Proteomic definition of a desmoglein linear determinant common to Pemphigus vulgaris and Pemphigus foliaceous
© Lucchese et al; licensee BioMed Central Ltd. 2006
Received: 28 June 2006
Accepted: 22 August 2006
Published: 22 August 2006
A number of autoimmune diseases have been clinically and pathologically characterized. In contrast, target antigens have been identified only in a few cases and, in these few cases, the knowledge of the exact epitopic antigenic sequence is still lacking. Thus the major objective of current work in the autoimmunity field is the identification of the epitopic sequences that are related to autoimmune reactions. Our labs propose that autoantigen peptide epitopes able to evoke humoral (auto)immune response are defined by the sequence similarity to the host proteome. The underlying scientific rationale is that antigen peptides acquire immunoreactivity in the context of their proteomic similarity level. Sequences uniquely owned by a protein will have high potential to evoke an immune reaction, whereas motifs with high proteomic redundancy should be immunogenically silenced by the tolerance phenomenon. The relationship between sequence redundancy and peptide immunoreactivity has been successfully validated in a number of experimental models. Here the hypothesis has been applied to pemphigus diseases and the corresponding desmoglein autoantigens.
Desmoglein 3 sequence similarity analysis to the human proteome followed by dot-blot/NMR immunoassays were carried out to identify and validate possible epitopic sequences.
Computational analysis led to identifying a linear immunodominant desmoglein-3 epitope highly reactive with the sera from Pemphigus vulgaris as well as Pemphigus foliaceous. The epitopic peptide corresponded to the amino acid REWVKFAKPCRE sequence, was located in the extreme N-terminal region (residues 49 to 60), and had low redundancy to the human proteome. Sequence alignment showed that human desmoglein 1 and 3 share the REW-KFAK–RE sequence as a common motif with 75% residue identity.
This study 1) validates sequence redundancy to autoproteome as a main factor in shaping desmoglein peptide immunogenicity; 2) offers a molecular mechanicistic basis in analyzing the commonality of autoimmune responses exhibited by the two forms of pemphigus; 3) indicates possible peptide-immunotherapeutical approaches for pemphigus diseases.
There are over 80 autoimmune diseases known or thought to be autoimmune in nature and, as a group, autoimmune diseases affect approximately 20% of the population. Multiple mechanisms of autoimmunity induction have been proposed including, among the others, molecular mimicry , viral epitope delivery , generation of neoantigenic epitopes after posttranslational modification , unusual TCR-binding properties that permit autoreactive T cells to escape deletion , presence of long regions of extreme structural disorder in the autoantigens , cellular injury and release of self antigens, which generate immune responses . However, the mechanisms leading to the breakdown of tolerance against enzyme autoantigen molecules remain poorly understood. The identification and comparative analysis of the autoantigenic immunoreactive determinants could elucidate the molecular basis of the autoimmune disease and offer new immunotherapeutical approaches.
Our labs have proposed that sequence similarity to the host proteome may influence peptide immunogenicity [6, 7]. According to this hypothesis, only peptide motifs having low similarity to the host proteome have the potential to raise an immune response. Conversely, no immune response can be evoked by antigenic protein fragments that are repeatedly represented in the protein set that form the proteome. In testing this work hypothesis, our current research is focused to the proteomic definition of the epitopic peptide repertoire associated to autoimmune diseases. In practice, based on the assumption that peptide sequences that are scarcely represented in human proteins might provoke autoimmune responses by offering antigenic determinants unknown to (or, better, scarcely encountered by) the immune system, we search for epitopic sequences of human pathogenic autoantigens by, first, selecting for autoantigen fragments not shared with the human proteome and, then, analyzing the immunoreactivity pattern of the not-shared peptides using sera from patients hosting the autoimmune disease. So far, the similarity hypothesis has been validated in a number of different experimental models [6–13].
