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Luis A Diaz - One of the best experts on this subject based on the ideXlab platform.

  • a lutzomyia longipalpis salivary protein induces cross reactive antibodies to pemphigus autoantigen desmoglein 1
    Journal of Investigative Dermatology, 2020
    Co-Authors: Luis A Diaz, Valeria Aoki, Gunter Hansfilho, Evandro A. Rivitti, Horacio Friedman, Phillip Prisayanh, Bahjat F. Qaqish, Brenda Temple, Morgan Karetnick, Samantha M Herbert
    Abstract:

    Fogo Selvagem (FS) is a blistering skin disease caused by pathogenic IgG4 autoantibodies to desmoglein 1 (DSG1). Preclinical FS and leishmaniasis are endemic to certain regions of Brazil and exhibit nonpathogenic anti-DSG1 antibodies. Recurring bites from Lutzomyia longipalpis, the sand fly vector of leishmaniasis, immunize individuals with L. longipalpis salivary antigens LJM17 and LJM11. We measured the antibody responses to LJM17, LJM11, and DSG1 in normal settlers and patients with FS from an endemic focus of FS and nonendemic control populations. We also immunized mice with these antigens and assessed the IgG response. Healthy individuals and patients with FS from endemic areas had significantly higher values of IgG4 anti-LJM17 antibodies than nonendemic controls (P

  • Divergent Specificity Development of IgG1 and IgG4 Autoantibodies in Endemic Pemphigus Foliaceus (Fogo Selvagem).
    ImmunoHorizons, 2017
    Co-Authors: Mike Maldonado, Luis A Diaz, Valeria Aoki, Gunter Hans-filho, Evandro A. Rivitti, Donna A. Culton, Phillip Prisayanh, Bahjat F. Qaqish, Jinsheng Yang, Ye Qian
    Abstract:

    We have shown that although the IgG response in Fogo Selvagem (FS) is mainly restricted to desmoglein (Dsg) 1, other keratinocyte cadherins are also targeted by FS patients and healthy control subjects living in the endemic region of Limao Verde, Brazil (endemic controls). Evaluating nonpathogenic IgG1 and pathogenic IgG4 subclass responses to desmosomal proteins may reveal important differences between pathogenic and nonpathogenic responses, and how these differences relate to the pathogenic IgG4 response and resultant FS. In this study, we tested by ELISA >100 sera from each FS patient, endemic control, and nonendemic control for IgG1 and IgG4 autoantibodies to keratinocyte cadherins besides Dsg1. IgG1 and IgG4 subclass responses in endemic controls are highly correlated between Dsg1 and other keratinocyte cadherins. This correlation persists in the IgG1 response among FS patients, but diminishes in IgG4 response, suggesting that IgG1 binds highly conserved linear epitopes among cadherins, whereas IgG4 binds mainly specific conformational epitopes on Dsg1. A confirmatory test comparing serum samples of 11 individuals before and after their FS onset substantiated our findings that IgG1 recognizes primarily linear epitopes on Dsg1 both before and after disease onset, whereas IgG4 recognizes primarily linear epitopes before disease onset, but recognizes more conformational epitopes on Dsg1 after the onset of disease. This study may provide a mechanism by which a specificity convergence of the IgG4 response to unique Dsg1 epitopes, most likely conformational pathogenic epitopes, leads to the onset of FS disease.

  • IgG Autoantibody Response Against Keratinocyte Cadherins in Endemic Pemphigus Foliaceus (Fogo Selvagem)
    2016
    Co-Authors: Gustavo Flores, Valeria Aoki, Gunter Hans-filho, Donna A. Culton, Phillip Prisayanh, Bahjat F. Qaqish, Mike Maldonado, Kirk James, Ro A. Rivitti, Luis A Diaz
    Abstract:

    It is well established that autoantibodies against desmoglein 3 and desmoglein 1 are relevant in the pathogenesis of pemphigus vulgaris and pemphigus foliaceus, including its endemic form, Fogo Selvagem (FS). Isolated reports have shown that in certain patients with these diseases, autoantibodies against other desmosomal cadherins and E-cadherin may also be present. The goal of this investigation was to determine if FS patients and normal individuals living in endemic areas possess autoantibodies against other desmosomal cadherins and E-cadherin. Testing a large number of FS and endemic control sera by ELISA we find a consistent and specific autoantibody response against desmoglein 1 and other keratinocyte cadherins in these individuals, which is quite different from US controls. Overall, the highest correlations among the autoantibody responses tested are in the endemic controls, followed by FS patients, and lowest in the US controls. These findings suggest that multiple, perhaps cross reactive, keratinocyte cadherins are recognized by FS patients and endemic controls

  • Update on Fogo Selvagem, an endemic form of pemphigus foliaceus
    The Journal of dermatology, 2015
    Co-Authors: Valeria Aoki, Evandro A. Rivitti, Luis A Diaz
    Abstract:

    Pemphigus are organ-specific autoimmune diseases, where autoantibodies (mainly immunoglobulin [Ig]G) directed against epidermal targets (glycoproteins of the desmosomal core) are detected. Endemic pemphigus foliaceus or Fogo Selvagem (FS) is one of the variants of pemphigus foliaceus pemphigus foliaceus that shares the same clinical and immunopathological features of the classic non-endemic pemphigus foliaceus form, including pathogenic IgG (mainly IgG4) autoantibodies directed against the ectodomain of desmoglein 1 (Dsg1), that lead to acantholysis. Pathogenesis of FS is complex, involving genetic, environmental and immunological factors. Human leukocyte antigen (HLA)-DRB1 alleles DRB1*0404, *1402, *1406 or *0102 have been previously identified as risk factors for FS (relative risk, >14). Individuals exposed to hematophagous insects are more susceptible to develop the disease. Non-pathogenic anti-Dsg1 antibodies of the IgG1 subclass, directed against the extracellular 5 domain of Dsg1, are detected in patients in the preclinical stage of the disease, and also in healthy controls living in endemic areas. In counterpart, patients with FS show pathogenic anti-Dsg1 IgG4 autoantibodies that bind the pathogenic extracellular 1 and 2 domains of Dsg1, emphasizing the intramolecular epitope-spreading hypothesis. A possible explanation for the development of the autoimmune process would be antigenic mimicry, initiated by environmental stimuli in those genetically predisposed individuals. Characterization of the pathogenesis of FS will allow the development of specific therapeutic targets, and the elucidation of other autoimmune processes.

