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• W2091510188 abstract "An ongoing sero-epidemiological study of the Terena reservation of Limao Verde, known to have a high prevalence and incidence of FS, has revealed important information about this autoimmune disease. During surveillance of this population of approximately 1,200, which began in 1994, we documented 43 FS cases and studied the transition from the normal state to the disease state in several of these individuals. Furthermore, we established that FS patients as well as a large number of normal individuals on the reservation possess anti-dsg1 autoantibodies. The following interesting observations were made: (1) the ectodomain of dsg1 contains epitopes recognized by both autoantibodies and T cells from FS patients; (2) pathogenic anti-dsg1 autoantibodies in FS belong to the IgG4 subclass; (3) nonpathogenic anti-dsg1 autoantibodies of the IgG1 subclass were detected in normal individuals from Limao Verde and in patients in the preclinical stage of the disease; (4) anti-dsg1 autoantibodies from normal individuals and patients in the preclinical stage of FS recognize the EC5 domain of dsg1, whereas pathogenic anti-dsg1 autoantibodies bind the EC1/EC2 domains; (5) houses of FS patients are rustic, with thatched roofs and walls and dirt floors; (6) there was a high frequency of hematophagous insects (bedbugs and kissing bugs) in the houses of FS patients; (7) previous studies revealed that the predominant black fly on this reservation belongs to the species Simunlium nigrimanum. These findings suggest that the environmental antigen(s) triggering the autoimmune response in FS may be linked to exposure to hematophagous insects. An ongoing sero-epidemiological study of the Terena reservation of Limao Verde, known to have a high prevalence and incidence of FS, has revealed important information about this autoimmune disease. During surveillance of this population of approximately 1,200, which began in 1994, we documented 43 FS cases and studied the transition from the normal state to the disease state in several of these individuals. Furthermore, we established that FS patients as well as a large number of normal individuals on the reservation possess anti-dsg1 autoantibodies. The following interesting observations were made: (1) the ectodomain of dsg1 contains epitopes recognized by both autoantibodies and T cells from FS patients; (2) pathogenic anti-dsg1 autoantibodies in FS belong to the IgG4 subclass; (3) nonpathogenic anti-dsg1 autoantibodies of the IgG1 subclass were detected in normal individuals from Limao Verde and in patients in the preclinical stage of the disease; (4) anti-dsg1 autoantibodies from normal individuals and patients in the preclinical stage of FS recognize the EC5 domain of dsg1, whereas pathogenic anti-dsg1 autoantibodies bind the EC1/EC2 domains; (5) houses of FS patients are rustic, with thatched roofs and walls and dirt floors; (6) there was a high frequency of hematophagous insects (bedbugs and kissing bugs) in the houses of FS patients; (7) previous studies revealed that the predominant black fly on this reservation belongs to the species Simunlium nigrimanum. These findings suggest that the environmental antigen(s) triggering the autoimmune response in FS may be linked to exposure to hematophagous insects. desmoglein-1 fogo selvagem pemphigus foliaceus pemphigus vulgaris The endemic form of pemphigus foliaceus (PF) was reported in 1903 by Paes-Leme in Brazil (Paes-Leme, 1903Paes-Leme C. Contribuicao ao estudo do Tokelau (Doctoral Thesis). Facultade de Medicina, Rio de Janeiro, Brazil1903Google Scholar). He described an epidemic of a unique blistering disease, thought to represent a clinical variant of tinea corporis (tinea imbricata or “tokelau”), in certain isolated regions of the state of São Paulo. Subsequently it was found (Vieira, 1937Vieira J.P. Contribuição ao estudo do Pemphigo no Estado de Sao Paulo.Empresa Gráfica Da Revista Dos Tribunais (Publisher). São Paulo, Brasil1937Google Scholar) that this endemic illness exhibited the same clinical features of PF reported by Cazenave in Paris in 1844 (Cazenave, 1844Cazenave P. Pemphigus chronique, general forme rare do pemphigus foliace.Ann Mal la Peu. 1844; 1: 208-210Google Scholar). In his classic monograph of 1937, Vieira established the salient clinical and histological features of this endemic form of PF, also known as fogo selvagem (FS) (Vieira, 1937Vieira J.P. Contribuição ao estudo do Pemphigo no Estado de Sao Paulo.Empresa Gráfica Da Revista Dos Tribunais (Publisher). São Paulo, Brasil1937Google Scholar). FS is distributed in impoverished rural areas of certain states of Brazil, where the disease is endemic (Paes-Leme, 1903Paes-Leme C. Contribuicao ao estudo do Tokelau (Doctoral Thesis). Facultade de Medicina, Rio de Janeiro, Brazil1903Google Scholar;Vieira, 1937Vieira J.P. Contribuição ao estudo do Pemphigo no Estado de Sao Paulo.Empresa Gráfica Da Revista Dos Tribunais (Publisher). São Paulo, Brasil1937Google Scholar). A cutaneous disease with similar features to FS has been described in other countries, including Colombia and Tunisia (Robledo et al., 1988Robledo M.A. Prada S.C. Jaramillo D. Leon W. South American pemphigus foliaceus. Study of an epidemic in El Bagre and Nechi, Colombia 1982–86.Br J Dermatol. 1988; 118: 737-744Crossref PubMed Scopus (56) Google Scholar;Morini et al., 1993Morini J.P. Jomaa B. Gorgi Y. et al.Pemphigus foliaceus in young women. An endemic focus in the Sousse area of Tunisia.Arch Dermatol. 1993; 129: 69-73Crossref PubMed Scopus (96) Google Scholar). FS is characterized by subcorneal epidermal blisters and autoantibodies against desmoglein 1 (dsg1) (Stanley et al., 1986Stanley J.R. Klaus-Kovtun V. Sampaio S.A.P. Antigenic specificity of fogo selvagem autoantibodies is similar to North American pemphigus foliaceus and distinct from pemphigus vulgaris autoantibodies.J Invest Dermatol. 1986; 87: 197-201Crossref PubMed Scopus (101) Google Scholar;Diaz et al., 1989aDiaz L.A. Sampaio S.A.P. Rivitti E.A. et al.Endemic pemphigus foliaceus (fogo selvagem). I. Clinical features and immunopathology.J Am Acad Dermatol. 1989; 20: 657-659Abstract Full Text PDF PubMed Scopus (131) Google Scholar). These autoantibodies are predominantly of the IgG4 subclass and are pathogenic, as demonstrated by passive transfer studies in neonatal mice (Roscoe et al., 1985Roscoe J.T. Diaz L.A. Sampaio S.A.P. et al.Brazilian pemphigus foliaceus autoantibodies are pathogenic to BALB/c mice by passive transfer.J Invest Dermatol. 1985; 85: 538-541Abstract Full Text PDF PubMed Scopus (165) Google Scholar;Rock et al., 1989Rock B. Martins C.R. Theofilopoulos A.N. et al.The pathogenic effect of IgG4 autoantibodies in endemic pemphigus foliaceus (fogo selvagem).N Engl J Med. 1989; 320: 1463-1469Crossref PubMed Scopus (234) Google Scholar). Previous studies in FS documented its familial nature. For example, in a series of 2686 patients reported from the Hospital for Pemphigus in Goiania (Brazil), by Auad (Auad, 1972Auad A. Penfigo foliaceo Sul-Americano no Estado de Goias.Brazil Revista Patologia Trop. 1972; 1: 293-346Google Scholar), 18% of cases were blood relatives, and 93% of these familial cases were found in genetically related family members. Recent studies have reported that the expression of DRB1*0404, 1402, or 1406 alleles is significantly linked to FS (p < 0.005, RR:14) (Moraes et al., 1997Moraes M.E. Fernandez-Vina M. Lazaro A. et al.An epitope in the third hypervariable region of the DRB1 gene is involved in the susceptibility to endemic pemphigus foliaceus (fogo selvagem) in three different Brazilian populations.Tissue Antigens. 