Lawrence S. Chan

The new pemphigus variants

Pemphigus describes a group of autoimmune diseases characterized by blisters and erosions of the skin and mucous membranes, acantholysis by histology, and autoantibodies directed against epidermal cell surface components. Since the early 1970s, the following new clinical variants of pemphigus have been reported: pemphigus herpetiformis, IgA pemphigus, and paraneoplastic pemphigus. In recent years, significant data have been obtained from laboratory investigation on these rare and atypical variants, especially regarding their specific target antigens. We review these variants, their clinical presentations, histologic findings, immunopathology, target antigens, theories of pathogenesis, treatment modalities, and clinical courses.

Restoration of type VII collagen expression and function in dystrophic epidermolysis bullosa

Dystrophic epidermolysis bullosa (DEB) is a family of inherited mechano-bullous disorders caused by mutations in the human type VII collagen gene (COL7A1). Individuals with DEB lack type VII collagen and anchoring fibrils, structures that attach epidermis and dermis. The current lack of treatment for DEB is an impetus to develop gene therapy strategies that efficiently transfer and stably express genes delivered to skin cells in vivo. In this study, we delivered and expressed full-length type VII collagen using a self-inactivating minimal lentivirus-based vector. Transduction of lentiviral vectors containing the COL7A1 transgene into recessive DEB (RDEB) keratinocytes and fibroblasts (in which type VII collagen was absent) resulted in persistent synthesis and secretion of type VII collagen. Unlike RDEB parent cells, the gene-corrected cells had normal morphology, proliferative potential, matrix attachment and motility. We used these gene-corrected cells to regenerate human skin on immune-deficient mice. Human skin regenerated by gene-corrected RDEB cells had restored expression of type VII collagen and formation of anchoring fibrils at the dermal–epidermal junction in vivo. These studies demonstrate that it is possible to restore type VII collagen gene expression in RDEB skin in vivo.

Oral cyclosporine for the treatment of alopecia areata: A clinical and immunohistochemical analysis

Cyclosporine inhibits the activation of helper T cells that may be pathogenic in alopecia areata. Therefore we treated six patients with alopecia areata (five men, one woman) with oral cyclosporine, 6 mg/kg/day for 12 weeks. Three patients had alopecia universalis, one had alopecia totalis, and two had patchy alopecia areata of the scalp. Hair regrowth in the scalp of all patients occurred within the second and fourth weeks of therapy, followed by hair regrowth of the face and chest (in the male patients), pubic area, extremities, and axillae. Overall, the site of best response was the scalp. Cosmetically acceptable terminal hair regrowth on the scalp occurred in three of six patients. Significant hair loss, however, occurred in all patients within 3 months of discontinuation of cyclosporine treatment. Clinical response correlated with changes in immune cell infiltration of the hair follicles. The number of leukocytes per hair follicle was quantified in transverse scalp biopsy sections stained with a panel of monoclonal antibodies. The degree of terminal hair regrowth correlated significantly with decreases in follicular epithelial human lymphocyte antigen-DR and intercellular adhesion molecule-1 expression, T cells, helper/inducer (CD4) T cells, suppressor/cytotoxic (CD8) T cells and Langerhans cells (CD1+DR+) from the hair follicles during cyclosporine therapy. A significant decrease in the CD4/CD8 ratio occurred early in the course of treatment and was maintained throughout the therapy. This decrease suggests that cyclosporine not only cleared immune cells from the hair follicles but also altered the balance of regulatory lymphocytes.(ABSTRACT TRUNCATED AT 250 WORDS)

Interleukin-1 receptor antagonist in normal and psoriatic epidermis.