In this study, we used the pemphigus autoimmune skin diseases and the corresponding desmoglein autoantigens as an experimental model . Indeed, pemphigus provides an exemplar paradigm for studying autoimmunity because of its clear-cut antigenic characterization [14, 15]. Desmoglein 3 (Dsg3) and desmoglein 1 (Dsg1) are the main autoantigenic target in Pemphigus vulgaris (PV) and Pemphigus foliaceus (PF), respectively [16, 17]. Moreover, epitope mapping revealed that autoantibodies (AAbs) from PV and PF patients recognize conformational epitopes hosted in the amino terminal ectodomain of Dsg3 and Dsg1 respectively [16, 18]. However, although it has been reported that pemphigus sera contain antibodies against continuous epitopes [16, 19], there is a general lack of data on the definition and specificity of Dsg linear epitopes. Therefore, given also that the molecular definition of linear Dsg autoepitopes could contribute to clarify unresolved aspects of pemphigus autoimmunity [20–22], we undertook an experimental study to define the linear epitopic sequences in Dsg3 by using the criterion of non-redundancy to human proteome as a search engine for epitopic peptides.
Here we describe how the search for sequences uniquely present in the human Dsg3 protein led to identifying an amino terminal linear Dsg3 motif that immunoreacts with sera from Pemphigus vulgaris as well as Pemphigus foliaceous.
Materials and methods
EC1/EC2 (aa 1–212) portion of human Dsg3 sequence (SWISS-PROT, P32926) was analysed for redundancy to human proteome using PIR protein database (141702 sequences) and peptide match program (pir.georgetown.edu/pirwww) . Sequence alignment was conducted by using SIM – Local similarity program (www.expasy.org) .
Sera were obtained from the outpatient Dermatology Clinic at the Weill-Cornell Medical College, New York, and Medical College of Wisconsin, Milwaukee. The diagnosis of PV and PF was made on the basis of clinical examination and biopsy as well as indirect IF serum titer. Sera from prostate cancer patients were used as controls.
Peptides were synthesized using standard Fmoc (N-(9-fluorenyl) methoxycarbonyl) solid phase peptide synthesis (PeptidoGenic Research & Co., Livermore, CA.; Primm srl, Milan, Italy). Peptide purity (>90%) was controlled by analytical HPLC, and the molecular mass confirmed by fast atomic bombardment mass spectrometry. Peptides used for dotblot immunoassay are: Dsg149–60REWIKFAAACRE, Dsg336–44EEMTMQQAK, Dsg349–60REWVKFAKPCRE, Dsg3190–204LNSKIAFKIVSQEPA, Dsg3373–380QVINVREG and Dsg3518–525NRYTGPYT. The 15N-labelled peptides used for NMR spectroscopy immunoanalysis are: Dsg349–60R EWV KFA KPCR E, Dsg3373–380QV INVR EG and Dsg3518–525NRY TGPY T peptides (with 15N-labelled amino acid residues given underlined). Control recombinant proteins corresponding to the EC domains of Dsg1 and Dsg3  were generously provided by Dr. M.S. Lin, Dept. of Dermatology, Medical College of Wisconsin.
Pemphigus serum reactivity against synthetic peptides was tested by immunodotblot assays. Nitrocellulose membrane (0.2 μm pore size, Biorad Laboratories, Milan, Italy) was pretreated with 1% glutaraldehyde. Dsg3 protein (10 μg) or peptides (4 μg) were spotted on the activated membranes and immunoassayed with PV or PF AAbs [8, 11, 13]. For Western blot assay, Dsg1 and Dsg3 proteins were resolved on sodium dodecylsulfate-10% polyacrylamide gel electrophoresis (SDS-10%PAGE), electroblotted onto PVDF membrane (Biorad Laboratories, Milan), and probed with PV or PF sera.