1997; 49: 35-40Crossref PubMed Scopus (99) Google Scholar). The hypervariable region of the DRB1 gene of these alleles at the level of residues 67–74 shares the same sequence: LLEQRRAA. This shared epitope may confer susceptibility to FS, as is hypothesized for rheumatoid arthritis (Gregersen et al., 1987Gregersen P.K. Silver J. Winchester R.J. The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis.Arthr Rheum. 1987; 30: 1205-1212Crossref PubMed Scopus (1983) Google Scholar). FS affects people of many races and ethnic backgrounds, including Brazilians of Portuguese, Spanish, German, African, and Japanese descent who live in the endemic areas. Strikingly, the prevalence of FS in some states, for example, São Paulo, has decreased dramatically in recent years (Diaz et al., 1989bDiaz L.A. Sampaio S.A.P. Rivitti E.A. et al.Endemic pemphigus foliaceus (fogo selvagem). II. Current and historic epidemiologic studies.J Invest Dermatol. 1989; 92: 4-12Abstract Full Text PDF PubMed Google Scholar). It is thought that a local environmental agent or agents acting on genetically predisposed individuals in these communities might trigger a pathogenic anti-dsg1 antibody response that leads to FS. A hospital-based case–control study previously showed that simuliid bites were 4.7 times more frequent in individuals developing FS than in control individuals (Lombardi et al., 1992Lombardi C. Borges P.C. Chaul A. et al.Environmental risk factors in endemic pemphigus foliaceus (fogo selvagem).J Invest Dermatol. 1992; 98: 847-850Crossref PubMed Scopus (67) Google Scholar). It has been known for decades that the humoral antiepidermal autoimmune response in FS is mediated by IgG autoantibodies (Beutner et al., 1968Beutner E.H. Prigenzi L.S. Hale W. Leme Cde A. Bler O.G. Immunofluorescent studies of autoantibodies to intercellular areas of epithelia in Brazilian pemphigus foliaceus.Proc Soc Exp Biol Med. 1968; 127: 81-86Crossref PubMed Scopus (72) Google Scholar;Rivitti et al., 1994Rivitti E.A. Sanches J.A. Miyauchi L.M. Sampaio S.A.P. Aoki V. Diaz L.A. Pemphigus foliaceus autoantibodies bind both epidermis and squamous mucosal epithelium but tissue injury is detected only in the epidermis.J Am Acad Dermatol. 1994; 31: 954-958Abstract Full Text PDF PubMed Scopus (16) Google Scholar). Moreover, it has been demonstrated that this IgG response is predominantly of the IgG4 subclass (Rock et al., 1989Rock B. Martins C.R. Theofilopoulos A.N. et al.The pathogenic effect of IgG4 autoantibodies in endemic pemphigus foliaceus (fogo selvagem).N Engl J Med. 1989; 320: 1463-1469Crossref PubMed Scopus (234) Google Scholar), although in some rare patients there is an IgG1 response exclusive of, or in combination with, IgG4 (Rock et al., 1989Rock B. Martins C.R. Theofilopoulos A.N. et al.The pathogenic effect of IgG4 autoantibodies in endemic pemphigus foliaceus (fogo selvagem).N Engl J Med. 1989; 320: 1463-1469Crossref PubMed Scopus (234) Google Scholar;Allen et al., 1993Allen E.M. Giudice G.J. Diaz L.A. Subclass reactivity of pemphigus foliaceus autoantibodies with recombinant human desmoglein.J Invest Dermatol. 1993; 100: 685-691Abstract Full Text PDF PubMed Google Scholar). Total IgG4, as well as the F(ab′)2 and Fab′ fragments of the FS IgG, is pathogenic in the mouse model of FS (Rock et al., 1990Rock B. Labib R.S. Diaz L.A. Monovalent Fab′ immunoglobulin fragments from endemic pemphigus foliaceus autoantibodies reproduce the human disease in neonatal BALB/c mice.J Clin Invest. 