Evandro A. Rivitti

The Pathogenic Effect of IgG4 Autoantibodies in Endemic Pemphigus Foliaceus (Fogo Selvagem)

Endemic pemphigus foliaceus, or fogo selvagem, is an autoimmune blistering skin disease caused by IgG autoantibodies to a desmosome-associated glycoprotein. We studied the IgG subclasses with autoantibody activity in serum from 29 patients with active disease and in the skin lesions of 18 patients by immunofluorescence, using IgG-subclass-specific monoclonal antibodies. The predominant disease autoantibodies present in all patients were of the IgG4 subclass. IgG1 and IgG2 autoantibodies were detected in low titer in the 29 patients: IgG1 in 23 patients and IgG2 in 9. IgG3 autoantibodies were not detected in the serum of any patient. Direct immunofluorescence testing of skin lesions showed a preferential deposition of IgG4 on the keratinocyte surface. The pathogenic effect of IgG4 was demonstrated by the passive transfer of fractions containing IgG4 autoantibodies from the patients to neonatal BALB/c mice. The disease of the patients was reproduced clinically, histologically, and immunologically in these animals. Only IgG4 autoantibodies were detected by direct immunofluorescence, bound to the epidermis in the lesions of the mice, and by immunoelectron microscopy at the keratinocyte surface. IgG4 has previously been reported to be a blocking or protective antibody because it has poor effector functions in vitro, as compared with the other IgG subclasses. The finding that it is the pathogenic autoantibody in fogo selvagem raises the possibility that it may also be important in other autoimmune disease.

The Role of Intramolecular Epitope Spreading in the Pathogenesis of Endemic Pemphigus Foliaceus (Fogo Selvagem)

We report here a relationship between intramolecular epitope spreading and the clinical onset of the endemic form of pemphigus foliaceus in a Brazilian community with a high prevalence and incidence of the disease. Also known as Fogo Selvagem (FS), this disease is characterized by severe skin blistering and pathogenic anti–desmoglein-1 (Dsg1) autoantibodies. These autoantibodies bind the Dsg1 ectodomain and trigger keratinocyte cell detachment, the hallmark of FS. We show that (a) sera from FS patients in the preclinical stage recognized epitopes on the COOH-terminal EC5 domain of Dsg1, (b) disease onset was associated with the emergence of antibodies specific for epitopes on the NH2-terminal EC1 and EC2 domains, (c) all sera from FS patients with active disease recognized the EC1 and/or EC2 domains, and (d) sera from FS patients in remission showed reactivity restricted to EC5. These results suggest that anti-Dsg1 autoantibodies in FS are initially raised against the COOH-terminal EC5 domain of Dsg1 in individuals without skin disease; in genetically predisposed subjects the autoimmune response may then undergo intramolecular epitope spreading toward epitopes on the NH2-terminal EC1 and EC2 domains of Dsg1 leading to disease onset. Moreover, intramolecular epitope spreading may also modulate remissions and relapses of FS.

The Prevalence of Antibodies against Desmoglein 1 in Endemic Pemphigus Foliaceus in Brazil

Background Pemphigus foliaceus is an autoimmune skin disease mediated by autoantibodies against desmoglein 1. The endemic form is thought to have an environmental cause. The Terena reservation of Limao Verde in Mato Grosso do Sul, Brazil, is a recently identified focus of the disease, with a prevalence of 3.4 percent in the population. We tested the hypothesis that normal subjects living in an endemic area have antibodies against desmoglein 1. Methods We used an enzyme-linked immunosorbent assay to detect antibodies against desmoglein 1 in serum samples from 60 patients with endemic pemphigus foliaceus (fogo selvagem) who lived in Limao Verde or elsewhere in Brazil, 372 normal subjects (without pemphigus foliaceus) from Limao Verde and surrounding locations, and 126 normal subjects from the United States and Japan. Results Antibodies against desmoglein 1 were detected in 59 of the 60 patients with fogo selvagem (98 percent) but in only 3 of the 126 normal subjects from the United States and Japan (2 perce...

