ライフサイエンスコーパス: Dsg3

1 ibody binding to desmoglein 1 and/or 3 (dsg1/dsg3).

2 gainst the desmosomal cadherin desmoglein-3 (Dsg3).

3 target the desmosomal cadherin desmoglein-3 (Dsg3).

4 ated by autoantibodies against desmoglein-3 (Dsg3).

5 keratinocyte adhesion protein desmoglein 3 (Dsg3).

6 toantibodies (autoAbs) against desmoglein 3 (Dsg3).

7 g, cultured keratinocytes through binding to Dsg3.

8 d in the response to an antigen unrelated to DSG3.

9 ely originates from a non-junctional pool of Dsg3.

10 eted followed by loss of detergent-insoluble Dsg3.

11 kb of 18q12 and is situated between DSG1 and DSG3.

12 ree antigenic fragments on the ectodomain of Dsg3.

13 ce that carry a spontaneous null mutation in Dsg3.

14 or tertiary (3 degrees) T cell responses to Dsg3.

15 a1*1401, also mount T cell responses against Dsg3.

16 upon 2 degrees or 3 degrees stimulation with Dsg3.

17 s vulgaris patients respond to both Dsg1 and Dsg3.

18 ies interfering with an adhesion function of Dsg3.

19 whereas the remaining four reacted only with Dsg3.

20 his study has minimal sequence homology with Dsg3.

21 keratin 14 and the desmoglein genes DSG1 and DSG3.

22 have defined this molecule as a desmoglein, DSG3.

23 Detection of desmoglein 3 (DSG3), a metastatic biomarker for head and neck squamous

24 ced binding of specific Dsg isoforms such as Dsg3, a process for which plaque proteins including Pkp

25 Here, we found that Dsg3(AA145-192)-specific cells preferentially utilize th

26 t appears that Valpha22 gene is expressed by Dsg3(AA145-192)-specific cells, whereas the Valpha10 gen

27 rentially utilize the TCRVbeta13 gene, while Dsg3(AA240-303)- and Dsg3 (AA570-614)-specific cells uti

28 e Valpha10 gene is predominantly utilized by Dsg3(AA240-303)-specific T cells.

29 TCRVbeta13 gene, while Dsg3(AA240-303)- and Dsg3 (AA570-614)-specific cells utilize Vbeta7 and Vbeta

30 ha gene in the group of cells proliferate to Dsg3 (AA570-614).

31 p38 MAPK activation and its association with DSG3, abrogated p38 MAPK-induced keratin filament retrac

32 observations suggest that PV IgG binding to dsg3 activates desmosomal signal transduction cascades l

33 roteins, and demonstrate that either Dsg1 or Dsg3 alone is sufficient to maintain keratinocyte adhesi

34 mal adhesion proteins, desmoglein (Dsg)1 and Dsg3 (also known as DG1 and DG3), which are present in t

35 duced from a PV patient causes a decrease of Dsg3 and desmoplakin but not desmocollin (Dsc) 3 in the

36 Dsg3 and Dsg1 are members of the desmoglein subfamily of

37 igus vulgaris patients after incubation with Dsg3 and Dsg1 fusion proteins.

38 dies to the desmoglein (DSG) family proteins DSG3 and DSG1, leading to loss of keratinocyte cell adhe

39 ing PV is characterized by autoantibodies to Dsg3 and Dsg1.

40 rated binding to Dsg3 or Dsg1 alone, or both Dsg3 and Dsg1.

41 (Dsg) 1; PV autoantibodies bind Dsg3 or both Dsg3 and Dsg1.

42 These data demonstrate cross-talk between dsg3 and EGFR, that this cross-talk is regulated by p38,

43 stal structures of ectodomains from Dsg2 and Dsg3 and from Dsc1 and Dsc2 show binding through a stran

44 y enhancing both the depletion of desmosomal DSG3 and intercellular adhesion defects.

45 Subsequently, Dsg3 and other desmosomal components rearrange into line

46 PKP-1 prevents loss of Dsg3 and other desmosomal proteins from cell-cell border

47 tant for keratinocyte cohesion compared with Dsg3 and that the latter forms a complex with p38 MAPK.

48 eproduce the effects of polyclonal PV IgG on Dsg3 and will facilitate future studies to further disse

49 target the desmosomal cadherin desmoglein 3 (Dsg3) and compromise keratinocyte cell-cell adhesion.