1990; 85: 296-299Crossref PubMed Scopus (108) Google Scholar;España et al., 1997España A. Diaz L.A. Mascaro Jr, J.M. Giudice G.J. Fairley J.A. Till G.O. Liu Z. Mechanisms of acantholysis in pemphigus foliaceus.Clin Immunol Immunopathol. 1997; 85: 83-89Crossref PubMed Scopus (43) Google Scholar). Additional studies showed that the autoantibody response in FS exhibits a limited heterogeneity, consisting of oligoclonal IgG1 and IgG4 banding, when tested with epidermal antigens by affinity immunoblotting (Calvanico et al., 1993Calvanico N.J. Swartz S.J. Diaz L.A. Affinity immunoblotting studies on the restriction of autoantibodies from endemic pemphigus foliaceus patients.J Autoimmunity. 1993; 6: 145-157Crossref PubMed Scopus (10) Google Scholar). These studies also showed that the auto-antibodies in FS exhibit an early IgG1 response followed by a sustained IgG4 response. The results of this investigation appear to be in agreement with a clinical and serological study carried out in Minas Gerais, Brazil. 1Dos Santos S: Perfil evolutivo das subclasses de imunoglobulinas gama em pacientes de penfigo foliaceo endemico. Doctoral thesis, Universidade Federal do Rio de Janeiro, 1996 By indirect immunofluourescence (IF) techniques, this investigator found that the IgG1 autoantibody response in FS is present early in the course of the disease (patients showing skin blisters of less than six months of evolution). The IgG1 autoantibodies were undetectable in sera of patients entering the chronic phase of the disease (disease of more than six months of evolution) or when patients were effectively treated. IgG4 autoantibodies, however, were the predominant subclass in the sera of these patients. It should be emphasized that human IgG4 antibody responses, as in FS, have been well documented in patients with filariasis (Ottesen et al., 1985Ottesen E.A. Skvaril F. Tripathy S.P. Poindexter R.W. Hassain R. Prominence of IgG4 in the IgG antibody response to human filariasis.J Immunol. 1985; 134: 2707-2712PubMed Google Scholar), bee handlers chronically exposed to bee venom (Aalberse et al., 1983Aalberse R.C. van der Gaag R. van Leeuwen J. Serological aspects of IgG4 antibodies. I. Prolonged immunization results in an IgG4-restricted response.J Immunol. 1983; 130: 722-726PubMed Google Scholar), and allergic individuals undergoing hyposensitization to environmental antigens (Oehling et al., 1998Oehling A.K. Sanz M.L. Resano A. Importance of IgG4 determination in in vitro immunotheraphy follow-up of inhalant allergens.Invest Allergol Clin Immunol. 1998; 8: 333-339PubMed Google Scholar). In none of these patients, however, was the IgG4 response pathogenic as it is in FS. Stanley and colleagues (Eyre and Stanley, 1988Eyre R.W. Stanley J.R. Identification of pemphigus vulgaris antigen extracted from normal human epidermis and comparison with pemphigus foliaceus antigen.J Clin Invest. 1988; 81: 807-812Crossref PubMed Scopus (187) Google Scholar;Stanley, 1989Stanley J.R. Pemphigus and pemphigoid as paradigms of organ-specific, autoantibody-mediated diseases.J Clin Invest. 1989; 83: 1443-1448Crossref PubMed Scopus (171) Google Scholar) demonstrated by immuno-precipitation techniques that the sera of patients with pemphigus foliaceus (PF) and pemphigus vulgaris (PV) recognize dsg1 and dsg3, respectively. These investigators also showed that FS sera recognize dsg1 (Stanley et al., 1986Stanley J.R. Klaus-Kovtun V. Sampaio S.A.P. Antigenic specificity of fogo selvagem autoantibodies is similar to North American pemphigus foliaceus and distinct from pemphigus vulgaris autoantibodies.J Invest Dermatol. 1986; 87: 197-201Crossref PubMed Scopus (101) Google Scholar). Sequence analysis of dsg1 and dsg3 revealed that both antigens belong to the cadherin family of calcium-dependent cell adhesion molecules (CAMs) (Figure 1) (Goodwin et al., 1990Goodwin L. Hill J.E. Raynor K. Raszi L. Manabe M. Cowin P. Desmoglein shows extensive homology to the cadherin family of cell adhesion molecules.Biochem Biophys Res Commun. 