Cutting Edge: Brazilian Pemphigus Foliaceus Anti-Desmoglein 1 Autoantibodies Cross-React with Sand Fly Salivary LJM11 Antigen

Abstract

The environmental factors that contribute to the development of autoimmune diseases are largely unknown. Endemic pemphigus foliaceus in humans, known as Fogo Selvagem (FS) in Brazil, is mediated by pathogenic IgG4 autoantibodies against desmoglein1 (Dsg1). Clusters of FS overlap with those of leishmaniasis, a disease transmitted by sand fly (Lutzomyia longipalpis) bites. In this study we show that salivary antigens from the sand fly, and specifically the LJM11 salivary protein, are recognized by FS antibodies. Anti-Dsg1 monoclonal autoantibodies derived from FS patients also cross-react with LJM11. Mice immunized with LJM11 generate anti-Dsg1 antibodies. Thus, insect bites may deliver salivary antigens that initiate a cross-reactive IgG4 antibody response in genetically susceptible individuals and lead to subsequent FS. Our findings establish a clear relationship between an environmental, non-infectious antigen and the development of potentially pathogenic autoantibodies in an autoimmune disease.

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

“…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 LJM11 sand fly salivary gland antigen (13), which suggests that the development of IgG4 Abs may be linked to immune responses to environmental antigens. Compared to investigations on 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 (14–19).…”

Pemphigus

“…These epidemiological associations suggest that an environmental agent might trigger a low-level autoantibody response against desmoglein 1 that in some genetically susceptible individuals becomes pathogenic. In fogo selvagem, the endemic form of pemphigus foliaceus in Brazil, an initial immune response against the sand fly salivary antigen LJM11 (a non-infectious protein from the sand fly Lutzomyia longipalpis , the vector of leishmaniasis 21 ) is speculated to cause a cross-reaction with desmoglein 1 (REFS 22,23), which may trigger the disease.…”

“…In endemic pemphigus foliaceus, anti-desmoglein 1 IgG4 monoclonal antibodies can crossreact with the sand fly antigen LJM11 (REF. 21). Collectively, these findings underscore the potentially double-edged sword of immunity, which can lead to autoimmunity in pemphigus.…”

From Epidemiology and Genetics to Diagnostics, Outcome Measures, and Novel Treatments in Autoimmune Bullous Diseases

“…Interestingly, various Dsg 3-specific T cells not only contribute to the generation of an anti-Dsg 3 IgG response but also directly cause interface dermatitis in vivo (Takahashi et al, 2011). In addition, an environmental, non-infectious agent (sand fly salivary antigen) may drive the generation of autoimmunity in pemphigus in endemic pemphigus foliaceus (Qian et al, 2012). Evidence for the pathogenicity of non-desmoglein-specific autoantibodies (e.g., autoantibodies directed against desmocollin 3) in pemphigus was summarized and discussed in detail (Rafei et al, 2011;Kalantari-Dehaghi et al, 2013).…”