50 s foliaceus autoantibodies are desmoglein-3 (Dsg3) and desmoglein-1 (Dsg1), respectively.

51 targeting desmosomal cadherins desmoglein 3 (DSG3) and DSG1, leading to loss of keratinocyte cohesion

52 o desmosomal adhesion proteins desmoglein 3 (Dsg3) and Dsg1.

53 utoantibodies directed against desmoglein 3 (Dsg3) and/or desmoglein 1(Dsg1).

54 imits of detection (LOD) were 0.10 fg/mL for DSG3, and 0.20 fg/mL for VEGF-A, VEGF-C and beta-Tub.

55 etween disease activity, the ELISA index for Dsg3, and/or IIF findings can occur in PV.

56 Here, we clone anti-Dsg3 antibodies (Abs) from four PV patients and identify

57 esional biopsy, with serum anti-Dsg1 or anti-Dsg3 antibodies (or both) detected by ELISA.

58 IF result was negative.OBSERVATIONS The anti-Dsg3 antibodies of our patient mainly recognized Ca2+-de

59 Anti-Dsg3 antibodies were detected in 53 of 146 normal subjec

60 and mucous membrane that coexpress Dsg1 and Dsg3, antibodies against either desmoglein alone do not

61 ent with PV in remission,who had a high anti-Dsg3 antibody ELISA index while the IIF result was negat

62 whereas the signaling of anti-desmoglein 3 (Dsg3) antibody involved JNK and biphasic p38 MAPK activa

63 dings identify the cis-adhesive interface of DSG3 as the immunodominant region targeted by pathogenic

64 of cell adhesion by altering the dynamics of Dsg3 assembly into desmosomes and the turnover of cell s

65 hosphorylation that could be responsible for Dsg3-associated cancer metastasis.

66 To define the mechanisms by which Dsg3 autoantibodies disrupt keratinocyte adhesion, the f

67 e sought to determine the prevalence of anti-Dsg3 autoantibodies in sera from normal subjects living

68 DSG3 autoantibodies stimulated DSG3-CAART IFN-gamma secr

69 Pathogenic PV dsg3 autoantibodies were used to initiate desmosome sign

70 s of skin and mucosae and anti-desmoglein-3 (Dsg3) autoantibodies bound to the surface of lesional ke

71 se patients that exhibited the combined Dsg1/Dsg3 autoantibody reactivity showed a proliferative resp

72 with acute pemphigus showed higher levels of Dsg3-autoreactive T(FH)17 cells.

73 6 Abs require few to no mutations to acquire Dsg3 autoreactivity, which may favour their early select

74 anti-Dsg3 response, as well as whether anti-Dsg3 B cells are Ag selected.

75 DSG3-CAART specifically lysed human anti-DSG3 B cells from PV patients and demonstrated activity

76 ximab that induced long-term remission, anti-Dsg3 B-cell clones were undetectable.

77 of the Dsg3 gene and the "balding" Dsg3(bal)/Dsg3(bal) mice that carry a spontaneous null mutation in

78 mutation of the Dsg3 gene and the "balding" Dsg3(bal)/Dsg3(bal) mice that carry a spontaneous null m

79 c cytotoxicity against cells expressing anti-Dsg3 BCRs in vitro and expand, persist, and specifically

80 ent keratinocytes did not exhibit changes in Dsg3 binding on the molecular level.

81 PK links autoantibody-mediated inhibition of DSG3 binding to skin blistering.

82 f five VH1-46 germline-reverted Abs maintain Dsg3 binding, compared with zero of five non-VH1-46 germ

83 combination are necessary and sufficient for Dsg3 binding.

84 y expressing exogenous Dsg3, thereby driving Dsg3 biosynthesis and desmosome assembly.

85 PV mAbs that cause endocytosis of Dsg3 but do not dissociate keratinocytes because of comp

86 c mAbs cause internalization of cell-surface Dsg3 but not Dsc3 through early endosomes.

87 g the interaction of activated p38 MAPK with Dsg3 but not with Dsg2.

88 eactivity showed a proliferative response to Dsg3, but not to Dsg1.