1990; 173: 1224-1230Crossref PubMed Scopus (89) Google Scholar;Koch et al., 1990Koch P.J. Walsh M.J. Schmelz M. Goldschmidt M.D. Zimbelmann R. Franke W.W. Identification of desmoglein, a constitutive desmosomal glycoprotein, as a member of the cadherin family of cell adhesion molecules.Eur J Cell Biol. 1990; 53: 1-12PubMed Google Scholar;Amagai et al., 1991Amagai M. Klaus-Kovtun V. Stanley J. Autoantibodies against a novel epithelial cadherin in pemphigus vulgaris, a disease of cell adhesion.Cell. 1991; 67: 869Abstract Full Text PDF PubMed Scopus (828) Google Scholar;Wheeler et al., 1991Wheeler G.N. Parker A.E. Thomas C.L. et al.Desmosomal glycoprotein DGI, a component of intracellular desmosome junctions, is related to the cadherin family of cell adhesion molecules.Proc Natl Acad Sci USA. 1991; 88: 4796-4800Crossref PubMed Scopus (152) Google Scholar;Buxton et al., 1993Buxton R.S. Cowin P. Franke W.W. et al.Nomenclature of the desmosomal cadherins.J Cell Biol. 1993; 121: 481-483Crossref PubMed Scopus (248) Google Scholar). The desmosomal cadherins share extensive homology with other members of this gene superfamily of CAMs, such as desmocollins, and E-and p-cadherins (Amagai et al., 1991Amagai M. Klaus-Kovtun V. Stanley J. Autoantibodies against a novel epithelial cadherin in pemphigus vulgaris, a disease of cell adhesion.Cell. 1991; 67: 869Abstract Full Text PDF PubMed Scopus (828) Google Scholar;Goodwin et al., 1990Goodwin L. Hill J.E. Raynor K. Raszi L. Manabe M. Cowin P. Desmoglein shows extensive homology to the cadherin family of cell adhesion molecules.Biochem Biophys Res Commun. 1990; 173: 1224-1230Crossref PubMed Scopus (89) Google Scholar;Koch et al., 1990Koch P.J. Walsh M.J. Schmelz M. Goldschmidt M.D. Zimbelmann R. Franke W.W. Identification of desmoglein, a constitutive desmosomal glycoprotein, as a member of the cadherin family of cell adhesion molecules.Eur J Cell Biol. 1990; 53: 1-12PubMed Google Scholar;Wheeler et al., 1991Wheeler G.N. Parker A.E. Thomas C.L. et al.Desmosomal glycoprotein DGI, a component of intracellular desmosome junctions, is related to the cadherin family of cell adhesion molecules.Proc Natl Acad Sci USA. 1991; 88: 4796-4800Crossref PubMed Scopus (152) Google Scholar;Buxton et al., 1993Buxton R.S. Cowin P. Franke W.W. et al.Nomenclature of the desmosomal cadherins.J Cell Biol. 1993; 121: 481-483Crossref PubMed Scopus (248) Google Scholar). As in other members of this family, the extracellular regions of dsg1 and dsg3 are composed of five domains (EC1 to EC5). The first four domains are cadherin homologous repeats that contain six putative calcium-binding sites, and the fifth domain, EC5, is a short membrane-proximal region with no significant sequence homology to the other cadherin repeats. The intracellular do-mains are linked to the keratinocyte cytoskeleton via desmosomal plaque proteins. It is thought that homophilic interactions between ectodomains of desmoglein molecules and the interactions of these molecules with the intracellular cytoskeleton bring about epidermal cell–cell adhesion (Buxton et al., 1993Buxton R.S. Cowin P. Franke W.W. et al.Nomenclature of the desmosomal cadherins.J Cell Biol. 1993; 121: 481-483Crossref PubMed Scopus (248) Google Scholar). Interestingly, ablation of the dsg3 gene is associated with spontaneous erosions of the skin and mucosas and suprabasilar acantholysis as seen in PV lesions (Koch et al., 1997Koch P.J. Mahoney M.G. Ishikawa H. et al.Targeted disruption of the pemphigus vulgaris antigen (desmoglein 3) gene in mice causes loss of keratinocyte cell adhesion with a phenotype similar to pemphigus vulgaris.J Cell Biol. 1997; 137: 1091-1102Crossref PubMed Scopus (363) Google Scholar). These dsg3 knockouts show no anti-dsg3 autoantibodies, however. Amagai and colleagues (Amagai et al., 2000Amagai M. Tsunoda K. Suzuki H. Nishifuji K. Koyasu S. Nishikawa T. Use of autoantigen-knockout mice in developing an active autoimmune disease model for pemphigus.J Clin Invest. 