The objective of these studies was to characterize the IL-1 inhibitory activity present in normal and psoriatic epidermis from clinically stable lesions. Fractionation of normal epidermal cytosol on a molecular sizing column failed to reveal the presence of IL-1 inhibitory bioactivity. However, specific ELISAs indicated that both the IL-1 receptor antagonist (IL-1ra) and IL-1 alpha were present in overlapping peaks. Further fractionation of the normal epidermal cytosol by anion exchange chromatography separated these two molecules, revealing the IL-1 inhibitory bioactivity of the IL-1ra molecule. Similar studies on psoriatic epidermal cytosol indicated the presence of IL-1 inhibitory bioactivity and IL-1ra protein. The IL-1 inhibitory bioactivity of both normal and psoriatic cytosol was neutralized by a mAb specific for IL-1ra. The ratio of IL-1ra to IL-1 alpha proteins was significantly increased in involved psoriatic skin compared with normal skin. By Western blot analysis this IL-1ra was approximately 20 kD, slightly larger than monocyte-derived IL-1ra and equivalent to an intracellular variant of IL-1ra expressed by keratinocytes. Polymerase chain reaction indicated the presence of mRNA for both forms of IL-1ra in normal epidermis, with both forms increased in psoriatic-involved skin. Immunofluorescence studies revealed the IL-1ra protein to be concentrated in the stratum granulosum of normal skin and in the basal-midbasal layers of psoriatic epidermis. These results suggest that the balance between intracellular IL-1ra and IL-1 alpha may be an important influence on keratinocyte growth and/or differentiation, as well as on the inflammatory potential of IL-1 in injured skin.

Partial albinism with immunodeficiency: Griscelli syndrome: Report of a case and review of the literature

Partial albinism with immunodeficiency (Griscelli syndrome) is an uncommon disorder characterized by pigmentary dilution and variable immunodeficiency. Features include a silvery-gray sheen to the hair, large clumped melanosomes in hair shafts, and prominent mature melanosomes in cutaneous melanocytes with sparse pigmentation of adjacent keratinocytes. Immunologic abnormalities most often include impaired natural killer cell activity, absent delayed-type hypersensitivity, and impaired responses to mitogens. Impaired helper T cell function and hypogammaglobulinemia have also been described. The syndrome can be differentiated from Chediak-Higashi syndrome by pathognomonic light and electron microscopic features in skin and hair, and absence of consistent granulocyte abnormalities, but similarly carries a poor prognosis without bone marrow transplantation. We describe a patient with Griscelli syndrome who presented with hepatosplenomegaly, hepatitis, pancytopenia, and silvery hair in the newborn period.

Immune-Mediated Subepithelial Blistering Diseases of Mucous Membranes: Pure Ocular Cicatricial Pemphigoid Is a Unique Clinical and Immunopathological Entity Distinct From Bullous Pemphigoid and Other Subsets Identified by Antigenic Specificity of Autoantibodies

BACKGROUND AND DESIGN There is much confusion in the clinical classification of immune-mediated subepithelial blistering diseases of mucous membranes. We conducted a 6-year comprehensive study to better classify this heterogeneous disease group. Indirect immunofluorescence was performed on a salt-split-skin substrate to detect circulating antibasement membrane antibodies (n = 47). Serologic reactivity against cultured keratinocyte antigens was examined by immunoblots (n = 38) and immunoprecipitation (n = 15). The results were correlated with the clinical features and direct immunofluorescence data of the entire patient group (n = 87) without preassignment of clinical diagnoses. chi 2 Statistical analyses compared these results with those of the classic bullous pemphigoid group (n = 36). RESULTS When compared with the bullous pemphigoid patients, a subset of patients with combined oral mucosal and skin lesions demonstrated marked similarity in direct and indirect immunofluorescence findings and in serologic reactivity to bullous pemphigoid antigens. By contrast, a subset of patients with only ocular lesions exhibited significantly lower in vivo deposits of IgG and C3, higher deposits of fibrin, virtual absence of circulating antibodies, and negative serologic reactivity to bullous pemphigoid antigens. CONCLUSIONS Ocular patients without skin or mouth lesions, in particular those with negative indirect immunofluorescence, should be distinctively classified as ocular cicatricial pemphigoid, a unique clinical and immunopathologic entity. Patients with mucous membrane involvement who also demonstrate skin lesions and antibodies to the root of salt-split-skin substrate should be classified as anti-BP Ag mucosal pemphigoid, even though they may exhibit severe oral and/or ocular diseases. The remaining mucous membrane patients are heterogeneous. Some can be classified on the basis of autoantibodies to other basement membrane determinants, or if serum autoantibody negative, on the basis of clinical features (ie, pure oral mucosal pemphigoid or overlapping mucosal involvement).