Spectroscopic analyses were carried out on sera pooled and partially purified by precipitation with 40% saturated (NH4)2SO4 (x 2). The precipitate was dissolved in phosphate-buffered saline (PBS), dialyzed against PBS with several changes for 24 h at 4°C, then aliquoted and stored at -20°C until assay. NMR spectra of the reaction of the synthetic 15N-labelled Dsg349–60 R EWV KFA KPCR E, Dsg3373–380QV INVR EG or Dsg3518–525NRY TGPY T peptide (with 15N-labelled amino acid residues given underlined) with partially purified AAbs from pooled sera of PV or PF or prostate cancer patients as control were recorded at 298°K on a Bruker Avance DRX500WB spectrometer. The spectra were acquired by heteronuclear single quantum correlation (HSQC) experiments as already detailed [8, 11, 26]. We used chemical shift statistics from the full BioMagResBank database, where the calculated statistics are derived from a total of 559392 chemical shifts (www.bmrb.wisc.edu). Sequence-specific correction factor tabulations were applied to backbone 1H and 15N resonances . Two-dimensional correlated spectroscopy spectra of peptide-AAbs complex were obtained using peptide:AAb ratio equal to 0.1:30, mg/mg. That is, NMR samples contained either 0.1 mg free Dsg349–60R EWV KFA KPCR E (or Dsg3373–380QV INVR EG or Dsg518–525NRY TGPY T) peptide; or 30 mg PV AAbs complexed with 0.1 mg Dsg349–60R EWV KFA KPCR E (or Dsg3373–380QV INVR EG or Dsg3518–525NRY TGPY T) peptide; or 30 mg PF AAbs complexed with 0.1 mg Dsg349–60R EWV KFA KPCR E (or Dsg3373–380QV INVR EG or Dsg3518–525NRY TGPY T) peptide; or 30 mg control AAbs complexed with 0.1 mg Dsg349–60R EWV KFA KPCR E (or Dsg3373–380QV INVR EG or Dsg3518–525NRY TGPY T) peptide, in 0.5 ml aqueous solution H2O/D2O (9:1, v/v).
Searching EC1/EC2 Dsg 3 for sequences non-redundant to the human proteome
Since the Dsg antigenic portions recognized by AAbs from PV patients mainly map to the NH2-terminal adhesive domain9 [18, 28], this preliminary study started by focusing on the extracellular (EC) portion of human Dsg3. The EC1/EC2 domain of Dsg3, spanning from amino acid 1 to 212, was searched for potential epitopic linear sequences with low redundancy to the self-proteome using the PIR protein database. Matching analysis to the human proteome was performed using pentamer probes, being 5 to 6 amino acids the minimal immunoreactive peptide length [29–31] Redundancy of a peptide sequence is defined here by the number of identical pentamers in common between the analyzed autoantigen and the human proteome.
Immunoreactivity of non-redundant EC1/EC2 Dsg3 peptides
The synthetic peptides, selected as above described and illustrated in Fig. 2, were bound to activated nitrocellulose membrane and tested as potential antigenic epitopes against serum from PV patients in dot immunoassays. Because of reports of anti-Dsg immune responses in healthy individuals [33–35], sera from prostate cancer patients were used as controls. Sera from PF patients were used as additional controls.
NMR probing of Dsg349–60REWVKFAKPCRE peptide immunoreactivity
Chemical shifts of 15N-labelled residues in Dsg49-60REWVKFAKPCRE peptide, and changes on control, PV or PF Aab addition
Chemical Shift Values:
Specifically, Fig. 4 shows the reaction between human AAbs and the immunoreactive Dsg349–60R EWV KFA KPCR E peptide. Fig. 4A reports the Arg, Val, Phe, and Ala selective 1H-15N correlations of the free peptide in aqueous solution, with the upper part of Fig. 4A displaying the Arg cross-peak signals due to the H and N atoms of amino η residues. On the whole, Fig. 4A clearly? shows that all of the expected signals are present and in basic agreement with the theoretical data relative to the 15N-labelled amino acids (see chemical shift values in Table 1). The addition of AAbs from control cancer sera did not alter the R EWV KFA KPCR E resonance signals, so that the spectrum of Fig. 4B could be assigned by reference to the control spectrum of the free peptide reported in Fig. 4A, both qualitatively and quantitatively. On the contrary, a complete signal deletion was provoked by the addition of AAbs from PF sera as illustrated in Fig.4C, upper and lower parts. Practically, Fig. 4C demonstrates that the PF AAbs were able to specifically neutralize and quantitatively precipitate the low similarity Dsg349–60R EWV KFA KPCR E peptide. In the presence of PV AAbs, well resolved resonances for 15N-labelled epitopic R EWV KFA KPCR E peptide residues were detectable (Fig. 4D, upper and lower panels), but the signal intensity was much weaker when compared to the control spectra reported in Fig. 4, panels A and B. That indicates that only a part of the 15N-labelled peptide had been complexed and buried by PV AAbs. No precipitation reaction was observed by using the control 15N-labelled Dsg3373–380QV INVR EG and Dsg3518–525NRY TGPY T peptides (not shown).
