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Dive into the research topics where Phillip Prisayanh is active.

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Featured researches published by Phillip Prisayanh.


Journal of Clinical Investigation | 2005

Complete FcRn dependence for intravenous Ig therapy in autoimmune skin blistering diseases.

Ning Li; Minglang Zhao; Julio Hilario-Vargas; Phillip Prisayanh; Simon Warren; Luis A. Diaz; Derry C. Roopenian; Zhi Liu

Numerous mechanisms of action have been proposed for intravenous Ig (IVIG). In this study, we used IgG passive transfer murine models of bullous pemphigoid (BP), pemphigus foliaceus (PF), and pemphigus vulgaris (PV) to test the hypothesis that the effect of IVIG in autoantibody-mediated cutaneous bullous diseases is to accelerate the degradation of pathogenic IgG by saturation of the MHC-like Fc receptor neonatal Fc receptor (FcRn). BP, PF, and PV are organ-specific antibody-mediated diseases in which autoantibodies target the hemidesmosomal antigen BP180 and desmosomal antigens Dsg1 and Dsg3, respectively. Antibodies against BP180, Dsg1, and Dsg3, when injected into neonatal mice, induce the BP, PF, and PV disease phenotypes, respectively. We found that FcRn-deficient mice were resistant to experimental BP, PF, and PV. Circulating levels of pathogenic IgG in FcRn-deficient mice were significantly reduced compared with those in WT mice. Administration of high-dose human IgG (HDIG) to WT mice also drastically reduced circulating pathogenic IgG levels and prevented blistering. In FcRn-deficient mice, no additional protective effect with HDIG was realized. These data demonstrate that the therapeutic efficacy of HDIG treatment in the pemphigus and pemphigoid models is dependent on FcRn. Thus, FcRn is a promising therapeutic target for treating such IgG-mediated autoimmune diseases.


Journal of Investigative Dermatology | 2008

E-cadherin is an additional immunological target for pemphigus autoantibodies

Flor Evangelista; David A. Dasher; Luis A. Diaz; Phillip Prisayanh; Ning Li

Pemphigus foliaceus (PF) and pemphigus vulgaris (PV) are autoimmune blistering diseases characterized by autoantibodies against desmoglein (Dsg)1 and Dsg3, respectively. The role of classical cadherins as immunological targets of pemphigus autoantibodies is unknown. In this study, we tested the reactivity of sera from patients with PF, Fogo Selvagem (FS), and PV by immunoprecipitation coupled with immunoblotting (IP-IB) and ELISA techniques using a baculovirus-expressed ectodomain of E-cadherin. By IP-IB, anti-E-cadherin reactivity was detected in all tested sera of PF (n=13) and FS (n=15) patients, and in 79% of mucocutaneous-type PV patients (n=33), but in none of the mucosal-type PV patients (n=7). By ELISA, anti-E-cadherin IgG was detected in most pemphigus sera that produced strong E-cadherin bands by IP-IB. The immunoreactivity of PF/FS sera with E-cadherin was also demonstrated by IP-IB using human epidermal extracts. However, immunofluorescence staining of A431DE cells (E-cadherin positive, Dsg1 negative) with pemphigus sera showed negative results. Immunoadsorption and competitive ELISA analysis suggest that most of the anti-E-cadherin antibodies cross-react with Dsg1, whereas others may represent independent antibodies that do not cross-react with Dsg1. The functional relevance of these anti-E-cadherin IgG autoantibodies detected in these pemphigus sera remains to be defined.