Early up‐regulation of Th2 cytokines and late surge of Th1 cytokines in an atopic dermatitis model

We investigated cytokine profiles in interleukin (IL)‐4 transgenic (Tg) mice with a skin inflammatory disease resembling human atopic dermatitis. cDNA microarray revealed that the mRNAs encoding IL‐1β, IL‐2, IL‐3, IL‐4, IL‐5, IL‐6, IL‐10, IL‐12p40, IL‐13, tumour necrosis factor (TNF)‐α, TNF‐β and interferon (IFN)‐γ were up‐regulated in the skin of late lesion Tg mice and to a lesser degree in non‐lesion Tg mice when compared to those of non‐Tg mice. Real time reverse transcription–polymerase chain reaction (RT‐PCR) analyses indicated that the cDNA copy numbers of IL‐1β, IL‐4, IL‐6, IL‐10, TNF‐α and IFN‐γ from the skin of late, early and non‐lesions increased significantly compared to non‐Tg mice. IL‐2 and IL‐12p40 cDNA copy numbers were increased significantly in early, but not late, lesions. Interestingly, IL‐1β, IL‐3, IL‐4, IL‐5, IL‐6, IL‐10, IL‐13, TNF‐α, and IFN‐γ cDNAs were increased significantly the skin of before‐onset and/or non‐lesion mice. Flow cytometry analyses demonstrated an increased percentage of keratinocytes producing IL‐4 as the disease progressed. The percentage of IL‐2, IL‐4, IL‐10 and IFN‐γ‐producing T cells and IL‐12‐producing antigen‐presenting cells in skin‐draining lymph nodes and inflammatory skin also increased, particularly in mice with late lesion. These results suggest that disease induction is primarily triggered by Th2 cytokines and that Th1, Th2 and non‐Th proinflammatory cytokines are all involved in the disease process.

Treatment of refractory epidermolysis bullosa acquisita with extracorporeal photochemotherapy

Treatment of epidermolysis bullosa acquisita (EBA) with conventional therapy frequently does not result in improvement. Extracorporeal photochemotherapy (ECP) is novel immunomodulating technique which might be of benefit in the treatment of autoimmune disease.We prospectively studied three patients with refractory EBA who were treated with ECP. All three patients had improvement in objective measurements of their disease severity while two of the three had significant subjective improvement in their skin fragility and the clinical activity of their disease.

The involvement of the JAK-STAT signaling pathway in chronic inflammatory skin disease atopic dermatitis

Atopic dermatitis (AD), a common chronic inflammatory skin disease, is characterized by inflammatory cell skin infiltration. The JAK-STAT pathway has been shown to play an essential role in the dysregulation of immune responses in AD, including the exaggeration of Th2 cell response, the activation of eosinophils, the maturation of B cells, and the suppression of regulatory T cells (Tregs). In addition, the JAK-STAT pathway, activated by IL-4, also plays a critical role in the pathogenesis of AD by upregulating epidermal chemokines, pro-inflammatroy cytokines, and pro-angiogenic factors as well as by downregulating antimicrobial peptides (AMPs) and factors responsible for skin barrier function. In this review, we will highlight the recent advances in our understanding of the JAK-STAT pathway in the pathogenesis of AD.

Ocular and oral mucous membrane pemphigoid (cicatricial pemphigoid).

Mucous membrane pemphigoid, a heterogeneous group of autoimmune blistering diseases, affects primarily the mucous membranes. Although oral and ocular mucosae can both be affected in a given patient, patients with involvement restricted to oral mucosae tend to have a benign outcome, whereas those with ocular disease commonly face treatment resistance, resulting in scarring and blindness. Diagnosis requires direct immunofluorescence microscopy to demonstrate a linear deposition of immunoglobulin (Ig) G or IgA, or complement component 3 (C3), at the epithelial basement membrane. Although the target antigens vary, subsets of patients affected exclusively by oral and ocular mucosal diseases have autoantibodies targeting α-6 and β-4 integrins, respectively.