2000; 105: 625-631Crossref PubMed Scopus (216) Google Scholar) used these dsg3 knockouts to study the pathogenesis of PV. They immunized mice with dsg3 and harvested their spleen cells, passively transferring them into SCID mice. The recipient animals developed anti-dsg3 antibodies and skin lesions typical of PV. We have shown that T cells from 13 of 15 patients with FS (Lin et al., 2000Lin M-S. Fu C-L. Aoki V. et al.Development and characterization of desmoglein-1 specific T lymphocytes from patients with endemic pemphigus foliaceus (fogo selvagem).J Clin Invest. 2000; 105: 207-213Crossref PubMed Scopus (64) Google Scholar) recognize epitopes located on the dsg1 ectodomain. The proliferation of T cells from FS patients to dsg1 was antigen specific because they did not respond when incubated with other epidermal antigens, such as BP180. Moreover, T cells from control groups, including patients with BP, lupus, and psoriasis, as well as normal individuals, were unresponsive to dsg1. The response of these T cell clones was blocked by anti-DR antibodies, but not by anti-DQ or anti-DP antibodies, indicating that the dsg1-specific response of FS T cells is restricted to HLA-DR. The FS T cell clones expressed CD3, CD4, CD45RO, and TCR-αβ, but not CD8, CD19, or CD45RA, suggesting that they are CD4 memory T cells. The T cell clones derived from FS patients produce IL-4, IL-5, and IL-6, but not IFN-γ, indicative that they secrete a TH2-like cytokine. The type II cytokines, such as IL-4, might be relevant in modulating the IgG subclass response in these patients. These findings strongly suggest that the ectodomain of these molecules is the target for both pathogenic autoantibodies and regulatory T cells. The epitopes recognized by FS autoantibodies and autoimmune T cells on dsg1 are the subject of intense investigation in different laboratories around the world. We have described two settlements of Amerindian natives in Brazil that exhibit a high prevalence of FS: a Xavante Reservation located in the eastern region of the state of Mato Grosso (Friedman et al., 1995Friedman H. Campbell I. Rocha-Alvarez R. et al.Endemic pemphigus foliaceus (fogo selvagem) in Native Americans from Brazil.J Am Acad Dermatol. 1995; 32: 949-956Abstract Full Text PDF PubMed Scopus (42) Google Scholar) and the Terena Reservation of Limao Verde (Hans-Filho et al., 1996Hans-Filho G. dos Santos V. Katayama J.H. et al.An active focus of high prevalence of fogo selvagem on an Amerindian reservation in Brazil.J Invest Dermatol. 1996; 107: 68-75Crossref PubMed Scopus (64) Google Scholar). Since 1994, a clinical and serological surveillance of the Terena population of approximately 1200 individuals settled in Limao Verde has revealed a prevalence of FS of 3.4% and an incidence of one to four new cases per year (Table 1). With a highly specific and sensitive dsg1 ELISA, the presence of dsg1-specific autoantibodies was investigated, in the sera of FS patients and controls (Warren et al., 2000Warren S.J.P. Lin M.S. Giudice G.J. et al.The prevalence of antibodies against desmoglein 1 in endemic pemphigus foliaceus in Brazil.N Engl J Med. 2000; 343: 23-30Crossref PubMed Scopus (128) Google Scholar). Included in this investigation was a large group of normal donors from the USA, England, Japan. and Brazil. Also, the control sera from Brazil included