89 We also showed that bal mice lack Dsg3 by IF, have typical PV oral lesions, and have a DSG

90 s, p38 knockdown prevents loss of desmosomal Dsg3 by PV mAbs, and exogenous p38 activation causes int

91 Dsg3 CAAR-T cells exhibit specific cytotoxicity against

92 preclinical data guided the trial design for DSG3-CAART and may help inform CAART preclinical develop

93 d tissue-bound autoantibodies, and increased DSG3-CAART engraftment.

94 l studies enabling a first-in-human trial of DSG3-CAART for mucosal PV.

95 DSG3 autoantibodies stimulated DSG3-CAART IFN-gamma secretion and homotypic clustering,

96 model with physiologic anti-DSG3 IgG levels, DSG3-CAART inhibited antibody responses against pathogen

97 DSG3-CAART specifically lysed human anti-DSG3 B cells fr

98 in 3 chimeric autoantibody receptor T cells (DSG3-CAART) expressing the pemphigus vulgaris (PV) autoa

99 Therefore, DSG3 can be a useful ancillary marker to separate SQCC f

100 vations demonstrate that T cell responses to Dsg3 can be detected in PV patients and in healthy donor

101 s (PV), autoantibodies against desmoglein 3 (Dsg3) cause loss of cell-cell adhesion of keratinocytes

102 s bind the desmosomal cadherin desmoglein-3 (dsg3), causing epidermal cell-cell detachment (acantholy

103 lation experiments demonstrated that soluble Dsg3 cell surface pools were rapidly depleted followed b

104 Using a series of Dsg3 chimeras and deletion constructs, we find that PKP-

105 rization, we could no longer detect any anti-Dsg3 clones in PV1 by APD.

106 ever, acantholytic cells retain cell surface Dsg3 compared with wild-type mice.

107 Furthermore, the internalized PV IgG-Dsg3 complex colocalized with markers for both endosomes

108 The PV IgG.Dsg3 complex failed to colocalize with clathrin, and inh

109 Dsg3 complexes localized at the cell surface are transpo

110 Furthermore, the Dsg3 cytoplasmic tail specified sensitivity to these inh

111 ction was unaltered in meibomian glands from Dsg3-deficient mice, we established an ex vivo slice cul

112 n and keratin filament retraction induced by Dsg3 depletion is ameliorated by specific p38 MAPK inhib

113 Because loss of cell cohesion and Dsg3 depletion is observed in the autoantibody-mediated

114 Moreover, because loss of cell adhesion by Dsg3 depletion was partially rescued by p38 MAPK inhibit

115 by reversing Ca(2+) insensitivity, promotes Dsg3 depletion.

116 ous p38 activation causes internalization of Dsg3, desmocollin 3, and desmoplakin.

117 antibodies against the desmosomal cadherin, DSG3 (desmoglein-3), cause acantholysis.

118 the normal tissue distributions of Dsg1 and Dsg3 determine the sites of blister formation.

119 rown from Dsg3(-/-) mice, we determined that Dsg3 did not serve as a surrogate antigen allowing antim

120 These changes in Dsg3 distribution are followed by depletion of detergent

121 ce, blocked the aggregation of Dsg1/Dsc1 and Dsg3/Dsc3 beads, respectively, whereas nonpathogenic mAb

122 ease inhibited the adhesion of Dsg1/Dsc1 and Dsg3/Dsc3 beads, respectively.

123 y cause internalization of newly synthesized Dsg3 during desmosome assembly, correlating with their p

124 eal epithelial cells did not express Dsc3 or Dsg3 during re-epithelialization.

125 h N- and COOH-terminal epitopes of the human Dsg3 ectodomain.

126 Within 6 h after PV IgG binding to Dsg3, electron microscopy revealed that desmosomes were

127 ted with the evolution of anti-DSG1 and anti-DSG3 ELISA values, respectively.

128 ncing of MK2 expression block PV mAb-induced Dsg3 endocytosis in human keratinocytes.

129 termine the relationship between p38MAPK and DSG3 endocytosis in pemphigus.

130 in- and dynamin-independent pathway and that Dsg3 endocytosis is tightly coupled to the pathogenic ac

131 Moreover, inhibition of Dsg3 endocytosis with genistein prevented disruption of

132 These findings demonstrate that Dsg3 endocytosis, keratin filament retraction, and the l

133 Inhibition of EGFR blocked PV IgG-triggered dsg3 endocytosis, keratin intermediate filament retracti

134 unction downstream to augment blistering via Dsg3 endocytosis.

