Heather M. Holahan

Human Eosinophils Express the High Affinity IgE Receptor, FcεRI, in Bullous Pemphigoid

Bullous pemphigoid (BP) is an autoimmune blistering disease mediated by autoantibodies targeting BP180 (type XVII collagen). Patient sera and tissues typically have IgG and IgE autoantibodies and elevated eosinophil numbers. Although the pathogenicity of the IgE autoantibodies is established in BP, their contribution to the disease process is not well understood. Our aims were two-fold: 1) To establish the clinical relationships between total and BP180-specific IgE, eosinophilia and other markers of disease activity; and 2) To determine if eosinophils from BP patients express the high affinity IgE receptor, FcεRI, as a potential mechanism of action for IgE in BP. Our analysis of 48 untreated BP patients revealed a correlation between BP180 IgG and both BP180 IgE and peripheral eosinophil count. Additionally, we established a correlation between total IgE concentration and both BP180 IgE levels and eosinophil count. When only sera from patients (n = 16) with total IgE≥400 IU/ml were analyzed, BP180 IgG levels correlated with disease severity, BP230 IgG, total circulating IgE and BP180 IgE. Finally, peripheral eosinophil count correlated more strongly with levels of BP180 IgE then with BP180 IgG. Next, eosinophil FcεRI expression was investigated in the blood and skin using several methods. Peripheral eosinophils from BP patients expressed mRNA for all three chains (α, β and γ) of the FcεRI. Surface expression of the FcεRIα was confirmed on both peripheral and tissue eosinophils from most BP patients by immunostaining. Furthermore, using a proximity ligation assay, interaction of the α- and β-chains of the FcεRI was observed in some biopsy specimens, suggesting tissue expression of the trimeric receptor form in some patients. These studies provide clinical support for the relevance of IgE in BP disease and provide one mechanism of action of these antibodies, via binding to the FcεRI on eosinophils.

Eosinophil localization to the basement membrane zone is autoantibody‐ and complement‐dependent in a human cryosection model of bullous pemphigoid

Bullous pemphigoid (BP) is an autoimmune blistering disease characterized by antibodies (IgG and IgE) targeting cell‐substrate adhesion proteins. A variety of BP models suggest that autoantibody‐dependent neutrophil degranulation is essential for blister formation. However, lesional biopsies reveal a predominance of eosinophils and few neutrophils. Our goal was to evaluate the role of antibodies and complement in eosinophil localization, degranulation and split formation at the dermo‐epidermal junction (DEJ) utilizing a human skin cryosection model of BP paired with a human eosinophilic cell line, 15HL‐60. Expression of receptors for IgG (FcγRII), IgE (FcεRI) and complement (CR1 and CR3) was confirmed on 15HL‐60 cells using flow cytometry. 15HL‐60 expression of granule protein [eosinophil derived neurotoxin (EDN) and eosinophil peroxidase (EPO)] mRNA and their degranulation in vitro was confirmed using RT‐PCR and ELISA, respectively. For cryosection experiments, BP or control sera or IgG and IgE antibodies purified from BP sera were utilized in combination with 15HL‐60 cells ± fresh complement. Both BP serum and fresh complement were required for localization of 15‐HL60 cells to the DEJ. Interestingly, eosinophil localization to the DEJ was dependent on IgG, but not IgE, and complement. However, no subepidermal split was observed. Additionally, the 15HL‐60 cells did not degranulate under any experimental conditions and direct application of cell lysate to cryosections did not result in a split. Our observation that eosinophil localization to the DEJ is dependent on IgG mediated complement fixation provides additional insight into the sequence of events during the development of BP lesions.

Health-related quality of life in patients with cutaneous T-cell lymphoma?

Little is currently known about health‐related quality of life (HRQoL) of patients with cutaneous T‐cell lymphoma (CTCL), a condition characterized by chronic, pruritic, visible lesions, features which may be uniquely influential.