samples from donors living in cities located at different distances from the Limao Verde reservation. As expected, FS patients from Limao Verde exhibited a positive dsg1 ELISA test. Anti-dsg1 autoantibodies were absent in control normal human sera from U.S., English, and Japanese donors (including 46 sera from U.S. Choctaw Indians) and from patients with other cutaneous autoimmune blistering diseases, such as bullous pemphigoid, herpes gestationis, and lupus erythematosus. Intriguingly, anti-dsg1 autoantibodies were detected not only in FS sera but also in sera of normal controls from the Limao Verde reservation (55% of 93 sera tested) and from inhabitants of other Brazilian cities (19% of 279 tested). The percentage of ELISA-positive sera among these normal control populations was inversely related to the distance from the endemic focus of Limao Verde (Figure 2). In five FS cases followed in Limao Verde for several years, anti-dsg1 autoantibodies were present in blood samples obtained one to five years prior to the onset of the disease. In this interesting subset, the titers of anti-dsg1 antibodies increased several fold once the disease was clinically apparent.Table IThe frequency of new FS cases on the Limao Verde Reservation (1994–2002). The population of this settlement has been relatively stable (∼1,200 individuals). Twenty-two FS cases were documented before 1994 (Hans-Filho et al., 1996Hans-Filho G. dos Santos V. Katayama J.H. et al.An active focus of high prevalence of fogo selvagem on an Amerindian reservation in Brazil.J Invest Dermatol. 1996; 107: 68-75Crossref PubMed Scopus (64) Google ScholarYears of Surveillance199419951996199719981999200020012002Number of cases411221154 Open table in a new tab As seen in Table 1, the number of new FS cases in Limao Verde in recent years is high, indicating that this focus of disease remains active. These results suggest that certain members of the Limao Verde population become sensitized to an environmental antigen(s) producing anti-dsg1 autoantibodies that, in the course of several years, can lead to FS. Moreover, the risk of exposure to the putative environmental antigen(s) appears to be higher in Limao Verde than in other Brazilian populations distant from this region. It can therefore be speculated that (1) the environmental antigen(s) is unique and present in optimal amounts in Limao Verde; (2) the Terena population is highly susceptible to FS because of the inbreeding that is common in this settlement; or (c) both environment and genetic predisposition is relevant. Although the molecular mechanisms of anti-dsg1 formation and the putative environmental antigen(s) in FS remain unknown, it is likely that epidermal dsg1 and the environmental antigen(s) share certain cross-reactive epitopes that are involved in FS pathogenesis. We extended our sero-epidemiological studies of the Terena people of Limao Verde (Warren et al., 2000Warren S.J.P. Lin M.S. Giudice G.J. et al.The prevalence of antibodies against desmoglein 1 in endemic pemphigus foliaceus in Brazil.N Engl J Med. 2000; 343: 23-30Crossref PubMed Scopus (128) Google Scholar) by adapting the dsg1 ELISA to measure the subclasses of IgG anti-dsg1 autoantibodies present in FS patients and controls (Warren et al., 2003Warren S.J.P. Arteaga L.A. Rivitti E.A. et al.The role of subclass switching in the pathogenesis of endemic pemphigus foliaceus.J Invest Dermatol. 