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In search of the Etiology of Autoimmune Pemphigus -A Scientific Report
by Ning Li, Ph.D., Julio Hilario-Vargas, M.S. and Luis A. Diaz, M.D. From the Department of Dermatology University of North Carolina School of Medicine Chapel Hill, NC.
Pemphigus is a name applied to a group of rare autoimmune skin blister diseases mediated by pathogenic anti-epidermal autoantibodies (1). These autoantibodies recognize desmosomal cadherin antigens, i.e. desmoglein 1 (Dsg1) and desmoglein 3 (Dsg3) and impair their function leading to epidermal cell detachment (acantholysis), which is manifested as skin blisters. Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are the two major types of the group. While the former is characterized by autoantibodies against Dsg3 and suprabasilar acantholysis, the latter is characterized by autoantibodies against Dsg1 and superficial acantholysis. The autoantibodies are predominantly IgG4 subclass and are pathogenic as demonstrated by passive transfer studies in neonatal mice. PV and PF are associated with certain HLA class II alleles, suggesting genetic factors play an important role in disease development. PV and PF are seen sporadically in different parts of the world, however, the endemic form of PF known as Fogo Selvagem (FS) which is clinically and immunopathologically identical to non-endemic PF is found in Brazil. Other endemic forms of PF have been described in Tunisia and Colombia. Epidemiological studies suggest that autoantibody formation and development of FS in these endemic regions of Brazil results from exposure to local environmental agents.
Our research group has been studying FS in Brazil for several years and has identified an Amerindian reservation of Limao Verde with a population of 1,200 inhabitants, where the prevalence of FS is 3.4% (2) (Figure 1). This reservation is the home of the Terena tribe; native settlers of the State of Mato Grosso do Sul. Using the sensitive ELISA assay, we detected anti-Dsg1 antibodies in serum of patients before the onset of clinical disease as well as in 55% of unaffected individuals living in this reservation (3). These anti-Dsg1 antibodies detected in the pre-clinical stage of FS belong to the IgG1 and IgG4 subclasses and recognize the COOH-terminal EC5 domain of the molecule. Remarkably, disease onset is associated with a significant increase of IgG4 antibodies that recognize the NH2-terminal EC1-2 domains of Dsg1 (4). < P>A recent case-control epidemiological study conducted in the Limao Verde reservation suggests that hematophagous insects (kissing bugs, sand and black flies) are potential risk factors for this disease (5). Interestingly, we have recently reported that anti-Dsg1 autoantibodies are detected in patients with tropical parasitic diseases mediated by three hematophagous vectors: onchocerciasis (black flies), leishmaniasis (sand flies) and Chagas disease (kissing bugs) (6). The anti-Dsg1 autoantibodies present in the serum of these patients also recognize the EC5 domain of Dsg1, like those detected in unaffected individuals living in the Limao Verde reservation. The three blood-feeding insects (simuliids, phlebotomines or triatomines) are all found in the Limao Verde reservation. It was also demonstrated that the FS sera do not react with the disease causing parasites (filaria, leishmania of trypanosome). Based on these findings we hypothesized (Figure 2) that a hematophagous insect product (saliva?), cross-reactive with the EC5 domain of human Dsg1, triggers an early non-pathogenic autoantibody response in humans. In certain genetically predisposed individuals, this response would spread to involve the EC1-2 domain of Dsg1 and trigger pathogenic autoantibody response and FS. However, the common presence of the hematophagous insects in other regions of the world and rarity of FS requires further investigation.
Among the different phenotypes of pemphigus, FS offers the unique opportunity to uncover the underlying mechanisms controlling the genetic and environmental interactions leading to autoimmune diseases in humans.
References
1. Udey MC, Stanley JR. Pemphigus--diseases of antidesmosomal autoimmunity. JAMA. 1999 Aug 11;282(6):572-6.
2. Hans-Filho G, dos Santos V, Katayama JH, Aoki V, Rivitti EA, Sampaio SAP, Friedman H, Moraes JR, Moraes ME, Eaton DP, Lopez AL, Hoffmann RG, Fairley JA, Giudice GJ, Diaz LA. An active focus of high prevalence of fogo selvagem on an Amerindian reservation in Brazil. J. Invest. Dermatol., 107:68-75, 1996.
3. Warren SJP, Lin MS, Giudice GJ, Hoffman RG, Hans-Filho G, Aoki V, Rivitti EA, dos Santos V and Diaz, LA: The prevalence of antibodies against desmoglein 1 in endemic pemphigus foliaceus in Brazil. N Engl J Med 343:23-30, 2000
4. Li N, Aoki V, Hans-Filho G, Rivitti EA and Diaz LA. The Role of Intramolecular Epitope Spreading in the Pathogenesis of Endemic Pemphigus Foliaceus (Fogo Selvagem). J Exp Med. 197:1501-1510, 2003
5. Aoki V, Millikan RC, Rivitti EA, Hans-Filho G, Warren SJP, Li N, and Diaz LA. Environmental Risk Factors in Endemic Pemphigus Foliaceus (Fogo Selvagem). J Invest Dermatol. 9:34-40, 2004.
6. Diaz LA, Arteaga LA, Hilario-Vargas J, Valenzuela JG, Li N, Warren S, Aoki V, Hans-Filho G, Eaton D, dos Santos V, Nutman TB, Antunez de Mayolo A, Qaqish BF, Sampaio SAP and Rivitti EA. Anti-desmoglein-1 antibodies in onchocerciasis, leishmaniasis and Chagas Disease suggest a possible etiological link to Fogo Selvagem. J Invest Dermatol, 123:1045-1051, 2004.
a reprint with figure 1 and figure 2 included is available from aarda by emailing aarda@aarda.org and requesting the full article.