Cutaneous Lesions of HIV-Positive Patients

Human immunodeficiency virus (HIV) is associated with several cutaneous conditions, including molluscum contagiosum, condyloma acuminata and, Kaposi sarcoma. Many treatment modalities, including physical ablation, chemical topical agents, immunomodulators, and antiviral treatments, have been employed to treat these. One treatment that has shown success is cryosurgery. Since recurrence and more aggressive disease is associated with HIV infection, close monitoring and repetition of treatments are often necessary.

Bullous lesions on the extremities of an incarcerated man

A 42-year-old Hispanic man presented with a pruritic and painful, erythematous bullous eruption on his right forearm, which had developed over a 24 h period (Fig. 1). The patient was currently in prison, and he reported having experienced intermittent, acute bilateral swelling of his hands and feet for the past 2 months, which occurred at the sites of prior handcuffing. On physical examination, acute oedema and macular erythema were noted on the bilateral distal upper extremities. Further examination of the right ventral forearm demonstrated tense, clear vesicles and bullae on a background of erythematous oedema. The clinical differential diagnoses entertained included chronic idiopathic urticaria (CIU), angio-oedema, drug hypersensitivity reaction and allergic contact dermatitis.

Erythema annulare‐like acantholytic dermatosis: a subset of pemphigus foliaceus

DEAR EDITOR, A number of patients have been described with an erythema annulare centrifigum (EAC)-like clinical presentation and direct immunofluorescence (IF) findings compatible with pemphigus. The disorder has been termed ‘erythema annulare-like acantholytic dermatosis (EAAD)’, and investigators have proposed that it might be a novel acantholytic disease rather than a subtype of pemphigus, due to the inability to pinpoint a known antigen. We recently had the opportunity to investigate such a patient, and with enzyme-linked immunosorbent assay (ELISA) techniques that were not available at the time of the initial description of EAAD, we were able to document autoantibodies directed against the pemphigus foliaceus antigen, desmoglein 1. A 63-year-old woman presented with ‘red bumps and circles’ on her hips, thighs, lower back and legs, present for 10 months. The patient also reported occasional vesicles within the lesions. Systemic symptoms such as fever, chills or weight loss were absent. Her past medical history was significant for diabetes and hypertension. Medications included gemfibrozil, metformin, verapamil and glyburide. An outside institution had biopsied her lower back and diagnosed the patient with a hypersensitivity reaction. Some relief was received from topical clobetasol, but topical fluocinonide, econazole, desoximetasone and oral antihistamines did not render significant benefit. Physical examination revealed 12–15 well-defined, annular, 1 0– 1 5-cm erythematous plaques on the bilateral thighs and lower back (Fig. 1). Several erosions were also noted on the right knee and shin. Examination of the oropharynx revealed normal mucosa. The differential diagnosis included erythema annulare centrifugum, granuloma annulare and linear IgA disease. Two punch biopsies were performed and histopathology demonstrated spongiotic dermatitis with eosinophils. Direct IF studies revealed intercellular IgG and C3 staining in the epidermis. Testing by ELISA for antidesmoglein autoantibodies (MBL International, Woburn, MA, U.S.A.) was positive for desmoglein 1 (100 95 U mL , normal level < 20) and negative for desmoglein 3. These findings supported a diagnosis of erythema annulare-like pemphigus foliaceus. Treatment was initiated with dexamethasone 3 mg daily (due to a subjective prednisone allergy) with excellent response. Herein we describe a patient with pemphigus foliaceus who presented with lesions that clinically mimicked EAC with histology and IF findings compatible with that previously reported as EAAD. Hashimoto et al. also documented the case presentation of annular lesions and midepidermal acantholysis, only later diagnosed as pemphigus foliaceus by immunoblotting. Similarly, the earliest case descriptions of EAAD predate the development of sensitive ELISA for the detection of pemphigus autoantibodies. Given the similar clinical and histological findings to our case and limitations on ELISA identification of autoantigens in pemphigus vulgaris and pemphigus foliaceus at that time, these past descriptions may also represent a unique morphology of pemphigus foliaceus. This case serves to encourage inclusion of pemphigus in the differential diagnosis of erythema annulare-like lesions and adds evidence that EAAD represents a morphological variant of pemphigus foliaceus.