Journal of Investigative Dermatology | 2009

Development of an IgG4-Based Predictor of Endemic Pemphigus Foliaceus (Fogo Selvagem)

Bahjat F. Qaqish; Phillip Prisayanh; Ye Qian; Eugenio Andraca; Ning Li; Valeria Aoki; Gunter Hans-Filho; Vandir dos Santos; Evandro A. Rivitti; Luis A. Diaz

Fogo selvagem (FS) is mediated by pathogenic, predominantly IgG4, anti-desmoglein 1 (Dsg1) autoantibodies and is endemic in Limao Verde, Brazil. IgG and IgG subclass autoantibodies were tested in a sample of 214 FS patients and 261 healthy controls by Dsg1 ELISA. For model selection, the sample was randomly divided into training (50%), validation (25%), and test (25%) sets. Using the training and validation sets, IgG4 was chosen as the best predictor of FS, with index values above 6.43 classified as FS. Using the test set, IgG4 has sensitivity of 92% (95% confidence interval (95% CI): 82-95%), specificity of 97% (95% CI: 89-100%), and area under the curve of 0.97 (95% CI: 0.94-1.00). The IgG4 positive predictive value (PPV) in Limao Verde (3% FS prevalence) was 49%. The sensitivity, specificity, and PPV of IgG anti-Dsg1 were 87, 91, and 23%, respectively. The IgG4-based classifier was validated by testing 11 FS patients before and after clinical disease and 60 Japanese pemphigus foliaceus patients. It classified 21 of 96 normal individuals from a Limao Verde cohort as having FS serology. On the basis of its PPV, half of the 21 individuals may currently have preclinical FS and could develop clinical disease in the future. Identifying individuals during preclinical FS will enhance our ability to identify the etiological agent(s) triggering FS.


Journal of Investigative Dermatology | 2011

IgE, IgM, and IgG4 anti-desmoglein 1 autoantibody profile in endemic pemphigus foliaceus (fogo selvagem).

Ye Qian; Phillip Prisayanh; Eugenio Andraca; Bahjat F. Qaqish; Valeria Aoki; Gunter Hans-Filhio; Evandro A. Rivitti; Luis A. Diaz