  • IgE anti-LJM11 sand fly salivary antigen may herald the onset of Fogo Selvagem in endemic Brazilian regions. J Invest Dermatol 135: 913–915. doi: 10.1038/jid.2014.430 PMID: 25285921
    2015
    Co-Authors: Ye Qian, Luis A Diaz, Jesus G Valenzuela, Valeria Aoki, Ro A. Rivitti, Gunter Hans-filhio, Joseph S. Jeong, Maha Abdeladhim, The Cooperative Group On Fogo
    Abstract:

    Fogo Selvagem (FS) is an endemic form of pemphigus foliaceus (PF) which is prevalent in certain regions of Brazil (Diaz et al., 1989). Genetic and environmental factors such as insect bites may contribute to the development of FS (Aoki et al., 2004; Diaz et al., 1989; Moraes et al., 1997). Blister formation in FS is mediated by predominantly IgG4 anti-desmoglein 1 (Dsg1) antibodies (Rock et al., 1989), which are predictors of FS (Qaqish et al., 2009). Our recent studies demonstrate that FS IgG4 antibodies cross-react with LJM11, a salivary protein from sand fly Lutzomyia longipalpis (Qian et al., 2012), suggesting that sand fly bites may deliver the antigen(s) that play a role in driving the development of these IgG4 autoantibodies in FS. The concomitant development of IgE and IgG4 has been well documented in allergy (Lichtenstein et al., 1968; Muller, 2005). In addition, insect bites are known to induce IgE responses. IgE response in PV and FS has been described by Nagel et al (Nagel et al., 2009) and us (Qian et al., 2012; Qian et al., 2011). We have demonstrated that FS patients have significantly higher IgG4 and IgE against sand fly salivary gland antigens (SGLL) and monoclonal IgG4 autoantibodies derived from FS patients cross-react with LJM11, a majo

Evandro A. Rivitti - One of the best experts on this subject based on the ideXlab platform.

  • a lutzomyia longipalpis salivary protein induces cross reactive antibodies to pemphigus autoantigen desmoglein 1
    Journal of Investigative Dermatology, 2020
    Co-Authors: Luis A Diaz, Valeria Aoki, Gunter Hansfilho, Evandro A. Rivitti, Horacio Friedman, Phillip Prisayanh, Bahjat F. Qaqish, Brenda Temple, Morgan Karetnick, Samantha M Herbert
    Abstract:

    Fogo Selvagem (FS) is a blistering skin disease caused by pathogenic IgG4 autoantibodies to desmoglein 1 (DSG1). Preclinical FS and leishmaniasis are endemic to certain regions of Brazil and exhibit nonpathogenic anti-DSG1 antibodies. Recurring bites from Lutzomyia longipalpis, the sand fly vector of leishmaniasis, immunize individuals with L. longipalpis salivary antigens LJM17 and LJM11. We measured the antibody responses to LJM17, LJM11, and DSG1 in normal settlers and patients with FS from an endemic focus of FS and nonendemic control populations. We also immunized mice with these antigens and assessed the IgG response. Healthy individuals and patients with FS from endemic areas had significantly higher values of IgG4 anti-LJM17 antibodies than nonendemic controls (P

  • Divergent Specificity Development of IgG1 and IgG4 Autoantibodies in Endemic Pemphigus Foliaceus (Fogo Selvagem).
    ImmunoHorizons, 2017
    Co-Authors: Mike Maldonado, Luis A Diaz, Valeria Aoki, Gunter Hans-filho, Evandro A. Rivitti, Donna A. Culton, Phillip Prisayanh, Bahjat F. Qaqish, Jinsheng Yang, Ye Qian
    Abstract:

    We have shown that although the IgG response in Fogo Selvagem (FS) is mainly restricted to desmoglein (Dsg) 1, other keratinocyte cadherins are also targeted by FS patients and healthy control subjects living in the endemic region of Limao Verde, Brazil (endemic controls). Evaluating nonpathogenic IgG1 and pathogenic IgG4 subclass responses to desmosomal proteins may reveal important differences between pathogenic and nonpathogenic responses, and how these differences relate to the pathogenic IgG4 response and resultant FS. In this study, we tested by ELISA >100 sera from each FS patient, endemic control, and nonendemic control for IgG1 and IgG4 autoantibodies to keratinocyte cadherins besides Dsg1. IgG1 and IgG4 subclass responses in endemic controls are highly correlated between Dsg1 and other keratinocyte cadherins. This correlation persists in the IgG1 response among FS patients, but diminishes in IgG4 response, suggesting that IgG1 binds highly conserved linear epitopes among cadherins, whereas IgG4 binds mainly specific conformational epitopes on Dsg1. A confirmatory test comparing serum samples of 11 individuals before and after their FS onset substantiated our findings that IgG1 recognizes primarily linear epitopes on Dsg1 both before and after disease onset, whereas IgG4 recognizes primarily linear epitopes before disease onset, but recognizes more conformational epitopes on Dsg1 after the onset of disease. This study may provide a mechanism by which a specificity convergence of the IgG4 response to unique Dsg1 epitopes, most likely conformational pathogenic epitopes, leads to the onset of FS disease.