Dsg1 and Dsg3 cross-react with PF and PV sera: sharing of the 75% consensus motif REW-KFAK–RE
It is res iudicata in pemphigus pathologies that Dsg3 is the autoantigen of the vulgaris form, whereas Dsg1 is the autoantigen of the foliaceous form [14, 15, 17–19, 33]. In agreement with this statement, in the experiments illustrated in Figs. 3 and 4, PF AAbs were initially used as additional controls. On the other hand, the peculiar data emerging from Figs. 3 and 4 is the highly specific reaction between the PF AAbs preparation and the peptide from PV-associated Dsg3 autoantigen. Indeed, given the caveat that the extent of the 15N-labelled peptide reaction monitored in the NMR spectroscopy analyses depends on the AAb titer of each of the pooled sera, the NMR spectra reported in Fig. 4 indicated that the reaction extent with AAbs from PF sera was even higher than that monitored with AAbs from PV sera. The finding was of interest also in the light of reports indicating a common desmoglein background in PV and PF, and coexistence of the two pemphigus forms in the same patient [36, 37].
To better understand and define the cross-reactivity between the PF AAbs and the PV associated Dsg3 peptide, we analyzed Dsg1 and Dsg3 protein immunoreactivity towards AAbs from PV and PF by Western blot analysis. Fig. 5, panels A and B, show that: i) both PV and PF AAbs recognize a linear desmoglein determinant; ii) the linear desmoglein determinant is common to Dsg1 and Dsg3, so confirming the NMR spectroscopic immunoreaction reported in Fig. 4C.
The cross reaction between the PF AAbs and the PV associated Dsg3 peptide was further investigated by Dsg1/Dsg3 sequence alignment. The sequence analysis demonstrates 75% identity in the fragment spanning aa 49 to 60:
with REW-KFAK–RE as a common consensus motif, and suggests that the shared amino acids of the consensus motif may represent the epitopic residues recognized by both PV and PF sera, so providing a theoretical molecular framework to the data reported in Figs. 3, 4 and 5. Final experimental confirmation was obtained in immunodotblot assays by using the synthetic Dsg149–60REWIKFAAACRE peptide with PV and PF sera. Fig. 5, panel C, illustrates that PF AAbs recognize both Dsg149–60REWIKFAAACRE and Dsg349–60 REWVKFAKPCRE peptides. Likewise, also PV AAbs recognize Dsg149–60REWIKFAAACRE as well as Dsg349–60REWVKFAKPCRE peptide (Fig. 5, panel D).
Using computational biology and proteomics, and applying sequence uniqueness as a search criterium, we have characterized a linear low-redundant Dsg3 segment which is immunorecognized by sera from PV patients as well as PF patients. These data appear of scientific, clinical, and therapeutical interest.
Scientifically, the present study demonstrates that analytical dissection of the human proteome allows to comparatively analyze the molecular basis of complex multi-faceted diseases such as the pemphigus, and precisely identify autoantigen portions involved in immune responses. As a matter of fact, the methodology used in this study was extremely effective for individuating one new desmoglein epitope. Sets of 40 synthetic peptides, each 15 residues in length and overlapping by ten amino acid residues, should had been screened to scan the EC1/EC2 Dsg3 sequence by using canonical peptide-mapping analysis. In our approach identification of an immunodominant linear desmoglein epitope involved only 6 synthetic peptides. The application of the proteomic approach to find unique sequences led to rapid, effective and inexpensive epitope identification when compared to other methods,
Clinically, we note that although other investigators have analyzed desmogleins for patterns of continuous immunoreactive peptides [19, 38, 39], this is the first time, as far as we know, that a linear determinant on Dsg3 is identified as a precise amino acid sequence immunoreactive with patients' sera. Likewise, this is the first time that a common link between PV and PF is presented in terms of a common Dsg3/Dsg1 immunoreactive motif, i.e. the consensus REW-KFAK–RE sequence. Given the caveat that immunogenicity and pathogenicity are not synonymous and further studies are necessary in order to assess the (patho)physiological significance of the present data, undoubtedly these experimental results might be of help in defining the autoantibody response of pemphigus diseases. Indeed, pemphigus is a group of diseases of the skin and mucous membranes that 1) include different forms and variants, 2) are characterized by complex autoantibody profiles, and 3) present blistering process as a minimum common clinical denominator [40–42]. Consequently, a major goal in understanding pemphigus autoimmunity is the identification of critical epitopes along the antigen portions involved in the calcium-dependent cell-cell adhesion process. In this context, the data presented in this work, describing the NH2 terminal calcium-adhesive Dsg349–60REWVKFAKPCRE immunoreactive peptide, might represent a prelude to an exact definition of the entire Dsg linear epitope pattern. Indeed, the individuation of the consensus motif as a common sequence recognized by PF and PV sera is an experimental point that might help in the fine definition of the AAb profile in pemphigo diseases. Moreover, it has to be mentioned that also the monoclonal humoral response to the ectodomain of human Dsg3 targets within the Dsg349–60 REWVKFAKPCRE sequence . This is an additional reason for further studying Dsg349–60 sequence in the context of the induction of bullous skin disease resembling PV through passive transfer of PV AAbs .