An endemic form of PF (pemphigus foliaceus) exists and is virtually exclusive to certain inland states of Brazil, where it is known as Fogo Selvagem (FS) (Diaz et al., 1989b). FS shows similar clinical, histological and immunological features to those observed in non-endemic PF (Diaz et al., 1989a; Stanley et al., 1986). The etiology of FS is unknown, but blister formation is mediated predominantly by IgG4 (Rock et al., 1989). Moreover, a progression from preclinical to clinical disease is associated with a sharp rise in IgG4 anti-Dsg1 (Warren et al., 2003), and these autoantibodies are predictors of FS (Qaqish et al., 2009). Emergence of self-reactive IgG4 anti-Dsg1 in FS is a mystery; however, there are some promising circumstantial clues that point toward the etiology of the disease. For example, the antigen-selected nature of anti-Dsg1 (Qian et al., 2009) and the presence of IgM anti-Dsg1 in healthy individuals in endemic areas of FS (Diaz et al., 2008) strongly suggest a recent or an ongoing exposure of settlers in these endemic regions to an environmental antigen(s) (Aoki et al., 2004; Diaz et al., 2004; Diaz et al., 2008) IgG4 and IgE antibodies develop in individuals chronically exposed to environmental allergens or during immunotherapy of patients with allergic diseases (Lichtenstein et al., 1968; Muller, 2005). Little is known about the IgE anti-Dsg1 response in FS, but recently Nagel et al (Nagel et al., 2009) have reported that IgE anti-Dsg3 correlated with disease activity in Pemphigus Vulgaris patients. In this investigation, we have evaluated the IgE, IgM and IgG4 anti-Dsg1 responses in a large cohort of FS patients and control individuals. A total of 558 sera were tested for IgE anti-Dsg1. Patient cohorts included 143 FS patients (Brazil), 39 non-endemic PF patients (USA and Japan), and 59 PV patients (USA and Japan). Healthy control (HC) cohorts included 161 healthy individuals living in endemic areas of FS (Brazil), 57 healthy individuals from non-endemic areas (Brazil), and 99 healthy individuals from USA (n= 76) and Japan (n= 23). Dsg1-specific ELISA were carried out as described (Qian et al., 2007) with a minor modification, i.e. the use of biotin labelled mouse anti-human IgE and HRP conjugated streptavidin (SouthernBiotech, Birmingham, AL). The levels of IgE anti-Dsg1 were expressed as index value units as reported by Amagai et al (Amagai et al., 1999) and Diaz et al (Diaz et al., 2008; Qaqish et al., 2009). The distribution of IgE index values in sera from FS, PF, and healthy individuals from Brazilian, Japanese and US donors is shown as box plots (Figure 1a). The statistical comparisons of these groups are shown in Table 1. The IgE anti-Dsg1 index values in the FS group were higher than in the other sets, while HC from US and Japan showed the lowest values. The differences in means between the FS group and all other groups tested were statistically significant at the 0.05 level. The difference between HC from endemic regions of Brazil and non-endemic regions of Brazil was not significant. However, the difference between HC from Brazil and USA/Japan was statistically significant. The significantly different IgE anti-Dsg1 levels between the FS group and the PF USA/Japan indicate that the IgE anti-Dsg1 response in FS is a distinctive serological feature of this disease. The significant difference in IgE anti-Dsg1 between HC Brazil (endemic and non-endemic) and HC USA/Japan needs to be explored in the future. The lack of difference between HC endemic Brazil and HC non-endemic is likely explained by the fact that these groups share certain living conditions, and perhaps environmental antigens. These antigens however may not be present in USA and Japan. Figure 1 IgE and IgG4 anti-Dsg1 in Fogo Selvagem patients and Control groups Table 1 1 Comparison of the IgE anti-Dsg1 Autoantibodies in FS and Control Groups We then analyzed the correlation between the IgE and IgG4 anti-Dsg1 responses in 143 FS and 317 HC. Figure 1b shows a plot of IgE against IgG4 anti-Dsg1, with superimposed regression lines, in the FS (red) and HC groups (blue). We found a correlation between IgE and IgG4 in the FS group (Spearman correlation r= 0.32, p<0.001), and less correlation in the HC group (r= 0.15, p= 0.07) suggesting that generation of these autoantibodies in FS may be linked and arising due to sensitizing to a common environmental allergen. These patterns of IgG4 and IgE responses are similar to those observed in allergic patients. Ongoing studies may demonstrate a stronger correlation between IgE and IgG4 anti-Dsg1 systems when testing sera from patients at different clinical and immunological stages of evolution. To evaluate the humoral IgM, IgG4 and IgE anti-Dsg1 responses in FS and HC, we extracted data on IgM and IgG4 anti-Dsg1 for the same subjects utilized in previous publications (Diaz et al., 2008; Qaqish et al., 2009). An ROC curve for IgM, IgE and IgG4 anti-Dsg1 index values was used to determine a cutoff point for sensitivity and specificity as described (Diaz et al., 2008; Qaqish et al., 2009). The percentages of positive sera for IgM, IgE and IgG4 anti-Dsg1 in the different groups were plotted and shown in Figure 1c. It is apparent that the triple response of IgM, IgG4 and IgE anti-Dsg1 is much higher in FS patients than in HC from the same endemic regions and HC from non-endemic regions of Brazil and USA/Japan (χ2, p<0.05, for IgM, IgE, and IgG4 anti-Dsg1). The percentages of positive individuals for IgM and IgE anti-Dsg1 were higher in the FS group (58% and 81% respectively) than in all other groups (χ2, p<0.05). As expected and also shown in Figure 1c, IgG4 anti-Dsg1 was detected in a large number of FS, PF and PV (90%, 77% and 33% respectively), which is a known feature of these diseases. These findings suggest a persistent antigenic stimulation of the immune system of individuals living in the endemic areas of FS. In summary, our findings further support the notion that the anti-Dsg1 response in FS patients may be initiated by sensitization to an environmental allergen(s). The cross-reactive IgE, IgM and pathogenic IgG4 anti-Dsg1 response may be the serological markers of these immunological responses.


