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

Abstract

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.

Pemphigus

“…Active areas of research focus on detailed characterization of desmoglein-reactive B cell lineages and their crossreactivity and specificity 23,88 , genetic susceptibility and gene expression profiles 30,202 , and immunological mechanisms in novel animal models 48,203,204 , among other topics. These studies have created translational research opportunities to develop novel strategies for autoimmune disease therapy (FIG.…”

“…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.…”

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

“…Thus, we cannot conclusively state IgG4 autoantibodies are also antigen selected. To further dissect the IgG4 antibody repertoires and the nature of the IgG4 antibody response in FS, we modified the original antibody phage display method [106] to isolate only IgG4 antibodies from FS patient blood samples [107]. Since the antibody phage display libraries that we generate comprise only IgG4 subclass from patients, we can focus on isolating only the potential pathogenic IgG4 antibodies from FS patients.…”

“…Since the antibody phage display libraries that we generate comprise only IgG4 subclass from patients, we can focus on isolating only the potential pathogenic IgG4 antibodies from FS patients. Using this modified antibody phage display method, 136 IgG4 monoclonal antibodies were isolated from three FS patient samples, including 14 clonally independent IgG4 monoclonal antibodies [107]. Among them, two IgG4 monoclonal antibodies originally isolated by hybridoma method were also identified [92, 107].…”

“…Using this modified antibody phage display method, 136 IgG4 monoclonal antibodies were isolated from three FS patient samples, including 14 clonally independent IgG4 monoclonal antibodies [107]. Among them, two IgG4 monoclonal antibodies originally isolated by hybridoma method were also identified [92, 107]. This method may prove to be a very useful tool for the study of IgG4 antibody repertoires and the mechanism by which IgG4 antibodies develop in patients with the newly categorized IgG4-related diseases [81-83].…”