Update on fogo selvagem, an endemic form of pemphigus foliaceus

Pemphigus are organ-specific autoimmune diseases, where autoantibodies (mainly IgG) directed against epidermal targets (glycoproteins of the desmosomal core) are detected. Endemic pemphigus foliaceus or fogo selvagem (FS) is one of the variants of pemphigus foliaceus (PF) that shares the same clinical and immunopathological features of the classic nonendemic PF form, including pathogenic IgG (mainly IgG4) autoantibodies directed against the ectodomain of desmoglein 1 (Dsg1), that lead to acantholysis. Pathogenesis of FS is complex, involving genetic, environmental and immunological factors. HLADRB1 alleles DRB1*0404, *1402, *1406 or *0102 have been previously identified as risk factors for FS (relative risk > 14). Individuals exposed to hematophagous insects are more susceptible to develop the disease. Nonpathogenic anti-Dsg1 antibodies of the IgG1 subclass, directed against the extra-cellular 5 domain of Dsg1 are detected in patients in the preclinical stage of the disease, and also in healthy controls living in endemic areas. In counterpart, patients with FS show pathogenic anti-Dsg1 IgG4 auto-antibodies that bind the pathogenic extracellular 1 and 2 domains of Dsg 1, emphasizing the intramolecular epitope spreading hypothesis. A possible explanation for the development of the autoimmune process would be antigenic mimicry, initiated by environmental stimuli in those genetically predisposed individuals. Characterization of the pathogenesis of FS will allow the development of specific therapeutic targets, and the elucidation of other autoimmune processes

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

Cutaneous manifestations of thrombophilia

O escopo deste artigo é revisar os estados de hipercoagulabilidade sangüínea (trombofilias) mais provavelmente encontrados por dermatologista. Seus sinais cutâneos incluem o livedo reticular, necrose cutânea, ulcerações e isquemia digital, púrpura retiforme, além de úlceras nas pernas. Revisamos seu tratamento adequado, bem como ressaltamos as manifestações cutâneas que impõem pesquisa laboratorial de trombofilias e os exames indicados nessas situações.The aim of this article is to review the hypercoagulable states (thrombophilia) most probably found by dermatologists; their cutaneous signs including livedo racemosa, skin necrosis, digital ischemia and ulcerations, retiform purpura and leg ulcers; their appropriate treatment; to describe the skin manifestations that require laboratory tests for thrombophilias and the tests indicated in these clinical conditions

Prevalência de auto-anticorpos antinucleares no soro de doadores de sangue normais

OBJECTIVE:To examine the presence of serum antinuclear autoantibodies in a healthy population. METHODS: Serum of 500 normal blood donors between 18 and 60 years of age were tested for the presence of autoantibodies. Antinuclear antibodies were detected by indirect immunofluorescence technique using HEp-2 epithelial cells as the substrate. The presence of dnaN was detected by indirect immunofluorescence technique using Critidia lucillae as the substrate. Anti-SSA (RO), anti-SSB (LA), anti-Sm, and anti-RNP were determined by double radial immunodiffusion. RESULTS: In the evaluation of the presence of serum antibodies, antinuclear antibodies were detected in 22.6% of the sera. The presence of other antibodies was not significant. The majority of the titers were 1:40. CONCLUSION: The presence of autoantibodies is not necessarily pathologic and has to be related to the age group, gender, and clinical condition of the patient.OBJETIVO: O objetivo deste trabalho foi detectar a presença de autoanticorpos em pessoas sadias. MÉTODOS: Foi estudado o soro de 500 doadores de sangue sadios, com idade entre 18 e 60 anos. Anticorpo antinuclear foi detectado por imunofluorescência indireta usando células Hep-2 como substrato. A pesquisa de anti-DNA-nativo (DNA-n) foi feita com a técnica de imunofluorescência indireta usando Critidia lucillae como substrato. A pesquisa de anti-SSA, anti-SSB, anti-Sm e anti-RNP foi feita utilizando a técnica de imunodifusão radial dupla. REUSLTADOS: A presença de anticorpo antinuclear foi detectada em 22,6% das amostras estudadas. A maioria apresentou títulos 1/40. A presença de outros anticorpos não foi significativa. CONCLUSÃO: A presença de autoanticorpos não é necessariamente patológica e deve ser correlacionada à idade, sexo e condição clínica do paciente

