Pemphigus is a rare autoimmune disease that results in blistering of the skin and oral cavity. It is caused by autoantibodies directed against cell-surface antigens on keratinocytes, which when targeted lose their cellular adhesion properties and separate from one another to form blisters within the epidermis. Differences in the particular antigens targeted by the antibodies and in the distribution of these antigens in the different regions of the body and in the separate layers of the epidermis result in different clinical manifestations of the disease. The disease is diagnosed based on its clinical manifestations (flaccid blisters and erosions on skin and oral mucosa), histology (epidermal acantholysis), and immunological abnormalities (circulating and tissue-fixed antibodies against keratinocyte surface antigens). Pemphigus, which if left untreated is almost always fatal, is generally managed with topical, oral, or intralesional corticosteroids. Other options include plasmapheresis and intravenous immunoglobulin (IVIg), coupled with cytotoxic drugs. Immunosupressants, anti-inflammatory drugs, and antibiotics are used as adjuvants, but apart from IVIg, these therapy options are non-specific and more research is needed to develop treatments with improved side-effect profiles.

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Understanding the acantholytic pathways leading to blistering in pemphigus vulgaris (PV) is a key to development of novel treatments. A novel paradigm of keratinocyte damage in PV, termed apoptolysis, links the suprabasal acantholytic and cell death pathways to basal cell shrinkage rendering a 'tombstone' appearance to PV lesions. In contrast to apoptolysis, the classic keratinocyte apoptosis mediating toxic epidermal necrolysis causes death and subsequent sloughing of the entire epidermis. Apoptolysis includes five consecutive steps. Current pemphigus research is elucidating new mechanisms of keratinocyte detachment in pemphigus vulgaris (PV) that lead to blistering. Identification of the key pathophysiologic elements will facilitate pharmacologic development of agents to prevent this breakdown in epidermal integrity. The classic studies demonstrating that PVIgG can induce suprabasal acantholysis -a histopathologic hallmark of PV -even in the skin of neonatal mice lacking either desmoglein (Dsg) 3 (1), plasminogen activator (2), or complement activity (3) narrowed the search for the pathophysiologically relevant targets. The results of the study by Pretel et al. (4) published in this issue of Experimental Dermatology underscore the most important pathophysiologic mechanisms in skin of PV patients. In a series of elegant experiments, these authors convincingly demonstrate that acantholysis in PV develops secondary to the PVIgGinduced EGF receptor (EGFR) ⁄ Src signalling that activates an apoptotic cascade through the serine ⁄ threonine protein kinase, mTOR. Furthermore, the suprabasal split occurs due to differences between basal and suprabasal cells in their responses to PVIgG, as was predicted by the Basal Cell Shrinkage hypothesis (5). The data presented by Pretel et al. (4), taken together with a bulk of in vitro and in vivo results reported in the literature, establish a novel paradigm where PVIgG signalling links the suprabasal acantholytic and apoptotic pathways to basal cell shrinkage. In marked

Melanocytes in human skin reside both in the epidermis and in the matrix and outer root sheath of anagen hair follicles. Comparative study of melanocytes in these different locations has been difficult as hair follicle melanocytes could not be cultured . In this study we used a recently described method of growing hair follicle melanocytes to characterize and compare hair follicle and epidermal melanocytes in the scalp of the same individual. Three morphologically and antigenically distinct types of melanocytes were observed in primary culture. These included (1) moderately pigmented and polydendritic melanocytes derived from epidermis; (2) small, bipolar, amelanotic melanocytes; and (3) large, intensely pigmented melanocytes; the latter two were derived from hair follicles. The three sub-populations of cells all reacted with melanocyte-specific monoclonal antibody. Epidermal and amelanotic hair follicle melanocytes proliferated well in culture, whereas the intensely pigmented hair follicle melanocytes did not. Amelanotic hair follicle melanocytes differed from epidermal melanocytes in being less differentiated, and they expressed less mature melanosome antigens. In addition, hair follicle melanocytes expressed some antigens associated with alopecia areata, but not antigens associated with vitiligo, whereas the reverse was true for epidermal melanocytes. Thus antigenically different populations of melanocytes are present in epidermis and hair follicle. This could account for the preferential destruction of hair follicle melanocytes in alopecia areata and of epidermal melanocytes in vitiligo.

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Alopecia areata (AA) is a nonscarring form of inflammatory hair loss in humans. AA-like hair loss has also been observed in other species. In recent years the Dundee experimental bald rat and the C3H/HeJ mouse have been put forward as models for human AA. AA in all species presents with a wide range of clinical features from focal, locally extensive, diffuse hair loss, to near universal alopecia. Histologically, all species have dystrophic anagen stage hair follicles associated with a peri- and intrafollicular inflammatory cell infiltrate. Autoantibodies directed against anagen stage hair follicle structures are a consistent finding. Observations on AA pathogenesis suggest nonhuman species can provide excellent models for the human disease. Ultimately, animal models will be used to determine the genetic basis of AA, potential endogenous and/or environmental trigger(s), mechanism(s) of disease initiation and progression, and allow rapid evaluation of new and improved disease treatments.

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