  • Update on Fogo Selvagem, an endemic form of pemphigus foliaceus
    The Journal of dermatology, 2015
    Co-Authors: Valeria Aoki, Evandro A. Rivitti, Luis A Diaz
    Abstract:

    Pemphigus are organ-specific autoimmune diseases, where autoantibodies (mainly immunoglobulin [Ig]G) directed against epidermal targets (glycoproteins of the desmosomal core) are detected. Endemic pemphigus foliaceus or Fogo Selvagem (FS) is one of the variants of pemphigus foliaceus pemphigus foliaceus that shares the same clinical and immunopathological features of the classic non-endemic pemphigus foliaceus form, including pathogenic IgG (mainly IgG4) autoantibodies directed against the ectodomain of desmoglein 1 (Dsg1), that lead to acantholysis. Pathogenesis of FS is complex, involving genetic, environmental and immunological factors. Human leukocyte antigen (HLA)-DRB1 alleles DRB1*0404, *1402, *1406 or *0102 have been previously identified as risk factors for FS (relative risk, >14). Individuals exposed to hematophagous insects are more susceptible to develop the disease. Non-pathogenic anti-Dsg1 antibodies of the IgG1 subclass, directed against the extracellular 5 domain of Dsg1, are detected in patients in the preclinical stage of the disease, and also in healthy controls living in endemic areas. In counterpart, patients with FS show pathogenic anti-Dsg1 IgG4 autoantibodies that bind the pathogenic extracellular 1 and 2 domains of Dsg1, emphasizing the intramolecular epitope-spreading hypothesis. A possible explanation for the development of the autoimmune process would be antigenic mimicry, initiated by environmental stimuli in those genetically predisposed individuals. Characterization of the pathogenesis of FS will allow the development of specific therapeutic targets, and the elucidation of other autoimmune processes.

  • IgE Anti-LJM11 Sand Fly Salivary Antigen May Herald the Onset of Fogo Selvagem in Endemic Brazilian Regions
    The Journal of investigative dermatology, 2014
    Co-Authors: Ye Qian, Jesus G Valenzuela, Valeria Aoki, Evandro A. Rivitti, Gunter Hans-filhio, Joseph S. Jeong, Maha Abdeladhim, Luis A Diaz
    Abstract:

    Fogo Selvagem (FS) is an endemic form of pemphigus foliaceus (PF) which is prevalent in certain regions of Brazil (Diaz et al., 1989). Genetic and environmental factors such as insect bites may contribute to the development of FS (Aoki et al., 2004; Diaz et al., 1989; Moraes et al., 1997). Blister formation in FS is mediated by predominantly IgG4 anti-desmoglein 1 (Dsg1) antibodies (Rock et al., 1989), which are predictors of FS (Qaqish et al., 2009). Our recent studies demonstrate that FS IgG4 antibodies cross-react with LJM11, a salivary protein from sand fly Lutzomyia longipalpis (Qian et al., 2012), suggesting that sand fly bites may deliver the antigen(s) that play a role in driving the development of these IgG4 autoantibodies in FS. The concomitant development of IgE and IgG4 has been well documented in allergy (Lichtenstein et al., 1968; Muller, 2005). In addition, insect bites are known to induce IgE responses. IgE response in PV and FS has been described by Nagel et al (Nagel et al., 2009) and us (Qian et al., 2012; Qian et al., 2011). We have demonstrated that FS patients have significantly higher IgG4 and IgE against sand fly salivary gland antigens (SGLL) and monoclonal IgG4 autoantibodies derived from FS patients cross-react with LJM11, a major immunogenic component from SGLL (Qian et al., 2012). In this study, we seek to determine whether IgE antibodies to either autoantigen (Dsg1) and/or environmental antigen (LJM11) are present among individuals living in FS endemic regions. All serum samples from controls and patients in this investigation were obtained from individuals studied during the last 25 years and kept in a bank of sera at the University of North Carolina Dermatology Research Laboratories. These studies are approved by the institutional review boards from the University of North Carolina, Chapel Hill, and the University of Sao Paulo, Sao Paulo, Brazil. Randomly selected serum samples (n=30) from FS patients, as well as serum samples of normal control individuals (HC) from FS endemic region (n=32), Limao Verde in Brazil (HC-LV) and non-FS endemic region, United States (n=32) (HC-US) were tested by ELISA for their reactivity with Dsg1, LJM11, and LJL143 which is another major component of SGLL. As expected, FS patients have significantly higher level of IgG4 anti-Dsg1 autoantibodies compared to HC-LV and HC-US (Fig 1a, left panel). Similarly, FS patients also have significantly higher IgG4 anti-LJM11 antibodies than HC-LV and HC-US groups (Fig 1a, middle panel). There is no significant difference between the levels of anti-LJL143 IgG4 antibodies in the sera of FS patients and the two control groups (Fig 1a, right panel), suggesting that LJM11 is the main component from SGLL recognized by IgG4 antibodies from FS patients. Because of the close association of the IgE and IgG4 development and our previous finding that FS patients have significant levels of IgE and IgG4 anti-SGLL (Qian et al., 2012), it is expected that FS patients may also have higher IgE anti-Dsg1 and anti-LJM11 compared to HC-LV and HC-US. As shown in Fig 1b, FS patients have significantly higher IgE anti-Dsg1 (Fig 1b, left panel) as we previously reported (Qian et al., 2012; Qian et al., 2011), and also have significantly higher level of IgE anti-LJM11 antibodies (Fig 1b, middle panel) than both HC-LV and HC-US. Importantly, HC-LV sera have higher levels of IgE anti-LJM11 antibodies than those from HC-US (Fig 1b, middle panel). The anti-LJL143 IgE levels are overall generally much lower (about 10 times lower) in FS, HC-LV and HC-US groups as compared to anti-LJM11 IgE levels in the same group (Fig 1b, middle and right panel). These findings suggest that the FS endemic area of LV where the sera of FS and HC-LV originated from, and where bites by Lutzomya longipalpis are prevalent, may harbor environmental factors that direct the development of these antibodies in FS endemic regions. Figure 1 FS patients have significantly higher IgG4 (A) and IgE (B) anti-Dsg1 and anti-LJM11 antibodies than normal control individual from FS and non-FS endemic regions Our findings that LV inhabitants and FS patients show significant levels of IgE anti-LJM11 antibodies suggest that FS patients during the pre-clinical stage of the disease (pre-FS) may also exhibit elevated levels of these IgE antibodies. It is known that pre-FS would eventually develop pathogenic IgG4 autoantibodies and clinical FS (post-FS) (Qaqish et al., 2009), and IgG4 antibody development lags behind the IgE response. Hence, individuals at risk to develop FS may develop IgE and IgG4 responses when exposed to LJM11 during the repeated bites of sand flies. To test this hypothesis, 12 FS patients whose serum samples were collected prior to the onset of clinical FS (1 to 4 years) and after their onset of FS were studied for anti-Dsg1 and anti-LJM11 IgE activity. The HC-LV and HC-US were also included as controls. As shown in Fig 2a (left panel), pre-FS and post-FS individuals exhibit higher levels of IgE anti-Dsg1 than the control groups. The right panel of Fig 2a shows that these pre-FS and post-FS individuals also have significantly higher levels of IgE anti-LJM11 as compared with HC-LV and HC-US. These results suggest that the IgE antibodies against Dsg1 and LJM11 develop before the onset of FS among susceptible individuals from this endemic area. In addition, similar to IgG4 antibodies in FS, IgE anti-LJM11 and anti-Dsg1 antibodies from both pre-FS and post-FS are also cross-reactive, as their IgE binding to LJM11 can be inhibited by Dsg1 autoantigen (Fig 2b). Notably, pre-FS individuals have significantly lower levels of IgE anti-Dsg1 than that from post-FS patients (Fig 2a, left panel), suggesting that anti-LJM11 IgE develops prior to that of IgE autoantibodies. Figure 2 IgE antibodies among Individuals before or after their onset of FS Considering that IgG4 and IgE antibody responses to allergens are closely linked, it is likely that the generation of IgE anti-LJM11, introduced by sand fly bites, result in the development of IgE and IgG4 to this antigen that cross-reacts with Dsg1 and subsequently lead to clinical FS. The definitive evolution and association of IgG4 and IgE antibody responses in FS requires further analysis of the CDR3 sequences of these two classes of antibody populations. Our current findings suggest that LJM11 might be the initial target of the IgE response in FS susceptible individuals, hence those individuals with higher levels of anti-LJM11 IgE may have a higher risk to develop FS. It may provide a basis for the possible employment of IgE as an early predictor of FS.