135 between these indexes and anti-Dsg1 and anti-Dsg3 enzyme-linked immunosorbent assay values has not be

136 Serum anti-Dsg1 and anti-Dsg3 enzyme-linked immunosorbent assay values were measu

137 ibited antibody responses against pathogenic DSG3 epitopes and autoantibody binding to epithelial tis

138 at CD4(+) T cells recognizing immunodominant Dsg3 epitopes in the context of the PV-associated HLA-DR

139 04:02-restricted T cell recognition of human Dsg3 epitopes leads to the induction of pathogenic IgG A

140 These findings suggest that the Dsg3 epitopes targeted by pathogenic mPV IgG are human s

141 e of this study was to determine the role of DSG3 expression in the diagnosis of SQCCs of the lung an

142 tent with this hypothesis, we found Dsg1 and Dsg3 expression overlapping in the companion layer.

143 the pathogenic antibodies were mapped to the DSG3 extracellular 1 (EC1) and EC2 subdomains, regions i

144 tor measurements in keratinocytes showed the Dsg3 extracellular domain is ordered at the individual d

145 sults demonstrate the critical importance of Dsg3 for adhesion in deep stratified squamous epithelia

146 stochemistry, sensitivity and specificity of DSG3 for lung cancers were 98% and 99%, respectively.

147 We showed that Dsg3 formed a complex with Ezrin at the plasma membrane

148 utants resulted in loss of cell cohesion and Dsg3 fragmentation.

149 , we isolated 15 IgG antibodies specific for DSG3 from 2 PV patients.

150 st, pathogenic mAbs caused late depletion of Dsg3 from preformed desmosomes at 24 hours, with effects

151 cytes with PV IgG causes a redistribution of DSG3 from the cell surface to endosomes, which target th

152 sing the pemphigus vulgaris (PV) autoantigen DSG3 fused to CD137-CD3zeta signaling domains, represent

153 ve response after exposure to either Dsg1 or Dsg3 fusion proteins.

154 3(null) mice with a targeted mutation of the Dsg3 gene and the "balding" Dsg3(bal)/Dsg3(bal) mice tha

155 Targeted disruption of the Dsg3 gene by homologous recombination (Dsg3tm1stan) in m

156 ion of up-regulated expression levels of the DSG3 gene in pulmonary squamous cell carcinomas (SQCCs).

157 IF, have typical PV oral lesions, and have a DSG3 gene mutation.

158 dentified a 14 bp deletion in exon 13 of the Dsg3 gene resulting in a frameshift and premature termin

159 ygous for a 1 bp insertion (2275insT) in the Dsg3 gene resulting in a nonfunctional Dsg3 mRNA.

160 eered mice with a targeted disruption of the DSG3 gene.

161 The microarray data showed that DSG3 had a sensitivity and specificity of 88% and 98%, r

162 Autoantibodies against desmoglein 3 (Dsg3) have also been detected in sera from patients with

163 We therefore generated a fully humanized Dsg3 (hDSG3) murine model utilizing a hDsg3 transgenic a

164 Anti-desmoglein (Dsg) 1 and Dsg3 IgG autoantibodies in pemphigus foliaceus and pemph

165 PV active immune model with physiologic anti-DSG3 IgG levels, DSG3-CAART inhibited antibody responses

166 Characterization of the anti-Dsg3 IgG(+) repertoire by antibody phage display (APD) a

167 ediated disease, in which anti-desmoglein 3 (Dsg3) IgG autoantibodies cause life-threatening blisteri

168 Th2-like cytokine profile, and responding of Dsg3 in a restriction to HLA-DRBI*0402 or 1401 alleles.

169 Ectopic expression of Dsg3 in cancer cell lines caused enhanced phosphorylatio

170 evertheless, because subsequent targeting of Dsg3 in Dsg2-depleted cells led to drastically enhanced

171 the hypothesis that coexpression of Dsg1 and Dsg3 in keratinocytes protects against pathology due to

172 Expression of Dsc3 and Dsg3 in limbus and conjunctiva coincides with their asso

173 esized that Dsg1 compensates for the loss of Dsg3 in the anagen hair follicles of these Dsg3-/- mice.

174 udy, we compared the involvement of Dsg2 and Dsg3 in the p38 MAPK-dependent regulation of keratinocyt

175 mpanion layer, and particularly the Dsg1 and Dsg3 in this layer, in anchoring the anagen hair to the

176 der of the desmosomal cadherin desmoglein 3 (Dsg3) in living cells.