Overlapping IgG4 Responses to Self- and Environmental Antigens in Endemic Pemphigus Foliaceus

The etiology of human autoimmune diseases in general remains largely unknown, although the genetic and environmental interplay may be relevant. This applies to the autoimmune diseases of the skin such as the pemphigus phenotypes and others. In this group, there is an endemic form of pemphigus foliaceus [also known as Fogo Selvagem (FS)] where the pathogenic IgG4 autoantibody response to the self-antigen, Desmoglein 1 (Dsg1) cross-react with the LJM11 sand fly salivary gland antigen. In this investigation we dissected the IgG4 autoantibody repertoires utilized by FS patients in response to endogenous self Dsg1 and exogenous LJM11 sand fly antigen. Based on analyses of the genetic clonal signatures of these antibodies, our results indicate that there is a significant overlap between these two responses as all identified IgG4 monoclonal antibodies cross-react to both Dsg1 and LJM11 antigens. Germline H and L chain V gene antibodies generated according to mutated cross-reactive monoclonal antibodies preserved their reactivity to both antigens. Our findings suggest that both Dsg1 autoantigen and LJM11 environmental antigen could be the initial antigenic stimulants for the IgG4 autoimmune responses in FS. These results support our hypothesis that LJM11 antigen plays a substantial role in triggering the IgG4 autoantibody development in FS, and provide new insights on how non-infectious environmental antigen(s) may drive the generation of autoantibodies in IgG4-related autoimmune diseases

Advances in pemphigus and its endemic pemphigus foliaceus (Fogo Selvagem) phenotype: A paradigm of human autoimmunity

Pemphigus encompasses a group of organ specific, antibody mediated autoimmune diseases of the skin characterized by keratinocyte detachment that leads to the development of blisters and erosions, which can become life-threatening. The pathogenic autoantibodies recognize desmogleins, which are members of the desmosomal cadherin family of cell adhesion molecules. Desmoglein 3 is targeted in pemphigus vulgaris while desmoglein 1 is targeted in pemphigus foliaceus and its endemic form, fogo selvagem. This review will briefly define the salient features of pemphigus and the proposed steps in pathogenesis. We will then summarize the most recent advances in three important areas of investigation: (i) epidemiologic, genetic, and immunologic features of fogo selvagem, (ii) molecular mechanisms of injury to the epidermis, and (iii) novel therapeutic strategies targeting specific steps in disease pathogenesis. The advances in each of these three seemingly separate areas contribute to the overall understanding of the pemphigus disease model. These recent advancements also underscore the dynamic interplay between the treatment of patients in a clinical setting and basic science research, which has led to an integrative understanding disease pathogenesis and treatment and allow pemphigus to serve as a paradigm of human autoimmunity

Development of an IgG4-based Classifier/Predictor of Endemic Pemphigus Foliaceus (Fogo Selvagem)

Fogo Selvagem (FS) is mediated by pathogenic, predominantly IgG4, anti-Dsg1 autoantibodies and is endemic in Limao Verde (LV), Brazil. IgG and IgG-subclass autoantibodies were tested in a sample of 214 FS patients and 261 healthy controls by Dsg1-ELISA. For model selection, the sample was randomly divided into training (50%), validation (25%) and test (25%) sets. Using the training and validation sets, IgG4 was chosen as the best predictor of FS, with index values above 6.43 classified as FS. Using the test set, IgG4 has sensitivity 92% (95% CI: 82−95%), specificity 97% (95% CI: 89−100%) and area under the curve 0.97 (95% CI: 0.94−1.00). The IgG4 positive predictive value (PPV) in LV (3% FS prevalence) was 49%. The sensitivity, specificity and PPV of IgG anti-Dsg1 were 87%, 91% and 23%, respectively. The IgG4-based classifier was validated by testing 11 FS patients before and after clinical disease and 60 Japanese pemphigus patients. It classified 21/96 normal individuals from a LV cohort as having FS serology. Based on its PPV, half of the 21 individuals may currently have preclinical FS and could develop clinical disease in the future. Identifying individuals during preclinical FS will enhance our ability to identify etiological agent(s) triggering FS