Polysensitivity in fixed drug eruption.
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Anticonvulsants↗
Biomedical subjects
T Shiohara
Publications and source records attributed to T Shiohara.
Epidermal T cells: their functional role and disease relevance for dermatologists.
T cells found within the epidermis in inflammatory dermatoses are generally accepted as making a major contribution to epidermal damage. On the other hand, those T cells residing in the murine epidermis are supposed to play an important role in protecting the epidermis from potentially dangerous immune reactions. Overwhelming evidence has accumulated that dendritic epidermal T cells (DETC) expressing monomorphic TCR gammadelta are responsible for the protection of epidermal structures against skin tumor, bacterial infection, and autoimmune attack. In animals congenitally lacking these gammadelta+ DETC, the epidermis is populated with bone marrow-derived TCR alphabeta+, CD8+ DETC. Although it remains unclear whether this subset of DETC could home to the epidermis to substitute for the physiologic function of gammadelta+ DETC or whether they would be pathologically relevant to epidermal injury, it should be noted that this subset represents the major fraction of T cells present in normal human epidermis and the most abundant in the lesional epidermis of fixed drug eruption (FDE). Because they are shown to kill target cells including keratinocytes upon stimulation and utilize a very limited range of TCR V alpha and Vbeta gene families, localized epidermal injury in FDE lesions would be mediated by activation of these epidermal T cells with autoaggressive potential. Epidermal T cells are thus likely to form several T-cell populations with different immunologic functions that are triggered by different modes of stimulation. Immune homeostasis in the epidermis would rely on a delicate balance between at least two types of epidermal T cells: autoaggressive T cells and protective T cells.
Animals↗
Complete resolution of psoriasis vulgaris after excision of thyroid cancer.
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Adenocarcinoma↗
Adult thymus contains dendritic epidermal T cell precursors that home to the epidermis in irradiated, but not in normal, mice.
It was generally assumed that Vgamma5+ fetal thymocytes are the only cells capable of homing to the epidermis. However, we have recently demonstrated that reconstitution of thymectomized irradiated mice with T-cell-depleted bone marrow (BM) cells results in the appearance of donor-type CD8+, TCR-alphabeta+ dendritic epidermal T cells (DETC) phenotypically distinct from their normal gammadelta+ counterparts. In the present study, we found that the epidermis of lethally irradiated, BM-reconstituted (XBM) mice was also repopulated by DETC of host origin as well as donor BM-derived DETC and that the host-derived DETC were rarely detected in the epidermis of athymic BM chimeras (ATXBM). This result indicates that the host-derived DETC are originated from intrathymic radioresistant cells that may share migratory capacities with the fetal thymocytes. We demonstrated that transfer of radioresistant intrathymic precursor cells into ATXBM mice resulted in the appearance of donor-type CD8+, TCR-alphabeta+ DETC. Contrary to our initial expectation, however, transferred normal adult thymocytes also gave rise to donor-type DETC with frequency similar to radioresistant thymocyte-derived DETC. These thymocyte-derived DETC were phenotypically similar to those derived from BM cells but differed in some respects. Tissue tropism by the CD8+ subset was observed only for the epidermis, but not for other lymphoid organs, such as lymph nodes. The epidermis of normal mice, unlike that of irradiated mice, was refractory to the appearance of the thymus-derived DETC. These results suggest that prior irradiation of the host may confer a susceptibility of the epidermis to repopulation of DETC precursors, which are otherwise incapable of migrating into the epidermis. This provides an explanation for why CD8+, TCR-alphabeta+ DETC of adult thymus or BM origin are rarely detected in the normal epidermis, but abundantly observed in the irradiated mice.
Aging↗
Resistance to cutaneous graft-vs.-host disease is not induced in T cell receptor delta gene-mutant mice.
The function of murine dendritic epidermal cells (dEC) remains largely speculative, probably because of the lack of a suitable in vivo model, although previous studies suggest that gamma/delta+ dEC may have originally evolved to serve as a self-protection mechanism(s). Our previous study demonstrated that the epidermis of mice that had spontaneously recovered from cutaneous graft-vs-host disease (GVHD) induced by local injection of CD4+ autoreactive T cells contained unexpectedly large numbers of dEC and became resistant to subsequent attempts to induce GVHD in a site-restricted manner, suggesting that the resistance is mediated by dEC. However, because alpha/beta+ dEC as well as gamma/delta+ dEC were greatly increased in number in the epidermis, it was unclear whether gamma/delta+ dEC are indeed responsible for this protection. The availability of this murine model and mice selectively lacking gamma/delta T cells as a result of disruption of the T cell receptor C delta gene segment allowed us to investigate the role of gamma/delta+ dEC. In the epidermis of gamma/delta T cell-deficient mice (delta-/-), a congenital lack of gamma/delta+ dEC was substituted for by alpha/beta+ dEC of either a CD4-8+ or a CD4-8- phenotype. After intradermal injection of the autoreactive T cells, delta-/- mice developed significantly enhanced delayed-type hypersensitivity responses and cutaneous GVHD, which persisted longer than in heterozygous littermate controls (delta+/-). Surprisingly, resistance to the cutaneous GVHD was not induced in the epidermis of delta-/- mice after spontaneous recovery from the GVHD, whereas the "susceptible" epidermis of delta-/+ mice contained large numbers of alpha/beta dEC comparable to those in "resistant" epidermis of delta+/- mice. Injection of day 16 fetal thymocytes from wild-type mice into delta-/- mice resulted in the appearance of donor-type gamma/delta+ dEC in the epidermis, and reconstitution with gamma/delta+ dEC restored the protective immune response of the epidermis against the GVHD to nearly normal levels. These results indicate that gamma/delta+ dEC are responsible for the site-restricted protection against cutaneous GVHD.
