Pemphigus Vulgaris Induced by Electrical Injury

Pathogenesis of PV Induced After Electrical Injury Normally, Dsg3 is not released into the blood or lymph in sufficient amounts to elicit an immune response; however, the aforementioned mechanisms of electrical injury may result in cellular rupture or necrosis. Following these processes, Dsg3 may be released and become available to the immune system, which could potentially lead to an autoantibody response toward Dsg3 and the subsequent development of PV. This is supported by the documentation of autoantibodies, including pemphiguslike auto-antibodies, appearing in patients following thermal burns,10-12 as well as by several case reports of pemphigus following thermal burns.13-17 A potential mechanism for the induction of PV following electrical injury is shown in the Figure.

Generation of an Immune Response to Self- Antigens—T-cell tolerance depends on the presentation of self-proteins to T cells. Normally, tolerance is established to self-antigens that, under normal conditions, are generated in sufficient amounts to be recognized by T cells undergoing deletion in the thymus or anergy in the periphery. Thus, there are a large number of self-antigens that are cryptic because they either are not generated at all or are generated at subthreshold levels for T-cell deletion or anergy. T cells specific for these cryptic epitopes are present in the normal repertoire and may become activated and generate an autoimmune response if the epitopes are presented at higher concentrations. 18 Excessive Release of Self-Antigens—Extensive thermal and electroporation damage to cell membranes, especially in desmosome-rich tissue such as skin and mucosal epithelium, may lead to extensive cell death and to the massive release of Dsg3 and other desmosomal/cell membrane antigens. Even if such antigens were unaltered (conformationally unchanged) by the electrical injury, excessive amounts available to antigen-presenting cells could predominate in the antigen-processing pathway and activate any specific T cells that are not anergic to this self-protein.18 These activated T cells could trigger the activation of B cells with the potential to differentiate into anti-Dsg3 IgG antibody-secreting plasma cells, which result in PV. Generation of Cryptic Peptides—Thermal degeneration and electroconformational denaturation of desmosomes and other cell membrane antigens may lead to the formation of cryptic peptides. These altered defective proteins may enter the antigen-processing pathway and be detected by cryptic peptide-specific T cells and B cells. Cryptic peptide-reactive lymphocytes may be present in the normal T-cell repertoire because cryptic peptides are not available during T cell and B cell development to provoke deletion or inactivation of these cells.18 If the cryptic peptides were similar to Dsg3, antibodies may be formed that may cross-react with native Dsg3, which results in PV. Inflammation Potentiating the Immune Response—Cutaneous trauma can activate the regulatory components of the immune system that are needed to activate and perpetuate an immune response. The skin is a significant source of proinflammatory cytokines,19 and injury to the skin can release these cytokines.19-22 Additionally, these cytokines can cross the epidermal basement membrane and enter the lymphatic and systemic circulations.22 For example, interleukins 1 and 6 released by skin injury have been implicated in the development of PV.23 Thus, cytokines may help to potentiate the immune response leading to the development of PV. Enhanced Antigen Processing and Spread of Anti–Self-Responses—After anti-Dsg3 antibodies are generated, enhanced self-antigen processing could occur as a result of antibody-mediated amplification of the anti–self-response. B cells are activated following antigen binding,24 and further release of Dsg3 from the inflammatory process would provide more stimulus for B-cell activation. Enhanced antigen processing that occurs with inflammation and the generation and expansion of cryptic peptides could result in epitope spreading of the disease to other self-antigens. Temporal Considerations—The mechanisms of generating self-antigen in amounts above T-cell activation thresholds could elicit the development of PV. The formation of antibodies after exposure to a new antigen would be expected to occur within 12 weeks.25 Thus, it seems reasonable that the first clinical signs of PV that result from the presence of anti-Dsg3 antibodies and subsequent binding to desmosomes in skin and mucosal epithelium may occur within weeks following the electrical injury. During this time, all of the immune events leading to both foreign responses and anti—self-responses occur, with the response manifested as clinical disease. Once established, the disease would generate sufficient antigens through continued cell membrane destruction.

Conclusion

In conclusion, we report a case of the new onset of PV occurring after a significant electrical injury. The electrical injury caused significant tissue injury that resulted in the release of self-antigen (Dsg3), proinflammatory mediators, and possibly cryptic peptides. These stimuli presumably led to the generation of anti-Dsg3 autoantibodies, which resulted in the clinical manifestations of PV.