  • analysis of anti desmoglein 1 autoantibodies in 68 healthy mother neonate pairs from a highly endemic region of Fogo Selvagem in brazil
    Journal of clinical & experimental dermatology research, 2014
    Co-Authors: Julio Hilariovargas, Valeria Aoki, Vandir Dos Santos, Evandro A. Rivitti, Donna A. Culton, Phillip Prisayanh, Irineu B Vitorio, Christopher Stamey, Gunter Hans Filho, Bahjat F. Qaqish
    Abstract:

    Objectives: Fogo Selvagem (FS) in Limao Verde (LV), Brazil shows clinical and histological features of pemphigus foliaceus (PF) and shares pathogenic IgG4 anti-desmoglein 1 (Dsg1) autoantibodies. Previously, our group reported that mothers with active FS deliver babies with normal skin and low/negative titers of IgG4 autoantibodies by indirect immunofluorescence. It was postulated that maternal pathogenic IgG4 autoantibodies do not cross the placenta due to differential receptor mediated transplacental passage of IgG subclasses. It was also thought that placental Dsg1 may immunoadsorb pathogenic autoantibodies from the mother; hence pathogenic IgG4 autoantibodies do not reach the baby. In this study we use a Dsg1-specific ELISA to test anti-Dsg1 autoantibodies of the IgM, IgG and the IgG subclasses in the sera of 68 pairs of normal mothers and their neonates living in a highly endemic area of FS. Determination of these baseline anti-Dsg1 autoantibodies will allow us to follow and predict in this and other cohorts the appearance of preclinical serological markers of FS. Methods: The sera of mothers and neonates living in the endemic region were tested by ELISA for IgM, IgG and IgG subclasses using recombinant Dsg1 and anti-IgG subclass-specific monoclonal antibodies. Results: The index values of anti-Dsg1 IgG1, IgG2 and IgG3 are similar in mothers and neonates (all p>0.18), while the index values of IgM, total IgG and IgG4 are higher in mothers (all p<0.001). Conclusions: Narrowing the IgM, IgG and IgG subclasses of mothers and neonates to autoantibodies against Dsg1, we found, as expected, that IgM remains only in maternal circulation. In three mothers and two neonates we detected IgG4 anti-Dsg1 autoantibodies above the normal range. The remaining IgG subclasses show low values. The results of the neonatal sera will serve as a baseline for ongoing seroepidemiological studies of children and adults in the endemic regions of FS.

Valeria Aoki - One of the best experts on this subject based on the ideXlab platform.