Journal of Investigative Dermatology | 2009

Original ArticleDevelopment of an IgG4-Based Predictor of Endemic Pemphigus Foliaceus (Fogo Selvagem)

Bahjat F. Qaqish; Phillip Prisayanh; Ye Qian; Eugenio Andraca; Ning Li; Valeria Aoki; Gunter Hans-Filho; Vandir dos Santos; Evandro A. Rivitti; Luis A. Diaz

Fogo selvagem (FS) is mediated by pathogenic, predominantly IgG4, anti-desmoglein 1 (Dsg1) autoantibodies and is endemic in Limao Verde, Brazil. IgG and IgG subclass autoantibodies were tested in a sample of 214 FS patients and 261 healthy controls by Dsg1 ELISA. For model selection, the sample was randomly divided into training (50%), validation (25%), and test (25%) sets. Using the training and validation sets, IgG4 was chosen as the best predictor of FS, with index values above 6.43 classified as FS. Using the test set, IgG4 has sensitivity of 92% (95% confidence interval (95% CI): 82-95%), specificity of 97% (95% CI: 89-100%), and area under the curve of 0.97 (95% CI: 0.94-1.00). The IgG4 positive predictive value (PPV) in Limao Verde (3% FS prevalence) was 49%. The sensitivity, specificity, and PPV of IgG anti-Dsg1 were 87, 91, and 23%, respectively. The IgG4-based classifier was validated by testing 11 FS patients before and after clinical disease and 60 Japanese pemphigus foliaceus patients. It classified 21 of 96 normal individuals from a Limao Verde cohort as having FS serology. On the basis of its PPV, half of the 21 individuals may currently have preclinical FS and could develop clinical disease in the future. Identifying individuals during preclinical FS will enhance our ability to identify the etiological agent(s) triggering FS.


Journal of Investigative Dermatology | 2012

IgG Autoantibody Response against Keratinocyte Cadherins in Endemic Pemphigus Foliaceus (Fogo Selvagem)

Gustavo Flores; Donna A. Culton; Phillip Prisayanh; Bahjat F. Qaqish; Kirk James; Mike Maldonado; Valeria Aoki; Gunter Hans-Filho; Evandro A. Rivitti; Luis A. Diaz

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.


British Journal of Dermatology | 2013

E‐cadherin autoantibody profile in patients with pemphigus vulgaris

M.E.F. Oliveira; Donna A. Culton; Phillip Prisayanh; Bahjat F. Qaqish; Luis A. Diaz

Pemphigus vulgaris (PV) is an autoimmune skin blistering disease. The main targets of autoantibodies are the desmosomal proteins desmoglein (Dsg)3 and Dsg1. Anti‐E‐cadherin antibody is the second most frequent antibody found in pemphigus foliaceus (fogo selvagem), but the frequency in PV is unknown.


Journal of clinical & experimental dermatology research | 2014

Analysis of Anti-desmoglein 1 Autoantibodies in 68 Healthy Mother/Neonate Pairs from a Highly Endemic Region of Fogo Selvagem in Brazil

Julio Hilario-Vargas; Irineu B Vitorio; Christopher R Stamey; Donna A. Culton; Phillip Prisayanh; Evandro A. Rivitti; Valeria Aoki; Günter Hans Filho; Vandir dos Santos; Bahjat F. Qaqish; Luis A. Diaz

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.