Therapeutically, the usage of proteomic sequence uniqueness as a guiding principle in identifying epitopic sequences along autoantigenic proteins offers the possibility of effective peptide-immunotherapies in autoimmune diseases. The peptide-immunotherapy approach is currently being explored with encouraging results in many autoimmune diseases [44–46]. Indeed, short peptide fragments might be used to selectively block and neutralize autoantibodies, once the effective epitopic sequences have been determined and the definition between immunogenic and pathogenic epitopes is clearly drawn. Moreover, the precise identification of amino acid sequences uniquely present in the autoantigen of interest would also eliminate the side effects deriving from possible cross-reactions. In this context, the proteomics-defined REWVKFAKPCRE sequence represents a suitable candidate for a possible peptide-immunotherapy in pemphigus diseases.
We are grateful to F.P.Fanizzi and M.S. Lin for precious help and critical discussion. Part of the experimental work was carried out at the NMR Unit of Carso Cancer Research Center, Regione Puglia, Italy. This study was supported by Zalmin A.Arlin Cancer Fund, NY, USA (AM); 60% MIUR, Italy (DK); European Community funding to the PhD course "Carcinogenesis, Aging and Immunoregulation", University of Bari, Italy.
- Oldstone MBA: Molecular mimicry and immune-mediated diseases. FASEB J. 1998, 12: 1255-1265.PubMedGoogle Scholar
- Croxford JL, Anger HA, Miller SD: Viral delivery of an epitope from Haemophilus influenzae induces central nervous system autoimmune disease by molecular mimicry. J Immunol. 2005, 174: 907-917.View ArticlePubMedGoogle Scholar
- Nissim A, Winyard PG, Corrigall V, Fatah R, Perrett D, Panayi G, Chernajovsky Y: Generation of neoantigenic epitopes after posttranslational modification of type II collagen by factors present within the inflamed joint. Arthritis Rheum. 2005, 52: 3829-3838. 10.1002/art.21479.View ArticlePubMedGoogle Scholar
- Hahn M, Nicholson MJ, Pyrdol J, Wucherpfennig KW: Unconventional topology of self peptide-major histocompatibility complex binding by a human autoimmune T cell receptor. Nat Immunol. 2005, 6: 490-496. 10.1038/ni1187.PubMed CentralView ArticlePubMedGoogle Scholar
- Carl PL, Temple BR, Cohen PL: Most nuclear systemic autoantigens are extremely disordered proteins: implications for the etiology of systemic autoimmunity. Arthritis Res Ther. 2005, 7: R1360-1374. 10.1186/ar1832.PubMed CentralView ArticlePubMedGoogle Scholar
- Willers J, Lucchese A, Kanduc D, Ferrone S: Molecular mimicry of phage displayed peptides mimicking GD3 ganglioside. Peptides. 1999, 20: 1021-1026. 10.1016/S0196-9781(99)00095-9.View ArticlePubMedGoogle Scholar
- Natale C, Giannini T, Lucchese A, Kanduc D: Computer-assisted analysis of molecular mimicry between human papillomavirus 16 E7 oncoprotein and human protein sequences. Immunol Cell Biol. 2000, 78: 580-585. 10.1046/j.1440-1711.2000.00949.x.View ArticlePubMedGoogle Scholar
- Dummer R, Mittelman A, Fanizzi FP, Lucchese G, Willers J, Kanduc D: Non-self discrimination as a driving concept in the identification of an immunodominant HMW-MAA epitopic peptide sequence by autoantibodies from melanoma cancer patients. Int J Cancer. 2004, 111: 720-726. 10.1002/ijc.20310.View ArticlePubMedGoogle Scholar