  • a lutzomyia longipalpis salivary protein induces cross reactive antibodies to pemphigus autoantigen desmoglein 1
    Journal of Investigative Dermatology, 2020
    Co-Authors: Luis A Diaz, Valeria Aoki, Gunter Hansfilho, Evandro A. Rivitti, Horacio Friedman, Phillip Prisayanh, Bahjat F. Qaqish, Brenda Temple, Morgan Karetnick, Samantha M Herbert
    Abstract:

    Fogo Selvagem (FS) is a blistering skin disease caused by pathogenic IgG4 autoantibodies to desmoglein 1 (DSG1). Preclinical FS and leishmaniasis are endemic to certain regions of Brazil and exhibit nonpathogenic anti-DSG1 antibodies. Recurring bites from Lutzomyia longipalpis, the sand fly vector of leishmaniasis, immunize individuals with L. longipalpis salivary antigens LJM17 and LJM11. We measured the antibody responses to LJM17, LJM11, and DSG1 in normal settlers and patients with FS from an endemic focus of FS and nonendemic control populations. We also immunized mice with these antigens and assessed the IgG response. Healthy individuals and patients with FS from endemic areas had significantly higher values of IgG4 anti-LJM17 antibodies than nonendemic controls (P

  • Fogo Selvagem: endemic pemphigus foliaceus.
    Anais brasileiros de dermatologia, 2018
    Co-Authors: Gunter Hans-filho, Valeria Aoki, Nelise Ritter Hans Bittner, Guilherme Canho Bittner
    Abstract:

    Fogo Selvagem or endemic pemphigus foliaceus is an autoimmune acantholytic anti-cadherin bullous disease that primarily affects seborrheic areas, which might disseminate. Brazil has the world's largest number of patients, mainly in the Central-West region, but the disease has also been reported in other South American countries. It affects young people and adults who have been exposed to rural areas, with occurrence of familial cases. Anti-desmoglein-1 autoantibodies are directed against desmosomal structures, with loss of adhesion of the upper layers of the epidermis, causing superficial blisters. The etiology is multifactorial and includes genetic, immune, and environmental factors, highlighting hematophagous insect bites; drug-related factors are occasionally involved. Flaccid blisters readily rupture to yield erosive-crusty lesions that sometimes resemble seborrheic dermatitis, actinic keratosis, and chronic cutaneous lupus erythematosus. The clinical presentation varies from localized to disseminated lesions. Clinical suspicion should be confirmed with histopathological and immunofluorescence tests, among others. The progression is usually chronic, and therapy varies according to clinical presentation, but generally requires systemic corticosteroid therapy associated with adjuvant immunosuppressive treatment to decrease the adverse effects of corticosteroids. Once the disease is under control, many patients remain stable on low-dose medication, and a significant proportion achieve remission.

  • Divergent Specificity Development of IgG1 and IgG4 Autoantibodies in Endemic Pemphigus Foliaceus (Fogo Selvagem).
    ImmunoHorizons, 2017
    Co-Authors: Mike Maldonado, Luis A Diaz, Valeria Aoki, Gunter Hans-filho, Evandro A. Rivitti, Donna A. Culton, Phillip Prisayanh, Bahjat F. Qaqish, Jinsheng Yang, Ye Qian
    Abstract:

    We have shown that although the IgG response in Fogo Selvagem (FS) is mainly restricted to desmoglein (Dsg) 1, other keratinocyte cadherins are also targeted by FS patients and healthy control subjects living in the endemic region of Limao Verde, Brazil (endemic controls). Evaluating nonpathogenic IgG1 and pathogenic IgG4 subclass responses to desmosomal proteins may reveal important differences between pathogenic and nonpathogenic responses, and how these differences relate to the pathogenic IgG4 response and resultant FS. In this study, we tested by ELISA >100 sera from each FS patient, endemic control, and nonendemic control for IgG1 and IgG4 autoantibodies to keratinocyte cadherins besides Dsg1. IgG1 and IgG4 subclass responses in endemic controls are highly correlated between Dsg1 and other keratinocyte cadherins. This correlation persists in the IgG1 response among FS patients, but diminishes in IgG4 response, suggesting that IgG1 binds highly conserved linear epitopes among cadherins, whereas IgG4 binds mainly specific conformational epitopes on Dsg1. A confirmatory test comparing serum samples of 11 individuals before and after their FS onset substantiated our findings that IgG1 recognizes primarily linear epitopes on Dsg1 both before and after disease onset, whereas IgG4 recognizes primarily linear epitopes before disease onset, but recognizes more conformational epitopes on Dsg1 after the onset of disease. This study may provide a mechanism by which a specificity convergence of the IgG4 response to unique Dsg1 epitopes, most likely conformational pathogenic epitopes, leads to the onset of FS disease.

  • IgG Autoantibody Response Against Keratinocyte Cadherins in Endemic Pemphigus Foliaceus (Fogo Selvagem)
    2016
    Co-Authors: Gustavo Flores, Valeria Aoki, Gunter Hans-filho, Donna A. Culton, Phillip Prisayanh, Bahjat F. Qaqish, Mike Maldonado, Kirk James, Ro A. Rivitti, Luis A Diaz
    Abstract:

    It is well established that autoantibodies against desmoglein 3 and desmoglein 1 are relevant in the pathogenesis of pemphigus vulgaris and pemphigus foliaceus, including its endemic form, Fogo Selvagem (FS). Isolated reports have shown that in certain patients with these diseases, autoantibodies against other desmosomal cadherins and E-cadherin may also be present. The goal of this investigation was to determine if FS patients and normal individuals living in endemic areas possess autoantibodies against other desmosomal cadherins and E-cadherin. Testing a large number of FS and endemic control sera by ELISA we find a consistent and specific autoantibody response against desmoglein 1 and other keratinocyte cadherins in these individuals, which is quite different from US controls. Overall, the highest correlations among the autoantibody responses tested are in the endemic controls, followed by FS patients, and lowest in the US controls. These findings suggest that multiple, perhaps cross reactive, keratinocyte cadherins are recognized by FS patients and endemic controls

  • Update on Fogo Selvagem, an endemic form of pemphigus foliaceus
    The Journal of dermatology, 2015
    Co-Authors: Valeria Aoki, Evandro A. Rivitti, Luis A Diaz
    Abstract:

    Pemphigus are organ-specific autoimmune diseases, where autoantibodies (mainly immunoglobulin [Ig]G) directed against epidermal targets (glycoproteins of the desmosomal core) are detected. Endemic pemphigus foliaceus or Fogo Selvagem (FS) is one of the variants of pemphigus foliaceus pemphigus foliaceus that shares the same clinical and immunopathological features of the classic non-endemic pemphigus foliaceus form, including pathogenic IgG (mainly IgG4) autoantibodies directed against the ectodomain of desmoglein 1 (Dsg1), that lead to acantholysis. Pathogenesis of FS is complex, involving genetic, environmental and immunological factors. Human leukocyte antigen (HLA)-DRB1 alleles DRB1*0404, *1402, *1406 or *0102 have been previously identified as risk factors for FS (relative risk, >14). Individuals exposed to hematophagous insects are more susceptible to develop the disease. Non-pathogenic anti-Dsg1 antibodies of the IgG1 subclass, directed against the extracellular 5 domain of Dsg1, are detected in patients in the preclinical stage of the disease, and also in healthy controls living in endemic areas. In counterpart, patients with FS show pathogenic anti-Dsg1 IgG4 autoantibodies that bind the pathogenic extracellular 1 and 2 domains of Dsg1, emphasizing the intramolecular epitope-spreading hypothesis. A possible explanation for the development of the autoimmune process would be antigenic mimicry, initiated by environmental stimuli in those genetically predisposed individuals. Characterization of the pathogenesis of FS will allow the development of specific therapeutic targets, and the elucidation of other autoimmune processes.

Gunter Hans-filho - One of the best experts on this subject based on the ideXlab platform.

  • Fogo Selvagem: endemic pemphigus foliaceus.
    Anais brasileiros de dermatologia, 2018
    Co-Authors: Gunter Hans-filho, Valeria Aoki, Nelise Ritter Hans Bittner, Guilherme Canho Bittner
    Abstract:

    Fogo Selvagem or endemic pemphigus foliaceus is an autoimmune acantholytic anti-cadherin bullous disease that primarily affects seborrheic areas, which might disseminate. Brazil has the world's largest number of patients, mainly in the Central-West region, but the disease has also been reported in other South American countries. It affects young people and adults who have been exposed to rural areas, with occurrence of familial cases. Anti-desmoglein-1 autoantibodies are directed against desmosomal structures, with loss of adhesion of the upper layers of the epidermis, causing superficial blisters. The etiology is multifactorial and includes genetic, immune, and environmental factors, highlighting hematophagous insect bites; drug-related factors are occasionally involved. Flaccid blisters readily rupture to yield erosive-crusty lesions that sometimes resemble seborrheic dermatitis, actinic keratosis, and chronic cutaneous lupus erythematosus. The clinical presentation varies from localized to disseminated lesions. Clinical suspicion should be confirmed with histopathological and immunofluorescence tests, among others. The progression is usually chronic, and therapy varies according to clinical presentation, but generally requires systemic corticosteroid therapy associated with adjuvant immunosuppressive treatment to decrease the adverse effects of corticosteroids. Once the disease is under control, many patients remain stable on low-dose medication, and a significant proportion achieve remission.

  • Divergent Specificity Development of IgG1 and IgG4 Autoantibodies in Endemic Pemphigus Foliaceus (Fogo Selvagem).
    ImmunoHorizons, 2017
    Co-Authors: Mike Maldonado, Luis A Diaz, Valeria Aoki, Gunter Hans-filho, Evandro A. Rivitti, Donna A. Culton, Phillip Prisayanh, Bahjat F. Qaqish, Jinsheng Yang, Ye Qian
    Abstract:

    We have shown that although the IgG response in Fogo Selvagem (FS) is mainly restricted to desmoglein (Dsg) 1, other keratinocyte cadherins are also targeted by FS patients and healthy control subjects living in the endemic region of Limao Verde, Brazil (endemic controls). Evaluating nonpathogenic IgG1 and pathogenic IgG4 subclass responses to desmosomal proteins may reveal important differences between pathogenic and nonpathogenic responses, and how these differences relate to the pathogenic IgG4 response and resultant FS. In this study, we tested by ELISA >100 sera from each FS patient, endemic control, and nonendemic control for IgG1 and IgG4 autoantibodies to keratinocyte cadherins besides Dsg1. IgG1 and IgG4 subclass responses in endemic controls are highly correlated between Dsg1 and other keratinocyte cadherins. This correlation persists in the IgG1 response among FS patients, but diminishes in IgG4 response, suggesting that IgG1 binds highly conserved linear epitopes among cadherins, whereas IgG4 binds mainly specific conformational epitopes on Dsg1. A confirmatory test comparing serum samples of 11 individuals before and after their FS onset substantiated our findings that IgG1 recognizes primarily linear epitopes on Dsg1 both before and after disease onset, whereas IgG4 recognizes primarily linear epitopes before disease onset, but recognizes more conformational epitopes on Dsg1 after the onset of disease. This study may provide a mechanism by which a specificity convergence of the IgG4 response to unique Dsg1 epitopes, most likely conformational pathogenic epitopes, leads to the onset of FS disease.

