the immune system. The outcome of a viral infection relies on a delicate balance between the capacity of the virus to replicate and spread in the host’s cell by inhibiting or evading the immune response and that of the host to eliminate it by mounting strong protective immune responses: the balance between viral spread and the kinetics of the immune responses determines whether elimination of the virus or immunopathology will predominate, because the protective immune response mediated by cytotoxic T cells causes damage to infected host cells [1]. Limited numbers of viruses can cause overt disease in an overwhelming majority of people with acute infections and are subsequently eliminated from the host: nevertheless, some of these viruses that were generally thought to be apparently eliminated may not be completely cleared from the host [2,3]. In contrast, most of other viruses, after the relatively short-lived acute infections, can persist in vivo for a prolonged period of time without causing disease. The viruses that can persist are thought to have a strategy to remain within the cells without disturbing the transcription or translation of the genes necessary for the infected cell’s survival. Although the viruses that persist for life are likely to be responsible for a wide variety of diseases of unknown etiology, the prolonged pathologic consequences of infection with these viruses are difficult to follow. * Tel.: +81-422-47-5511; fax: +81-422-41-4741.