177 scribed in B cells reacting to desmoglein 3 (Dsg3) in the autoimmune disease pemphigus vulgaris (PV),

178 ion of the desmosomal cadherin desmoglein 3 (DSG3) in the pathogenesis of PV.

179 ored desmosome-containing pool revealed that Dsg3, in contrast to Dsg2, is present in relevant amount

180 Over 90% are specific for both Dsg1 and Dsg3 indicating extensive cross-reactivity between these

181 pletion of Dsg2, siRNA-mediated silencing of Dsg3 induced p38 MAPK activation, which is in line with

182 cells recognizing immunodominant epitopes of Dsg3 initiate the production of Dsg3-reactive IgG autoan

183 Cell-surface DSG3 internalization and depletion from both the deterge

184 APK is capable of regulating PV IgG-mediated DSG3 internalization and that previously isolated mechan

185 r, these results suggest that PV IgG-induced Dsg3 internalization is mediated through a clathrin- and

186 Dsg3 internalization was associated with retraction of k

187 docytic machinery involved in PV IgG-induced Dsg3 internalization, human keratinocytes were incubated

188 ing KCs demonstrated that PV IgG cause rapid Dsg3 internalization, which likely originates from a non

189 ependent pathways had little or no effect on Dsg3 internalization.

190 e inhibitor genistein dramatically inhibited Dsg3 internalization.

191 V IgG causes internalization of cell-surface DSG3 into endosomes (as early as 4 h), which are then de

192 e and trigger its internalization along with DSG3 into the endosomal pathway, where it is ultimately

193 epidermis of normal mice) where Dsg1 without Dsg3 is expressed, anti-Dsg1 antibodies alone can cause

194 tudies demonstrate that upon PV IgG binding, Dsg3 is internalized and enters an endo-lysosomal pathwa

195 DSG3 is membrane-bound protein in HNSCC cells of invaded

196 esides its function as an adhesion molecule, Dsg3 is strengthening cell cohesion via modulation of p3

197 tor receptor and Src was affected neither in Dsg3(-/-) KCs nor due to absorption of antimitochondrial

198 tion of interacting with F-actin and CD44 as Dsg3 knockdown impaired these associations.

199 ion and Dsg2 was enhanced at the membrane in Dsg3 knockout cells, we conclude that Dsg2 compensates f

200 cells, we conclude that Dsg2 compensates for Dsg3 loss of function.

201 eratinocytes with pathogenic monovalent anti-Dsg3 mAbs produced from a PV patient causes a decrease o

202 The pathogenic anti-Dsg1 and anti-Dsg3 mAbs, which bind the transadhesive interface, block

203 autoantibodies that fail to recognize murine Dsg3 (mDsg3); thus, passive transfer experiments of mPV

204 Taken together, our study identifies a novel Dsg3-mediated c-Jun/AP-1 regulatory mechanism and PKC-de

205 To test whether Dsg3 mediates adhesion, we genetically engineered mice w

206 DSG3 -/- mice had no DSG3 mRNA by RNase protection assay

207 The runting and hair loss phenotype of DSG3 -/- mice is identical to that of a previously repor

208 Using KCs grown from Dsg3(-/-) mice, we determined that Dsg3 did not serve as

209 vement in the clinical manifestations of the Dsg3(-/-) mice.

210 ion of ETA, Dsg3-/- mice, but not Dsg3+/+ or Dsg3+/- mice, showed striking loss of anagen hair, which

211 The oral lesions in DSG3-/- mice reduce their food intake, resulting in a ru

212 Four hours after injection of ETA, Dsg3-/- mice, but not Dsg3+/+ or Dsg3+/- mice, showed st

213 oliative toxin A (ETA) to inactivate Dsg1 in Dsg3-/- mice.

214 f Dsg3 in the anagen hair follicles of these Dsg3-/- mice.

215 e molecule force mappings revealed increased Dsg3 molecules but not Dsg1 molecules binding strength i

216 DSG3 -/- mice had no DSG3 mRNA by RNase protection assay and no Dsg3 protein

217 We demonstrate that, although a Dsg3 mRNA transcript was detectable in Dsg3bal-Pas skin,

218 Expression of DSG3 mRNA was evaluated in bulk laser capture microdisse

219 n the Dsg3 gene resulting in a nonfunctional Dsg3 mRNA.

