Non-infectious environmental antigens as a trigger for the initiation of an autoimmune skin disease

Abstract

Pemphigus represents a group of organ specific autoimmune blistering disorders of the skin mediated by pathogenic autoantibodies with well-defined antigenic targets. While most of these diseases are sporadic, endemic forms of disease do exist. The endemic form of pemphigus foliaceus (also known as fogo selvagem, FS) exhibits epidemiological features that suggest exposure to hematophagous insect bites are a possible precipitating factor of this autoimmune disease, and provides a unique opportunity to study how environmental factors contribute to autoimmune disease development. FS patients and healthy individuals from endemic regions show an autoreactive IgM response that starts in early childhood and becomes restricted to IgG4 autoantibodies in FS patients. In searching for triggering environmental antigens, we have found that IgG4 and IgE autoantibodies from FS patients cross-react with a salivary antigen from sand flies. The presence of these cross-reactive antibodies and antibody genetic analysis confirming that these antibodies evolve from the same naïve B cells provides compelling evidence that this non-infectious environmental antigen could be the initial target of the autoantibody response in FS. Consequently, FS serves as an ideal model to study the impact of environmental antigens in the development of autoimmune disease.

Divergent Specificity Development of IgG1 and IgG4 Autoantibodies in Endemic Pemphigus Foliaceus (Fogo Selvagem)

“…From this large pool of individuals, a small fraction will develop FS, which is heralded by the appearance of IgG4 anti-Dsg1 autoantibodies (13); 5) the IgG response of patients and endemic controls to other desmosomal cadherins reveals significant differences among FS patients, endemic controls, and United States controls (14); 6) there is a parallel response of anti-Dsg1 IgE autoantibodies in FS patients and endemic controls, which correlates with the IgG4 response (40); and 7) monoclonal IgG4 anti-Dsg1 autoantibodies derived from FS patients cross-react with the salivary protein of Lutzomyia longipalpis LJM11 (5), suggesting an environmental trigger of FS. It is hypothesized that exposure of genetically susceptible individuals to salivary Ags delivered by insect bites may be the trigger of autoantibody production in FS (5, 41), although other environmental triggers may contribute to the development of disease as well (4). …”

“…Genetically, FS exhibits a strong association with the HLA-DRB1*0102, 0404, and 1402 alleles (3). A sand fly salivary gland Ag, LJM11, has been identified as one of the possible environmental triggers for FS because serum autoantibodies and monoclonal anti-Dsg1 autoantibodies from FS patients cross-react to LJM11 environmental Ag (4, 5). …”

An unresponsive progressive pustular and crusting dermatitis with acantholysis in nine cats

“…isolation was not performed on these cases, notwithstanding that the history, presentation and histopathology were inconsistent with these pathogens. Another possibility is an immunological reaction to envenomation by a geographically restricted ectoparasite, as seen in endemic Brazilian pemphigus foliaceus (fogo selvagem), although there is no report of such an entity afflicting humans in these cats’ geographical area …”

From bench to bedside: evolving therapeutic targets in autoimmune blistering disease

“…Developing deeper insights into the pathogenesis of these rare subtypes may allow for adaptation of the therapies discussed below . Although our discussion is restricted to emerging drug treatments, it is important to recognize the impact of non‐infectious exposures on development of AIBD which may allow for large scale societal changes with resultant positive impacts on community health …”

“…54 Although our discussion is restricted to emerging drug treatments, it is important to recognize the impact of non-infectious exposures on development of AIBD which may allow for large scale societal changes with resultant positive impacts on community health. 55 We herein review the exciting emerging treatments in autoimmune blistering disease.…”