Journal of Investigative Dermatology | 2010

The Thomsen-Friedenreich Antigen-Binding Lectin Jacalin Interacts with Desmoglein-1 and Abrogates the Pathogenicity of Pemphigus Foliaceus Autoantibodies In Vivo

Ning Li; Moonhee Park; Minglang Zhao; Julio Hilario-Vargas; David M. McInnes; Phillip Prisayanh; Zhi Liu; Luis A. Diaz

Pemphigus foliaceus (PF) is an autoimmune skin blistering disease mediated by pathogenic autoantibodies against the desmosomal core glycoprotein desmoglein-1 (Dsg1). This study demonstrated that the O-glycan-specific plant lectin jacalin binds Dsg1 and inhibits the interaction of Dsg1/PF IgG. N-glycosylation is not involved in the interaction of Dsg1/jacalin or Dsg1/PF IgG. Subcutaneous injection of jacalin into neonatal mice drastically reduced PF IgG deposition at the epidermal cell surface and blocked PF IgG-induced skin blisters, both clinically and histologically. Interestingly, another plant lectin, peanut agglutinin, which shares the same carbohydrate specificity toward the O-linked carbohydrate structure known as Thomsen-Friedenreich antigen (TF antigen, Galβ1-3GalNAcα-O-Ser/Thr), also bound Dsg1 and blocked the skin blistering. In contrast, the plant lectin vicia villosa-B4 (VVL-B4), which shares the carbohydrate specificity toward the O-linked monosaccharide known as Thomsen-nouveau antigen (GalNAc-α1-O-Ser/Thr), did not bind Dsg1 and did not show a protective effect against the disease induced by the autoantibodies. Collectively, these results suggest that the binding of jacalin to O-linked TF carbohydrate motifs on Dsg1 impairs the Dsg1/PF autoantibody interactions and abrogates its pathogenicity in vivo. TF-specific binding ligands may have a potential therapeutic value for PF.


Journal of Autoimmunity | 2018

Pathogenic IgG4 autoantibodies from endemic pemphigus foliaceus recognize a desmoglein-1 conformational epitope

Flor Evangelista; Aleeza J. Roth; Phillip Prisayanh; Brenda Temple; Ning Li; Ye Qian; Donna A. Culton; Zhi Liu; Oliver J. Harrison; Julia Brasch; Barry Honig; Lawrence Shapiro; Luis A. Diaz

Fogo Selvagem (FS), the endemic form of pemphigus foliaceus, is mediated by pathogenic IgG4 autoantibodies against the amino-terminal extracellular cadherin domain of the desmosomal cadherin desmoglein 1 (Dsg1). Here we define the detailed epitopes of these pathogenic antibodies. Proteolytic footprinting showed that IgG4 from 95% of FS donor sera (19/20) recognized a 16-residue peptide (A129LNSMGQDLERPLELR144) from the EC1 domain of Dsg1 that overlaps the binding site for an adhesive-partner desmosomal cadherin molecule. Mutation of Dsg1 residues M133 and Q135 reduced the binding of FS IgG4 autoantibodies to Dsg1 by ∼50%. Molecular modeling identified two nearby EC1 domain residues (Q82 and V83) likely to contribute to the epitope. Mutation of these residues completely abolished the binding of FS IgG4 to Dsg1. Bead aggregation assays showed that native binding interactions between Dsg1 and desmocollin 1 (Dsc1), which underlie desmosome structure, were abolished by Fab fragments of FS IgG4. These results further define the molecular mechanism by which FS IgG4 autoantibodies interfere with desmosome structure and lead to cell-cell detachment, the hallmark of this disease.

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Luis A. Diaz

University of North Carolina at Chapel Hill

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Bahjat F. Qaqish

University of North Carolina at Chapel Hill

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Donna A. Culton

University of North Carolina at Chapel Hill

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Ning Li

University of North Carolina at Chapel Hill

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Valeria Aoki

University of São Paulo

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Ye Qian

University of North Carolina at Chapel Hill

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Gunter Hans-Filho

Federal University of Mato Grosso do Sul

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Flor Evangelista

University of North Carolina at Chapel Hill

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Zhi Liu

University of North Carolina at Chapel Hill

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