Implicating bites from a leishmaniasis sand fly vector in the loss of tolerance in pemphigus.

Soumaya Marzouki,Ines Zaraa,Maha Abdeladhim,Shaden Kamhawi,Hechmi Louzir,Mourad Mokni,Melika Ben Ahmed,Jesus G Valenzuela,Chaouki Benabdesselem,Fabiano Oliveira

doi:10.1172/jci.insight.123861

Abstract

A possible etiological link between the onset of endemic pemphigus in Tunisia and bites of Phlebotomus papatasi, the vector of zoonotic cutaneous leishmaniasis, has been previously suggested. We hypothesized that the immunodominant P. papatasi salivary protein PpSP32 binds to desmogleins 1 and 3 (Dsg1 and Dsg3), triggering loss of tolerance to these pemphigus target autoantigens. Here, we show using far-Western blot that the recombinant PpSP32 protein (rPpSP32) binds to epidermal proteins with a MW of approximately 170 kDa. Coimmunoprecipitation revealed the interaction of rPpSP32 with either Dsg1 or Dsg3. A specific interaction between PpSP32 and Dsg1 and Dsg3 was further demonstrated by ELISA assays. Finally, mice immunized with rPpSP32 twice per week exhibited significantly increased levels of anti-Dsg1 and -Dsg3 antibodies from day 75 to 120. Such antibodies were specific for Dsg1 and Dsg3 and were not the result of cross-reactivity to PpSP32. In this study, we demonstrated for the first time to our knowledge a specific binding between PpSP32 and Dsg1 and Dsg3, which might underlie the triggering of anti-Dsg antibodies in patients exposed to sand fly bites. We also confirmed the development of specific anti-Dsg1 and -Dsg3 antibodies in vivo after PpSP32 immunization in mice. Collectively, our results provide evidence that environmental factors, such as the exposure to P. papatasi bites, can trigger the development of autoimmune antibodies.

Highlights

Pemphigus is an organ-specific autoimmune bullous disease characterized by keratinocyte detachment, resulting from the presence of autoantibodies targeting 2 major desmoglein (Dsg) proteins, Dsg1 and Dsg3, approximately 160 and 130 kDa, respectively [1]
Our recent results support such a hypothesis as an increase in the frequency and level of antibodies directed against salivary proteins of P. papatasi was demonstrated in patients with pemphigus compared with healthy subjects [5]
Such antibodies are essentially composed of the IgG4 isotype and directed against the commonly recognized salivary proteins of P. papatasi, more against the salivary protein, PpSP32, the immunodominant protein recognized by all subjects naturally exposed to the bites of this vector [5,6,7]

Summary

Introduction

Pemphigus is an organ-specific autoimmune bullous disease characterized by keratinocyte detachment, resulting from the presence of autoantibodies targeting 2 major desmoglein (Dsg) proteins, Dsg and Dsg, approximately 160 and 130 kDa, respectively [1]. In Tunisia, zoonotic cutaneous leishmaniasis (ZCL) attributed to Leishmania major (L. major) is more prevalent in rural areas where a higher incidence of Tunisian endemic pemphigus has been reported [4]. Such areas are characterized by high densities of Phlebotomus papatasi (P. papatasi), the vector of ZCL. Such findings may suggest the involvement of sand fly bites — the injected insect salivary proteins — in triggering the disease. A persistent exposure to P. papatasi bites may, be a possible etiologic link to pemphigus in Tunisia

Methods

Results

Conclusion