Endemic pemphigus foliaceus (fogo seivagem). I. Clinical features and immunopathology

Endemic pemphigus foliaceus is an autoimmune disease that has remarkable features. Endemic foci are found in characteristic environments within the interior of Brazil. The epidemiologic data strongly suggest that an environmental factor initiates the autoantibody response in the host. As such it is an important disease for in-depth study. A group of interested investigators in both Brazil and the United States has been formed to attempt to do just that. As part of the overall effort, this Cooperative Research Group for the Study of Fogo Selvagem presents a definition of the disease, a proposed clinical classification for various forms of the disease, and an outline of what is currently known of its immunopathologic characteristics.

Desmoglein-1–specific T lymphocytes from patients with endemic pemphigus foliaceus (fogo selvagem)

Fogo selvagem (FS), the endemic form of pemphigus foliaceus, is a cutaneous autoimmune disease characterized by subcorneal blistering of the epidermis and the production of autoantibodies against the desmosomal antigen desmoglein-1 (Dsg1). Previously, we showed that mice injected with autoantibodies from FS patients develop a skin disease that reproduces the clinical, histological, and immunological features of FS, indicating that autoantibodies play an essential role in the development of this disease. The purpose of this study was to characterize the autoimmune T-cell response associated with FS. We provide here the first evidence, to our knowledge, that the great majority of FS patients have circulating T lymphocytes that specifically proliferate in response to the extracellular domain of Dsg1. Long-term T cells developed from these patients also responded to Dsg1, and this antigen-specific response was shown to be restricted to HLA-DR molecules. These Dsg1-reactive FS T cells exhibited a CD4-positive memory T-cell phenotype and produced a T helper 2-like cytokine profile. These findings represent the initial steps in defining the role of T cells in FS autoimmunity.

HLA antigens and risk for development of pemphigus foliaceus (fogo selvagem) in endemic areas of Brazil

Endemic pemphigus foliaceus (EPF), is an autoimmune disease associated with production of IgG antibodies against epidermal antigens. We have tested 38 patients and 50 control subjects living in endemic areas to investigate whether HLA genes are associated with host factors that determine whether or not exposed individuals will develop this disease. A variant of HLA-DR1, an antigen common in Blacks (DRB1*0102), was found to be the main susceptibility factor (relative risk=7.3, P<0.0002). Two amino acids, in positions 85 and 86 of DRB1, distinguish DRB1*0102 from DRB1*0101. These residues appear to be involved in the formation of a functional epitope that causes T cell recognition and determines disease susceptibility. Moreover, subjects having DQw2 did not develop the disease, while the frequency of DQw2 in controls was 22% (RR=0.04, P<0.006). Thus HLA genes appear to play a crucial role in the response to an environmental factor which in this setting frequently leads to the development of autoimmune disease. An HLA-DQ allele, DQw2, appears to be associated with factors that prevent the development of the disease in exposed individuals.

Activated status of basophils in chronic urticaria leads to interleukin-3 hyper-responsiveness and enhancement of histamine release induced by anti-IgE stimulus

Background Basophils and mast cells are the main target cells in chronic idiopathic urticaria (CIU). Besides the basopenia, intrinsic defects of the anti‐IgE cross‐linking signalling pathway of basophils have been described in CIU.

Actinic cheilitis: histologic study of the entire vermilion and comparison with previous biopsy.

Background:  Actinic cheilitis (AC), is the very superficial, incipient form of actinically induced squamous cell carcinoma of the lower lip. Few studies of actinic cheilitis analyzed the entire lip vermilion searching for microscopic areas of progressing carcinoma.