- Kanduc D, Fanizzi FP, Lucchese G, Stevanovic S, Sinha AA, Mittelman A: NMR probing of in silico identification of anti-HPV16 E7 mAb linear peptide epitope. Peptides. 2004, 25: 243-250. 10.1016/j.peptides.2003.12.004.View ArticlePubMedGoogle Scholar
- Kanduc D: Defining peptide sequences: from antigenicity to immunogenicity through redundancy. Curr Pharmacogenomics. 2006, 4: 33-37. 10.2174/157016006776055374.View ArticleGoogle Scholar
- Lucchese A, Willers J, Mittelman A, Kanduc D, Dummer R: Proteomic scan for tyrosinase peptide antigenic pattern in vitiligo and melanoma: role of sequence similarity and HLA-DR1 affinity. J Immunol. 2005, 175: 7009-7020.View ArticlePubMedGoogle Scholar
- Mittelman A, Tiwari R, Lucchese G, Willers J, Dummer R, Kanduc D: Identification of monoclonal anti-HMW-MAA antibody linear peptide epitope by proteomic database mining. J Invest Dermat. 2004, 123: 670-675. 10.1111/j.0022-202X.2004.23417.x.View ArticleGoogle Scholar
- Lucchese A, Mittelman A, Lin MS, Kanduc D, Sinha AA: Epitope definition by proteomic similarity analysis: identification of the linear determinant of the anti-Dsg3 MAb 5H10. J Transl Med. 2004, 2: 43-10.1186/1479-5876-2-43.PubMed CentralView ArticlePubMedGoogle Scholar
- Amagai M: Desmoglein as a target in autoimmunity and infection. J Am Acad Dermatol. 2003, 48: 244-252. 10.1067/mjd.2003.7.View ArticlePubMedGoogle Scholar
- Pias EK, Hilario-Vargas J, Li N, Diaz LA: Humoral autoimmunity in pemphigus. Autoimmunity. 2004, 37: 283-286. 10.1080/08916930410001710848.View ArticlePubMedGoogle Scholar
- Hacker-Foegen MK, Janson M, Amagai M, Fairley JA, Lin MS: Pathogenicity and epitope characteristics of anti-desmoglein-1 from pemphigus foliaceus patients expressing only IgG1 autoantibodies. J Invest Dermatol. 2003, 121: 1373-1378. 10.1111/j.1523-1747.2003.12608.x.View ArticlePubMedGoogle Scholar
- Karpati S, Amagai M, Prussick R, Cehrs K, Stanley JR: Pemphigus vulgaris antigen, a desmoglein type of cadherin, is localized within keratinocyte desmosomes. J Cell Biol. 1993, 122: 409-415. 10.1083/jcb.122.2.409.View ArticlePubMedGoogle Scholar
- Kowalczyk AP, Anderson JE, Borgwardt JE, Hashimoto T, Stanley JR, Green KJ: Pemphigus sera recognize conformationally sensitive epitopes in the amino-terminal region of desmoglein-1. J Invest Dermatol. 1995, 105: 147-152. 10.1111/1523-1747.ep12316680.View ArticlePubMedGoogle Scholar
- Hashimoto T, Amagai M, Garrod DR, Nishikawa T: Immunofluorescence and immunoblot studies on the reactivity of Pemphigus vulgaris and pemphigus foliaceus sera with desmoglein 3 and desmoglein 1. Epithelial Cell Biol. 1995, 4: 63-69.PubMedGoogle Scholar
- Nguyen VT, Ndoye A, Shultz LD, Pittelkow MR, Grando SA: Antibodies against keratinocyte antigens other than desmogleins 1 and 3 can induce Pemphigus vulgaris-like lesions. J Clin Invest. 2000, 106: 1467-1479.PubMed CentralView ArticlePubMedGoogle Scholar
- Grando SA, Pittelkow MR, Shultz LD, Dmochowski M, Nguyen VT: Pemphigus: an unfolding story. J Invest Dermatol. 2001, 117: 990-995. 10.1046/j.0022-202x.2001.01489.x.View ArticlePubMedGoogle Scholar