  • IgG Autoantibody Response Against Keratinocyte Cadherins in Endemic Pemphigus Foliaceus (Fogo Selvagem)
    2016
    Co-Authors: Gustavo Flores, Valeria Aoki, Gunter Hans-filho, Donna A. Culton, Phillip Prisayanh, Bahjat F. Qaqish, Mike Maldonado, Kirk James, Ro A. Rivitti, Luis A Diaz
    Abstract:

    It is well established that autoantibodies against desmoglein 3 and desmoglein 1 are relevant in the pathogenesis of pemphigus vulgaris and pemphigus foliaceus, including its endemic form, Fogo Selvagem (FS). Isolated reports have shown that in certain patients with these diseases, autoantibodies against other desmosomal cadherins and E-cadherin may also be present. The goal of this investigation was to determine if FS patients and normal individuals living in endemic areas possess autoantibodies against other desmosomal cadherins and E-cadherin. Testing a large number of FS and endemic control sera by ELISA we find a consistent and specific autoantibody response against desmoglein 1 and other keratinocyte cadherins in these individuals, which is quite different from US controls. Overall, the highest correlations among the autoantibody responses tested are in the endemic controls, followed by FS patients, and lowest in the US controls. These findings suggest that multiple, perhaps cross reactive, keratinocyte cadherins are recognized by FS patients and endemic controls

  • The Role of Intramolecular Epitope Spreading in the Pathogenesis of Endemic Pemphigus Foliaceus (Fogo Selvagem)
    2013
    Co-Authors: Valeria Aoki, Gunter Hans-filho, Ro A. Rivitti, Luis A Diaz
    Abstract:

    We report here a relationship between intramolecular epitope spreading and the clinical onset of the endemic form of pemphigus foliaceus in a Brazilian community with a high prevalence and incidence of the disease. Also known as Fogo Selvagem (FS), this disease is characterized by severe skin blistering and pathogenic anti–desmoglein-1 (Dsg1) autoantibodies. These autoantibodies bind the Dsg1 ectodomain and trigger keratinocyte cell detachment, the hallmark of FS. We show that (a) sera from FS patients in the preclinical stage recognized epitopes on the COOH-terminal EC5 domain of Dsg1, (b) disease onset was associated with the emergence of antibodies specific for epitopes on the NH2-terminal EC1 and EC2 domains, (c) all sera from FS patients with active disease recognized the EC1 and/or EC2 domains, and (d) sera from FS patients in remission showed reactivity restricted to EC5. These results suggest that anti-Dsg1 autoantibodies in FS are initially raised against the COOH-terminal EC5 domain of Dsg1 in individuals without skin disease; in genetically predisposed subjects the autoimmune response may then undergo intramolecular epitope spreading toward epitopes on the NH2-terminal EC1 and EC2 domains of Dsg1 leading to disease onset. Moreover, intramolecular epitope spreading may also modulate remissions and relapses of FS. Key words: autoimmunity • autoantibodies • desmogleins • epitope spreading • pemphigu

  • Profile of Trypanosoma cruzi Reactivity in a Population at High Risk for Endemic Pemphigus Foliaceus (Fogo Selvagem)
    The American journal of tropical medicine and hygiene, 2012
    Co-Authors: Joaquim X. Sousa, Luis A Diaz, Donald P Eaton, Gunter Hans-filho, Lanzani Freitas, Livia Delgado, Ligia Maria F. Ichimura, Flávia Cristaldi, Renata Orlandi, Norival Kesper
    Abstract:

    Fogo Selvagem (FS) is an autoimmune bullous disease with pathogenic IgG autoantibodies recognizing desmoglein 1 (Dsg1), a desmosomal glycoprotein. In certain settlements of Brazil, a high prevalence of FS (3%) is reported, suggesting environmental factors as triggers of the autoimmune response. Healthy individuals from endemic areas recognize nonpathogenic epitopes of Dsg1, and exposure to hematophagous insects is a risk factor for FS. Fogo Selvagem and Chagas disease share some geographic sites, and anti-Dsg1 has been detected in Chagas patients. Indeter- minate Chagas disease was identified in a Brazilian Amerindian population of high risk for FS. In counterpart, none of the FS patients living in the same geographic region showed reactivity against Trypanosoma cruzi. The profile of anti- Dsg1 antibodies showed positive results in 15 of 40 FS sera and in 33 of 150 sera from healthy individuals from endemic FS sites, and no cross-reactivity between Chagas disease and FS was observed.

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  • a lutzomyia longipalpis salivary protein induces cross reactive antibodies to pemphigus autoantigen desmoglein 1
    Journal of Investigative Dermatology, 2020
    Co-Authors: Luis A Diaz, Valeria Aoki, Gunter Hansfilho, Evandro A. Rivitti, Horacio Friedman, Phillip Prisayanh, Bahjat F. Qaqish, Brenda Temple, Morgan Karetnick, Samantha M Herbert
    Abstract:

    Fogo Selvagem (FS) is a blistering skin disease caused by pathogenic IgG4 autoantibodies to desmoglein 1 (DSG1). Preclinical FS and leishmaniasis are endemic to certain regions of Brazil and exhibit nonpathogenic anti-DSG1 antibodies. Recurring bites from Lutzomyia longipalpis, the sand fly vector of leishmaniasis, immunize individuals with L. longipalpis salivary antigens LJM17 and LJM11. We measured the antibody responses to LJM17, LJM11, and DSG1 in normal settlers and patients with FS from an endemic focus of FS and nonendemic control populations. We also immunized mice with these antigens and assessed the IgG response. Healthy individuals and patients with FS from endemic areas had significantly higher values of IgG4 anti-LJM17 antibodies than nonendemic controls (P

  • Endemic pemphigus vulgaris.
    Archives of dermatology, 2007
    Co-Authors: Rosicler Rocha-alvarez, Valeria Aoki, Evandro A. Rivitti, Horacio Friedman, Iphis Campbell, David A. Dasher, Alex G. Ortega-loayza, Luis A Diaz
    Abstract:

