Colonies were randomly selected from Dsg1 and LJM11 panning of these three IgG4 APD libraries. 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. 360A 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 360A of autoantibodies in IgG4-related autoimmune diseases. Introduction Fogo Selvagem (FS) is an endemic form of pemphigus foliaceus (PF) found in certain says of Brazil (1, 2). The hallmark of this disease is the presence of intraepidermal vesicles due to epidermal cell detachment (acantholysis) (3) induced by pathogenic IgG4 anti-desmoglein 1 (Dsg 1) autoantibodies (autoAbs) (4C8). FS shows similar clinical, histological and immunological features to those observed in non-endemic PF (9, 10). Epidemiologic and immunogenetic studies suggest that both genetic and environmental factors contribute to the development of FS (1, 11, 12). Previous studies suggest that exposure to hematophagous insect bites in genetically predisposed individuals may be a risk factor for FS (12). To strengthen this hypothesis we have shown that IgG4 anti-Dsg1 autoAbs cross-react with 360A LJM11 sand travel salivary gland antigen (13), which suggests that this development of IgG4 Abs may be linked to immune responses to environmental antigens. Compared to investigations around the pathogenesis and genetic predisposition of autoimmune diseases, etiological studies regarding environmental triggers of these diseases are lacking due to low prevalence and the clinical heterogeneity of the diseases (14C19). Similarly, the random nature of autoimmune skin diseases in North America makes it hard to assess their etiological commonality and further dissect their causes. In this regard the endemic Nrp1 nature of FS provides an priceless model and rare opportunity to study the environmental factors within the FS endemic region and their contribution to the development of FS. IgG4 Abs are known to be elevated in patients with FS (20C22), other bullous dermatoses (23), as well as autoimmune pancreatitis (24), Mikulicz’s disease (main Sjogren’s syndrome) (25), and other diseases (26). Recently, the terms IgG4-related disease and IgG4-related skin disease have been proposed (26C28). Among some autoimmune diseases, increased serum levels of total IgG4 are often observed and certain specific histopathological features, such as IgG4 360A plasma cell infiltration in effected tissues or organs, are present. (26C28). On the other hand, increased circulating anti-Dsg1 IgG4 autoAbs are characteristic of FS/PF as these anti-epidermal autoAbs are pathogenic and are detected bound to the surface of detached keratinocytes in lesional and perilesional epidermis of these patients (4). In FS/PF the lesional skin does not show IgG4 B cell or plasma cell infiltrates. In 1989 Rock et al exhibited that this IgG4 response in FS is usually pathogenic (20). Later studies confirmed that the bulk of pathogenic anti-Dsg1 autoAbs in FS are predominantly IgG4 (21). IgG4 anti-Dsg 1 Abs from FS patients are pathogenic in mice (8, 29); much like those in PF (30) using an IgG passive transfer mouse model. One study showed that progression from your preclinical to the clinical stage of the disease is associated with a dramatic rise in IgG4 anti-Dsg1 autoAbs (21) and that the level of anti-Dsg1 IgG4 Abs can be used as a predictor of FS (22). Our recent finding that IgG4 autoAbs in FS cross-react with an LJM11 sand travel antigen (13) suggests that the development of IgG4 autoAbs in patients may be.