- Stanley JR, Nishikawa T, Diaz LA, Amagai M: Pemphigus: is there another half of the story?. J Invest Dermatol. 2001, 116: 489-490. 10.1046/j.1523-1747.2001.01307.x.View ArticlePubMedGoogle Scholar
- Wu CH, Huang H, Arminski L, Castro-Alvear J, Chen Y, Hu ZZ, Ledley RS, Lewis KC, Mewes HW, Orcutt BC, Suzek BE, Tsugita A, Vinayaka CR, Yeh LS, Zhang J, Barker WC: The Protein Information Resource: an integrated public resource of functional annotation of proteins. Nucleic Acids Res. 2002, 30: 35-37. 10.1093/nar/30.1.35.PubMed CentralView ArticlePubMedGoogle Scholar
- Huang XQ, Miller W: A time-efficient, linear-space local similarity algorithm. Adv Appl Mathem. 1991, 12: 337-357. 10.1016/0196-8858(91)90017-D.View ArticleGoogle Scholar
- Arteaga LA, Prisayanh PS, Warren SJ, Liu Z, Diaz LA, Lin MS, Cooperative Group on Fogo Selvagem Research: A subset of pemphigus foliaceus patients exhibits pathogenic autoantibodies against both desmoglein-1 and desmoglein-3. J Invest Dermatol. 2002, 118: 806-811. 10.1046/j.1523-1747.2002.01743.x.View ArticlePubMedGoogle Scholar
- Schleucher J, Schwendinger M, Sattler M, Schmidt P, Schedletzky O, Glaser SJ, Sorensen OW, Griesinger C: A general enhancement scheme in heteronuclear multidimensional NMR employing pulsed field gradients. J Biomol NMR. 1994, 4: 301-306. 10.1007/BF00175254.View ArticlePubMedGoogle Scholar
- Schwarzinger S, Kroon GJA, Foss TR, Chung J, Wright PE, Dyson HJ: Sequence-dependent correction of random coil NMR chemical shifts. J Am Chem Soc. 2001, 123: 2970-2978. 10.1021/ja003760i.View ArticlePubMedGoogle Scholar
- Tsunoda K, Ota T, Aoki M, Yamada T, Yamada T, Nagai T, Nakagawa T, Koyasu S, Nishikawa T, Amagai M: Induction of pemphigus phenotype by a mouse monoclonal antibody against the amino-terminal adhesive interface of desmoglein 3. J Immunol. 2003, 170: 2170-2178.View ArticlePubMedGoogle Scholar
- Lindner K, Mole SE, Lane DP, Kenny MK: Epitope mapping of antibodies recognising the N-terminal domain of simian virus large tumour antigen. Intervirology. 1998, 41: 10-16. 10.1159/000024910.View ArticlePubMedGoogle Scholar
- Reddehase MJ, Rothbard JB, Koszinowski UH: A pentapeptide as minimal antigenic determinant for MHC class I-restricted T lymphocytes. Nature. 1989, 337: 651-653. 10.1038/337651a0.View ArticlePubMedGoogle Scholar
- Hemmer B, Kondo T, Gran B, Pinilla C, Cortese I, Pascal J, Tzou A, McFarland HF, Houghten R, Martin R: Minimal peptide length requirements for CD4(+) T cell clones-implications for molecular mimicry and T cell survival. Int Immunol. 2000, 12: 375-383. 10.1093/intimm/12.3.375.View ArticlePubMedGoogle Scholar
- Wucherpfennig KW, Yu B, Bhol K, Monos DS, Argyris E, Karr RW, Ahmed AR, Strominger JL: Structural basis for major histocompatibility complex (MHC)-linked susceptibility to autoimmunity: charged residues of a single MHC binding pocket confer selective presentation of self-peptides in Pemphigus vulgaris. Proc Natl Acad Sci USA. 1995, 92: 11935-11939. 10.1073/pnas.92.25.11935.PubMed CentralView ArticlePubMedGoogle Scholar
- Veldman C, Hohne A, Dieckmann D, Schuler G, Hertl M: Type I regulatory T cells specific for desmoglein 3 are more frequently detected in healthy individuals than in patients with pemphigus vulgaris. J Immunol. 2004, 172: 6468-6475.View ArticlePubMedGoogle Scholar
