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

Antigen Selection of Anti-DSG1 Autoantibodies During and Before the Onset of Endemic Pemphigus Foliaceus

Fogo selvagem (FS), the endemic form of pemphigus foliaceus (PF), is characterized by pathogenic anti-desmoglein 1 (DSG1) autoantibodies. To study the etiology of FS, hybridomas that secrete either IgM or IgG (predominantly IgG1 subclass) autoantibodies were generated from the B cells of eight FS patients and one individual 4 years before FS onset, and the H and L chain V genes of anti-DSG1 autoantibodies were analyzed. Multiple lines of evidence suggest that these anti-DSG1 autoantibodies are antigen selected. First, clonally related sets of anti-DSG1 hybridomas characterize the response in individual FS patients. Second, H and L chain V gene use seems to be biased, particularly among IgG hybridomas, and third, most hybridomas are mutants and exhibit a bias in favor of CDR (complementary determining region) amino acid replacement (R) mutations. Strikingly, pre-FS hybridomas also exhibit evidence of antigen selection, including an overlap in V(H) gene use and shared multiple R mutations with anti-DSG1 FS hybridomas, suggesting selection by the same or a similar antigen. We conclude that the anti-DSG1 response in FS is antigen driven and that selection for mutant anti-DSG1 B cells begins well before the onset of disease.US Public Health Service[R01-AR30281]US Public Health Service[RO1-AR32599,]US Public Health Service[T32AR07369]Dermatology FoundationAmerican Skin Association[R01-AI43587

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