2003; 120: 104-108Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar). We found that normal subjects living in the endemic area possess low levels of IgG1 and IgG4 anti-dsg1 autoantibodies, whereas FS patients have similar levels of IgG1 but a mean 19.3-fold higher IgG4 response. Additionally, FS patients in remission show weak IgG4 anti-dsg1 autoantibody titers, and a 74.3-fold higher IgG4 response is associated with active disease. Finally, in five patients from whom we had blood samples both before and after the onset of clinical disease, a mean 103-fold rise in IgG4 was associated with disease onset, but only a mean 3.45 rise in IgG1. These results suggest that the early antibody response in normal subjects living in Limao Verde and in patients before the onset of clinical disease is mainly IgG1. Acquisition of an IgG4 response is a key step in disease development. These results support the notion that progression from a preclinical to a clinical phase of the disease, as well as the transition from disease in remission to active disease, is closely associated with subclass switching from IgG1 to IgG4 (Warren et al., 2003Warren S.J.P. Arteaga L.A. Rivitti E.A. et al.The role of subclass switching in the pathogenesis of endemic pemphigus foliaceus.J Invest Dermatol. 2003; 120: 104-108Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar). Ongoing studies in our laboratory indicate that IgG1 subclass anti-dsg1 autoantibodies from a normal subject from Limao Verde (exhibiting a single IgG1 anti-dsg1 response) are incapable of inducing disease in neonatal mice in passive transfer experiments when injected with amounts as high as 15 mg/g body weight. In contrast, mice injected with IgG4 anti-dsg1 autoantibodies from an FS patient at the dose of 1.5 mg/g body weight develop extensive skin disease. Finally, the results of our study of IgG subclasses of anti-dsg1 autoantibodies make it possible to identify a subgroup of normal subjects—namely, those with an increased level of IgG4 anti-dsg1 autoantibodies—who may be at a higher risk of developing clinical disease. Additionally, the level of IgG4 anti-dsg1 autoantibodies, as measured by IgG-subclass ELISA, may be one of the most sensitive indicators of clinical activity in patients with FS. The epitopes recognized by PF sera on dsg1 are conformation sensitive (Kowalczyk et al., 1995Kowalczyk A.P. Anderson J.E. Borgwardt T. Hashimoto S J.R. Green K.J. Pemphigus sera recognize conformationally sensitive epitopes in the amino-terminal region of desmoglein-1.J Invest Dermatol. 1995; 105: 147-152Crossref PubMed Scopus (75) Google Scholar) and calcium dependent (Eyre and Stanley, 1987Eyre R.W. Stanley J.R. Human autoantibodies against a desmosomal protein complex with a calcium-sensitive epitope are characteristic of pemphigus foliaceus patients.J Exp Med. 1987; 165: 1719-1724Crossref PubMed Scopus (126) Google Scholar;Labib et al., 1991Labib R.S. Rock B. Robledo M.A. Anhalt G.J. The calcium-sensitive epitope of pemphigus foliaceus antigen is present on a murine tryptic fragment and constitutes a major antigenic region for human autoantibodies.J Invest Dermatol. 1991; 96: 144-147Abstract Full Text PDF PubMed Google Scholar). Additionally, pathogenic anti-dsg1 autoantibodies target the ectodomain of dsg1 (Amagai et al., 1995Amagai M. Hashimoto T. Green K.J. Shimizu N. Nishikawa N. Antigen-specific immunoadsorption of pathogenic autoantibodies in pemphigus foliaceus.J Invest Dermatol. 1995; 104: 895-901Crossref PubMed Scopus (225) Google Scholar;Emery et al., 1995Emery D.J. Diaz L.A. Fairley J.A. Lopez A. Taylor A. Giudice G.J. Pemphigus foliaceus and pemphigus vulgaris autoantibodies react with the extracellular domain of desmoglein-1.J Invest Dermatol. 1995; 104: 323-328Crossref PubMed Scopus" @default.
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• W2091510188 date "2004-01-01" @default.
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• W2091510188 title "Environmental Risk Factors in Endemic Pemphigus Foliaceus (Fogo Selvagem)" @default.
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