    Background Investigators from Brasilia, Brazil, observed several patients with a mucocutaneous disease that resembles pemphigus vulgaris clinically and histologically but with epidemiological features of Fogo Selvagem. Our objective was to characterize antidesmoglein 3 and antidesmoglein 1 autoantibody profiles in these unique patients who reside in Goiânia and Brasilia, Brazil, known endemic regions of Fogo Selvagem. Observations We performed serological evaluation of 8 patients with a mucocutaneous disease clinically and histologically consistent with pemphigus vulgaris, as well as 27 healthy relatives of patients with Fogo Selvagem who reside in these endemic areas. Serum samples from all 8 patients bound desmoglein 3 by cold immunoprecipitation and from 6 patients by enzyme-linked immunosorbent assay, while serum samples from 4 patients bound desmoglein 1 by cold immunoprecipitation and by enzyme-linked immunosorbent assay. Antidesmoglein 3 autoantibodies were detected in 4 of 27 healthy donors by cold immunoprecipitation and by enzyme-linked immunosorbent assay, whereas antidesmoglein 1 autoantibodies were detected in 6 individuals by cold immunoprecipitation and in 3 individuals by enzyme-linked immunosorbent assay. Conclusion These findings provide serological evidence of a new endemic variant of pemphigus vulgaris.

  • The profile of Fogo Selvagem (endemic pemphigus foliaceus) at the University Hospital of Brasilia-Brazil. Epidemiological and clinical considerations.
    International journal of dermatology, 2005
    Co-Authors: Ana Maria Quinteiro Ribeiro, Rosicler Rocha Aiza Alvarez, Horacio Friedman, Iphis Campbell
    Abstract:

    Background  Endemic pemphigus foliaceus (EPF) or Fogo Selvagem (FS) is an endemic autoimmune disease, characterized by flaccid bullae induced by IgG4 subclass antibodies. The authors demonstrate the epidemiological and clinical status of patients who have been followed at the University Hospital of Brasilia (HUB) for more than 15 years. Methods  One hundred and ninety-six patients with FS took part in the project. In setting up this study a historical descriptive cohort of patients was put together. In order to collect data, the authors used a questionnaire where the patient indicated the sex, age at the onset, occupation, origin, clinical status, including scalp compromise, evolution, cofactors influencing clinical worsening and the treatment compliance. In order to minimize loss to follow up, the authors used the statistical method of incidence density (patients/years). Results  The disease occurred in 58.4% of the young patients in the 11–30-year age bracket, and 52% came from urban areas. These patients included students and teachers. Localized disease predominated as compared with the generalized presentation of this condition. Fifty-nine percent of the patients evolved to the recurrent form. Those patients with the evolutional form, in remission for more than 1 year (94%), had been followed for more than 5 years. Even patients with the less active forms of the disease had scalp lesions. Thus scalp lesions are not an indicator of bad prognosis. Conclusions  In the present study, the disease affected patients from a higher sociocultural class than previously described. Furthermore, in contrast to other reports, a substantial number of the patients lived in urban areas, although often spending some time in a rural setting for leisure or professional activities. This study suggests that the longer the follow up, the higher the likelihood that the disease would progress to a more controlled clinical presentation. Scalp lesions were not related to adverse prognosis. Sun, heat and infections act as triggering factors for the immunological imbalance, worsening the disease.

  • Fogo Selvagem penfigo foliaceo endemico no hospital universitario de brasilia aspectos imunologicos
    Anais Brasileiros De Dermatologia, 2002
    Co-Authors: Ana Maria Quinteiro Ribeiro, Rosicler Rocha Aiza Alvarez, Horacio Friedman, Iphis Campbell
    Abstract:

    BACKGROUND - Fogo Selvagem has unique clinical and epidemiological characteristics. The most commonly used diagnostic tests for this disease are histopathology, and direct and indirect immunofluorescence. OBJECTIVES - Analyze the direct (DIF) and indirect (IIF) immunofluorescence findings of patients with Fogo Selvagem (FS) at the University Hospital of Brasilia (HUB). MATERIAL AND METHODS - Results from the histopathology, and DIF and IIF tests were collected from 176 patients diagnosed with FS, at the HUB, from March 1985 to March 1999. The IIF titles were correlated with the number of active cutaneous lesions. RESULTS - The histopathology demonstrated acantholysis in 88% of the exams. Direct IF tests were positive for IgG in 88% of patients and for C3, in 54%. 90 to 95% of the lesion free patients or those with up to 6 lesions had IIF titles of up to 1/160. CONCLUSIONS - IIF was very useful in evaluating not only the activity of the disease, but also in helping to establish a diagnosis. The complement seems to collaborate with triggering the appearance of lesions.

  • Comparison of Black Fly Species (Diptera: Simuliidae) on an Amerindian Reservation with a High Prevalence of Fogo Selvagem to Neighboring Disease-Free Sites in the State of Mato Grosso do Sul, Brazil
    Journal of medical entomology, 1998
    Co-Authors: Donald P Eaton, Luis A Diaz, Valeria Aoki, Vandir Dos Santos, Gunter Hans-filho, Evandro A. Rivitti, Sebastiao A.p. Sampaio, Horacio Friedman, Mark Gottlieb, George J. Giudice
    Abstract:

    Fogo Selvagem is an autoimmune blistering skin disease that principally occurs among rural Brazilians living in geographically clumped disease foci. Exposure to hematophagous black flies possibly is related to the cause of the disease. We compared the occurrence, proportions, and richness of simuliid species immatures and the biting activity of adult females within a recently discovered, high prevalence focus of Fogo Selvagem, the Limao Verde Terena Reservation, to that of neighboring regions with no reported cases of Fogo Selvagem. Nine black fly species were collected from 12 stream sites during 5 trips to the Fogo Selvagem focus. The species showed longitudinal (upstream-downstream) trends in occurrence, proportions, and richness, and the abundance of simuliid immatures was greater at downstream sites. The most prevalent species at the focus, Simulium nigrimanum (Macquart), dominated the stream sites with highly abundant simuliid assemblages, and was the most common black fly in human bait collections. This species was absent or in very low numbers in neighboring valleys and villages that did not have cases of Fogo Selvagem.