Animals↗
Ketosis is involved in the origin of prurigo pigmentosa.
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3-Hydroxybutyric Acid↗
T cell receptor (TCR) repertoire and function of human epidermal T cells: restricted TCR V alpha-V beta genes are utilized by T cells residing in the lesional epidermis in fixed drug eruption.
Human epidermis contains a phenotypically heterogeneous population of T cells. No information however, is available regarding the TCR repertoire of these T cells and their relevant physiologic and pathologic functions in vivo. To this end, T cells were prepared from the lesional epidermis in two patients with fixed drug eruption (FDE) and their phenotype, function and TCR repertoire were examined in parallel. Both epidermal T cells, termed FDE-1 and -2 cells, respectively, expressed alpha beta TCR, but displayed some phenotypic heterogeneity. These T cells were induced to display cytolytic activity by ligation of the CD3/TCR-alpha beta complex. Comparative analyses of TCR V alpha and V beta expression in the epidermal T cells and the paired peripheral blood lymphocytes (PBL) by quantitative polymerase chain reaction (PCR) demonstrated that the epidermal T cells, but not the paired PBL, utilized a very limited range of V alpha and V beta genes. These results indicate that some expansion or preferential migration of epidermal T cells that recognize a restricted set of antigens expressed within the epidermis could occur in situ following ingestion of the causative drug. The persistence of these epidermal T cells in FDE lesions suggests their pathologic role in a drug-induced flare.
Base Sequence↗
Time-course analyses of exercise-induced lesions in a patient with urticarial vasculitis.
Using immunoperoxidase techniques, we examined the histological changes of exercise-induced lesions of urticarial vasculitis over a 24 h period. At 3 h, endothelial swelling and an eosinophilic infiltrate was seen. Neutrophils were increased in number by 10 h. Typical leucocytoclastic vasculitis with red blood cell extravasation developed by 24 h. Maximal deposition of eosinophil peroxidase was at 10 h compared to significant neutrophil elastase deposits at 24 h. This demonstrates the importance of the eosinophil in the development of the lesions of urticarial vasculitis.
Exercise↗
Ofuji's disease and cytokines: Remission of eosinophilic pustular folliculitis associated with increased serum concentrations of interferon gamma.
BACKGROUND AND OBJECTIVE: Eosinophilic pustular folliculitis (EPF) is a distinct inflammatory dermatosis of unknown etiology. The aim of this study is to evaluate the serum levels of cytokines in 3 patients with EPF before and after treatment with indomethacin. RESULTS: Serum levels of interleukin 4 (IL-4) were elevated in patients with EPF. The remission of EPF was associated with increased serum concentrations of interferon gamma with no essential change of serum levels of IL-4. CONCLUSION: These results suggest that subtle changes in serum levels of cytokines are involved in the remission of EPF and that indomethacin may provide the remission of EPF by altering cytokine production in patients with EPF.
Adult↗
Cytokines in alopecia areata: contrasting cytokine profiles in localized form and extensive form (alopecia universalis).
Recent studies have suggested that cytokines play a critical role in the pathophysiology of alopecia areata; however, no information is available regarding the difference in cytokine profiles in these patients. Serum levels of cytokines, including interferon gamma (IFN-gamma), tumor necrosis factor alpha, interleukin 1 alpha (IL-1 alpha), IL-2, IL-4, and IL-6, were measured using radioimmunoassay or enzyme-linked immunosorbent assay techniques in patients with the localized form and the extensive form (alopecia universalis). The serum levels of IL-1 alpha and IL-4 were significantly elevated in patients with the localized form. In contrast, the serum levels of IFN-gamma and IL-2 were significantly elevated in patients with the extensive form. These results indicate that immune responses in the localized form and the extensive form of alopecia areata are regulated by Th2 cytokines and Th1 cytokines, respectively.
Adult↗
Photolocalized eruption associated with acute hepatitis B virus infection.
We describe a 24-year-old woman with acute hepatitis B virus infection who developed extensive erythematous papules in a photolocalized distribution. The eruption occurred during the prodromal phase, and subsided with the development of jaundice. She had had moderate sunburn 18 days prior to the development of the eruption, which was accentuated on the tanned area. To our knowledge, this is the first case of a photolocalized eruption due to hepatitis B virus infection.
Acute Disease↗
Dysregulated expression of the IL-2 receptor beta-chain abrogates development of NK cells and Thy-1+ dendritic epidermal cells in transgenic mice.