Deep fungal infections in tropical countries

Deep mycoses are diseases that require knowledge of numerous medical specialties. According to modern concepts, deep mycoses are considered under two aspects: subcutaneous and systemic mycosis. Subcutaneous mycoses are characterized by a heterogeneous group of infections that often result from direct penetration of the fungus into the skin through trauma; and they spread by local tissue invasion in the inoculation area. The disease usually remains localized, slowly spreads to adjacent tissue, and eventually to lymphatic; or, more rarely, hematogenous dissemination is observed. A variety of clinical presentation is frequent, leading to a broad range of differential diagnoses. Chromomycosis, pheohyphomycosis, sporotrichosis, entomophthoramycosis, lobomycosis, and rhinosporidiosis belong to the group of the subcutaneous mycoses. Systemic mycosis consists of infections caused by truly pathogenic fungi and also those produced by fungi with small intrinsic pathogenicity, that is, enhanced by immunocompromised hosts, leading to the disease. In tropical regions, it is the first condition that leads to specific interest, whereas subcutaneous mycosis is found worldwide. The true systemic mycoses are produced in normal individuals when a minimal inoculated particle penetrates into the body. In the majority of cases, the respiratory tract may be the first site of entry, leading to initial lung infection; fungi then spread by hematogenous or eventually lymphatic vessels to other organs, including the skin. These diseases have a restricted geographic distribution due to the limited geographic occurrence of the etiologic agents. The majority of patients are represented by adult men as a consequence of prolonged exposure to fungi due to professional reasons. Apparently, black individuals show a higher risk of developing disseminated forms. The racial influence seems to have existed among Japanese immigrants in Brazil, who developed severe disseminated forms of paracoccidioidomycosis. Obviously, the direct contact with the land favors the opportunity to acquire fungal disease, justifying its higher frequency among rural peasants. After penetrating the human body, fungi usually arouse an adequate defensive response; these are the so-called infections without disease that occur in paracoccidioidomycosis, coccidioidomycosis, histoplasmosis, and cryptococcosis. Under these circumstances, the infection may be totally silent, or with discrete clinical symptoms, such as fever, with or without erythema nodosum; infectious state is detected only by positive intradermal tests utilizing involved fungal antigens. Epidemiological inquiries dealing with these intradermal tests show variable positive results in different regions, where they are performed according to fungi distribution; the percentage of positive results of these tests in populations demonstrate a direct relationship to the occurrence of the disease in the studied area. The association of these fungal diseases to other morbid processes, either infectious or carcinogenic, is occasionally cited. For example, cryptococcosis is sometimes associated with lymphomas, paracoccidioidomycosis, and pulmonary tuberculosis. Another possibility concerning systemic mycosis is the reactivation of a quiescent fungal focus in individuals living in endemic areas who acquired the silent infection, as demonstrated by positive response to intradermal tests. It is interesting to observe the development of the disease in these individuals after many years, due to multiple reasons that lead to an impaired immune response (aging, immunosupressant drugs, concomitant diseases). This event may happen many years after exposure to fungi, when the patient is no longer living in the endemic area, or is living in a country where the disease does not occur, making the diagnosis extremely difficult. This condition is the socalled imported pathology.

Body dysmorphic disorder among dermatologic patients: Prevalence and clinical features

BACKGROUND An impairing preoccupation with a nonexistent or slight defect in appearance is the core symptom of body dysmorphic disorder (BDD), a psychiatric condition common in dermatology settings. OBJECTIVE We sought to determine the prevalence of BDD in dermatologic patients, comparing general and cosmetic settings, and describing some demographic and clinical characteristics. METHODS In all, 300 patients were consecutively assessed. Screening and diagnoses were performed with validated instruments plus a best estimate diagnosis procedure. The final sample comprised 150 patients in the cosmetic group, 150 patients in the general dermatology group, and 50 control subjects. Standard statistical analyses were performed (chi(2), nonparametric tests, logistic regression). RESULTS The current prevalence was higher in the cosmetic group (14.0%) compared with general (6.7%) and control (2.0%) groups. No patient had a previous diagnosis. Frequently the reason for seeking dermatologic treatment was not the main BDD preoccupation. Patients with BDD from the cosmetic group were in general unsatisfied with the results of dermatologic treatments. LIMITATIONS Cross-sectional study conducted in a university hospital is a limitation. It is uncertain if the findings can be generalized. Retrospective data regarding previous treatments are not free from bias. CONCLUSIONS BDD is relatively common in a dermatologic setting, especially among patients seeking cosmetic treatments. These patients have some different features compared with general dermatology patients. Dermatologists should be aware of the clinical characteristics of BDD to identify and refer these patients to mental health professionals.