- Veldman CM, Gebhard KL, Uter W, Wassmuth R, Grotzinger J, Schultz E, Hertl M: T cell recognition of desmoglein 3 peptides in patients with pemphigus vulgaris and healthy individuals. J Immunol. 2004, 172: 3883-3892.View ArticlePubMedGoogle Scholar
- Gebhard KL, Veldman CM, Wassmuth R, Schultz E, Schuler G, Hertl M: Ex vivo analysis of desmoglein 1-responsive T-helper (Th) 1 and Th2 cells in patients with pemphigus foliaceus and healthy individuals. Exp Dermatol. 2005, 14: 586-592. 10.1111/j.0906-6705.2005.00329.x.View ArticlePubMedGoogle Scholar
- Harman KE, Gratian MJ, Shirlaw PJ, Bhogal BS, Challacombe SJ, Black MM: The transition of pemphigus vulgaris into pemphigus foliaceus: a reflection of changing desmoglein 1 and 3 autoantibody levels in pemphigus vulgaris. Br J Dermatol. 2002, 146: 684-687. 10.1046/j.1365-2133.2002.04608.x.View ArticlePubMedGoogle Scholar
- Feliciani C, Motta A, Castellaneta M, Federica M, De Benedetto A, Toto P, Tulli A: Coexisting pemphigus vulgaris and pemphigus foliaceus in the same patient. Int J Dermatol. 2005, 44: 139-141. 10.1111/j.1365-4632.2005.02071.x.View ArticlePubMedGoogle Scholar
- Bhol K, Natarajan K, Nagarwalla N, Mohimen A, Aoki V, Ahmed AR: Correlation of peptide specificity and IgG subclass with pathogenic and nonpathogenic autoantibodies in pemphigus vulgaris: a model for autoimmunity. Proc Natl Acad Sci USA. 1995, 92: 5239-5243. 10.1073/pnas.92.11.5239.PubMed CentralView ArticlePubMedGoogle Scholar
- Hacker MK, Janson M, Fairley JA, Lin MS: Isotypes and antigenic profiles of pemphigus foliaceus and pemphigus vulgaris autoantibodies. Clin Immunol. 2002, 105: 4-74. 10.1006/clim.2002.5259.View ArticleGoogle Scholar
- Hanakawa Y, Schechter NM, Lin C, Garza L, Li H, Yamaguchi T, Fudaba Y, ishifuji K, Sugai M, Amagai M, Stanley JR: Molecular mechanisms of blister formation in bullous impetigo and staphylococcal scalded skin syndrome. J Clin Invest. 2002, 110: 53-60. 10.1172/JCI200215766.PubMed CentralView ArticlePubMedGoogle Scholar
- Hanakawa Y, Stanley JR: Mechanisms of blister formation by staphylococcal toxins. J Biochem (Tokyo). 2004, 136: 747-750.View ArticleGoogle Scholar
- Payne AS, Hanakawa Y, Amagai M, Stanley JR: Desmosomes and disease: pemphigus and bullous impetigo. Curr Opin Cell Biol. 2004, 16: 536-543. 10.1016/j.ceb.2004.07.006.View ArticlePubMedGoogle Scholar
- Anhalt GJ, Labib RS, Voorhees JJ, Beals TF, Diaz LA: Induction of pemphigus in neonatal mice by passive transfer of IgG from patients with the disease. N Engl J Med. 1982, 306: 1189-1196.View ArticlePubMedGoogle Scholar
- de Graaf KL, Barth S, Herrmann MM, Storch MK, Otto C, Olsson T, Melms A, Jung G, Wiesmuller KH, Weissert R: MHC class II isotype- and allele-specific attenuation of experimental autoimmune encephalomyelitis. J Immunol. 2004, 173: 2792-2802.View ArticlePubMedGoogle Scholar
- Larche M, Wraith DC: Peptide-based therapeutic vaccines for allergic and autoimmune diseases. Nat Med. 2005, 11: S69-76. 10.1038/nm1226.View ArticlePubMedGoogle Scholar
- Goulvestre C, Chereau C, Nicco C, Mouthon L, Weill B, Batteux F: A mimic of p21WAF1/CIP1 ameliorates murine lupus. J Immunol. 2005, 175: 6959-6967.View ArticlePubMedGoogle Scholar
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