The IL-2 receptor beta-chain (IL-2R beta), a specificity-determining subunit in the IL-2R complex with a restricted tissue distribution pattern, is essential for signal transduction. Our previous studies demonstrate that the continuous treatment of mice with anti-IL-2R beta resulted in the complete disappearance of NK cells and Thy-1+ dendritic epidermal cells (Thy-1+ dEC), suggesting that signals through IL-2R beta are critically involved in development of these lymphocyte subsets. However, these lymphocyte subsets are reported to be apparently unaffected in the IL-2-deficient mice. To further examine the biological roles of the IL-2R beta, transgenic mice carrying the IL-2R beta transgene were generated. In these mice, high levels of the cell surface expression of the IL-2R beta were observed in essentially all hematopoietic lineage cells, and CD4+ T cells as well as CD8+ T cells showed vigorous cell proliferation upon IL-2 stimulation. Surprisingly, NK cells marked with a high expression of NK1.1 in the spleen and Thy-1+ dEC in the skin were completely absent in transgenic mice. However, the development of other lymphocyte subsets including conventional alpha beta TCR+ cells, gamma delta TCR+ cells and B cells remained apparently intact. From these observations together with previous data on IL-2-deficient mice, we speculate that factors, other than IL-2 that utilizes the IL-2R beta as its functional receptor subunit, may have a vital role in the development of NK cells and Thy-1+ dEC. Implications for possible in vivo functions of over-expressed IL-2R beta are discussed.
Animals↗
Immediate-type hypersensitivity response followed by a late reaction is induced by repeated epicutaneous application of contact sensitizing agents in mice.
Repeated administration of antigen often leads to consequences different from those expected with fewer encounters with the antigen, but little attention has been paid to the effects of repeated epicutaneous application of antigens. To investigate whether repeated epicutaneous application of a contact-sensitizing agent that is generally thought to evoke a typical delayed-type hypersensitivity response could result in adverse or different consequences, BALB/c mice were sensitized with 2,4,6-trinitro-1-chlorobenzine and then were repeatedly elicited on the original sensitized site with the same antigen for 24-48 d. Detailed analyses showed that the time-course of antigen-specific hypersensitivity responses shifted from a delayed-type hypersensitivity to an immediate-type response followed by a late reaction as epicutaneous applications were repeated, a finding different from that previously reported. Development of these hypersensitivity responses was antigen specific, and this shift was associated with epidermal hyperplasia, accumulation of large numbers of mast cells and CD4+ T cells beneath the epidermis, and elevated serum levels of antigen-specific IgE. The immediate-type response to 2,4,6-trinitro-1-chlorobenzine was also induced in 2,4,6-trinitro-1-chlorobenzine-treated, genetically mast cell-deficient W/Wv mice that contained significant numbers of mast cells, but not in similarly treated S1/S1d mice devoid of mast cells. Our experimental system would provide a simple, reproducible animal model for chronic skin inflammation induced by various antigens.
Animals↗
Lichen spinulosus in a patient with Crohn's disease.
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Crohn Disease↗
What is new in fixed drug eruption?
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Antigen Presentation↗
Erythema nodosum, lichen planus and lichen nitidus in Crohn's disease: report of a case and analysis of T cell receptor V gene expression in the cutaneous and intestinal lesions.
A wide variety of cutaneous manifestations have been described in association with Crohn's disease (CD). We describe a patient with a 2-year history of CD who developed both lichen planus (LP) and lichen nitidus (LN) in addition to erythema nodosum (EN) lesions. The clinical course of EN reflected the activity of the bowel disease, whereas LP and LN appeared to persist independently of the ongoing disease activity. Immunohistochemical studies of the infiltrates in these cutaneous and intestinal lesions showed that the majority of the infiltrates were T cells expressing T cell receptor (TCR)-alpha beta. Analyses of TCR V gene expression in these infiltrating T cells demonstrated a different pattern of V beta expression that provides an explanation for the difference in the clinical courses of these lesions. LP and LN lesions are likely to be mediated by T cells with antigen specificity distinct from those that cause EN and intestinal lesions.
Adult↗
Cholestatic hepatitis occurring shortly after etretinate therapy.
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Aged↗
An unexpected increase in circulating IFN-gamma by cyclosporin A in atopic patients: a discrepancy between in vitro and in vivo events.
Defective interferon gamma (IFN-gamma) production has been suggested to be relevant to immunologic abnormalities observed in atopic dermatitis (AD). We describe two patients with severe AD who were treated with oral cyclosporin A (Cy-A) and in whom the serum levels of IL-1 alpha, IFN-gamma and tumor necrosis factor alpha (TNF-alpha) were sequentially measured. Cy-A, known to inhibit IFN-gamma production in vitro, caused a rapid rise in serum IFN-gamma, but not Il-1 alpha and TNF alpha, levels in the patients and the IFN-gamma levels appeared to be inversely related to the therapeutic efficacy. The observed increase in serum IFN-gamma levels during Cy-A therapy may have contributed to a marked clinical improvement of the AD.
Administration, Oral↗