ABSTRACT
Granzyme B and perforin messenger RNA (mRNA) expression has been shown to be a specific in vivo activation marker for cytotoxic cells. The aim of this study was to assess the contribution of cell-mediated cytotoxicity in the pathogenesis of lichen sclerosus. In situ hybridization and immunohistochemistry were performed on serial tissue sections of lesional skin biopsies and normal skin as control. Immunohistochemical staining showed that the cellular infiltrate of diseased skin consisted predominantly of T cells (CD3+) and some B cells (CD20+). Among T cells CD4+ and CD8+ cells were found in about equal numbers. In normal skin samples perforin and granzyme B mRNA expressing cells were only rarely found. In contrast, in biopsies from diseased skin a high percentage of infiltrating cells expressed mRNA for perforin and granzyme B. The perforin and granzyme B expressing cells were found in the dermal infiltrate and intraepidermally in close proximity to keratinocytes suggesting in situ activation of these cells. These findings provide evidence that cell-mediated cytotoxicity plays a significant role in tissue destruction in lichen sclerosus.
Subject(s)
Granzymes/genetics , Lichen Sclerosus et Atrophicus/genetics , Membrane Glycoproteins/genetics , Pore Forming Cytotoxic Proteins/genetics , RNA, Messenger/genetics , RNA, Messenger/metabolism , Adult , Aged , Cytotoxicity, Immunologic , Female , Gene Expression , Humans , In Situ Hybridization , Leukocytes, Mononuclear/immunology , Leukocytes, Mononuclear/pathology , Lichen Sclerosus et Atrophicus/immunology , Lichen Sclerosus et Atrophicus/metabolism , Lichen Sclerosus et Atrophicus/pathology , Male , Middle Aged , Perforin , T-Lymphocytes/immunology , T-Lymphocytes/pathologyABSTRACT
PURPOSE OF REVIEW: Cutaneous eruptions are among the most common adverse drug reactions and may often represent a challenging diagnostic problem. This review focuses on histopathological and immunohistochemical findings of drug-induced maculo-papular exanthems and discusses the value of skin biopsies and consequent histopathological examination in the diagnosis of these reactions. RECENT FINDINGS: Data from immunohistological studies indicate that CD4+ T cells expressing cytotoxic granule proteins such as perforin and granzyme B are critically involved in the pathogenesis and contribute to the generation of typical histopathological features of drug-induced maculo-papular exanthems, i.e. an interface dermatitis with vacuolar alteration and some apoptotic basal keratinocytes. In addition, an upregulation of both type 1 (i.e. IFN-gamma, TNF-alpha) and type 2 (i.e. IL-5) cytokines has been reported. IL-5 together with other chemokines (i.e. eotaxin/CCL-11) provides an explanation for tissue eosinophilia, which may be suggestive of a drug eruption if present. SUMMARY: There are no absolute histological or immunohistological criteria for the diagnosis of drug-induced maculo-papular exanthems and even if the observed histological changes are compatible with a drug-induced eruption, biopsy may not definitely exclude alternative causes since there is considerable overlap with features seen in other entities. In mild cases with no severe signs or symptoms and a clear temporal relationship, clinical information and the morphologic pattern of skin lesions are often sufficient for diagnosis. However, in complex and severe cases or when the precise morphology is unclear, histopathological findings may provide some clues and assist in reaching a correct diagnosis.
Subject(s)
Drug Eruptions/pathology , Exanthema/pathology , Skin Diseases, Vesiculobullous/chemically induced , Skin Diseases, Vesiculobullous/pathology , Biopsy, Needle , Diagnosis, Differential , Drug Eruptions/diagnosis , Drug Hypersensitivity/pathology , Exanthema/diagnosis , Female , Follow-Up Studies , Humans , Immunohistochemistry , Male , Risk Assessment , Sensitivity and Specificity , Severity of Illness Index , Skin TestsABSTRACT
Mast cell chymase is a chymotrypsin-like serine proteinase primarily stored in secretory mast cell granules. Mast cell chymase has various effects on angiotensin, metalloproteases, lipoproteins, procollagen, neuropeptides and cytokines. Recent studies have demonstrated that chymase inhibitors inhibit skin inflammation. In this study we sought to determine the role of mast cell chymase in atopic dermatitis (AD) in comparison with its role in psoriasis and normal skin. Skin biopsy specimens were obtained from non-lesional and lesional skin of patients with chronic AD and psoriasis and from normal skin of non-atopic and non-psoriatic controls. The number of mast cells containing chymase was determined by immunohistochemistry using a chymase-specific monoclonal antibody. A significantly (P < 0.05) enhanced number of chymase-positive cells was found in lesional AD skin as compared to normal skin as well as to lesional and non-lesional skin of patients with psoriasis. A significant (P < 0.05) increase in the number of chymase-positive cells was also found in non-lesional AD skin in comparison to psoriasis. An enhanced, albeit not statistically significant difference was noted in non-lesional AD skin as compared to normal skin. In conclusion, these results suggest that mast cell chymase may play an integral part in eliciting and maintaining cutaneous inflammation in AD but not in psoriasis. The increased proteinase activity of mast cell chymase may also be involved in promoting a skin barrier defect in AD, which subsequently enhances the skin's permeability to allergens and microbes and thereby aggravates the eczema.