220 We used both the Dsg3(null) mice with a targeted mutation of the Dsg3 gen

221 liaceus IgGs produce a distinct phenotype in Dsg3(null) mice.

222 sive transfer of pemphigus IgG to normal and DSG3(null) neonatal mice, we show that in the areas of e

223 filament retraction, and promoted desmosomal DSG3 oligomerization.

224 ype keratinocytes showed increased levels of Dsg3 oligomers during acquisition of hyperadhesion, and

225 bolished the formation of Ca(2+) independent Dsg3 oligomers.

226 ated by autoantibodies against desmoglein 3 (Dsg3) on epidermal keratinocytes.

227 used by autoantibodies against desmoglein 3 (Dsg3) on epidermal keratinocytes.

228 t desmoglein (Dsg) 1; PV autoantibodies bind Dsg3 or both Dsg3 and Dsg1.

229 olecules between human Dsg1 and either human Dsg3 or canine Dsg1, we show that for cleavage, human-sp

230 ScFv mAbs demonstrated binding to Dsg3 or Dsg1 alone, or both Dsg3 and Dsg1.

231 However, keratinocytes lacking Dsg3 or Pkp1 or 3 revealed reduced Ca(2+) independency.

232 al at birth, but by 8-10 d weighed less than DSG3 +/- or +/+ littermates, and at around day 18 were g

233 Utilizing a desmoglein-3 mouse model (Dsg3(-/-)) or keratin 5-specific reporter mice, the inve

234 fter injection of ETA, Dsg3-/- mice, but not Dsg3+/+ or Dsg3+/- mice, showed striking loss of anagen

235 d assays coated with recombinant Dsg1, Dsc1, Dsg3, or Dsc3 ectodomains were developed.

236 Live cell imaging revealed Dsg3 order decreased more rapidly (lambda = 5.5 min), in

237 re 2 methods that are widely used to measure Dsg3 orDsg1 antibody titers in PV.

238 phosphorylation, among others, was found in Dsg3-overexpressing cells and the activation of c-Jun/AP

239 The increased Ezrin phosphorylation in Dsg3-overexpressing cells could be abrogated substantial

240 ical study using antibodies directed against DSG3, p63, and CK5/6 was also performed.

241 g3-reactive CD4(+) T cells by distinct human Dsg3 peptides that bind to HLA-DRbeta1*04:02 is tightly

242 major T cell population stimulated by these Dsg3 peptides was CD4 positive.

243 Using Dsg3 peptides, one immunodominant peptide (residues 161-

244 patients responded to at least one of three Dsg3 peptides.

245 ther patient groups did not respond to these Dsg3 peptides.

246 followed by depletion of detergent-insoluble Dsg3 pools and by the loss of cell adhesion strength.

247 series of deletion clones indicated that the DSG3 promoter demonstrated keratinocyte-specific express

248 o DSG3 mRNA by RNase protection assay and no Dsg3 protein by immunofluorescence (IF) and immunoblots.

249 s from two normals were also stimulated by a Dsg3 protein devoid of the EC2-3 (deltaN1), suggesting t

250 conformational epitopes and targeted mature Dsg3 protein.We report this case focusing on the discrep

251 RNAs that silenced expression of Dsg1 and/or Dsg3 proteins, blocked approximately 50% of p38 MAPK act

252 Finally, these results identify Dsg3-reactive CD4(+) T cells as potential therapeutic ta

253 Activation of Dsg3-reactive CD4(+) T cells by distinct human Dsg3 pept

254 epitopes of Dsg3 initiate the production of Dsg3-reactive IgG autoantibodies is still missing.

255 ino acid residues predisposing VH1-46 Abs to Dsg3 reactivity reside in CDR2.

256 eactivity; most mutations abolish VP6 and/or Dsg3 reactivity.

257 Here, we report that Dsg3 regulates the activity of c-Jun/AP-1 as well as pro

258 autoantibodies against desmoglein (Dsg)1 and Dsg3, respectively.

259 tigen BP180 and desmosomal antigens Dsg1 and Dsg3, respectively.

260 sing the diversity and clonality of the anti-Dsg3 response, as well as whether anti-Dsg3 B cells are

261 The Dsg3 responses of these T cells were restricted to HLA-D

262 ted against the desmosomal adhesion molecule Dsg3, resulting in severe mucosal erosions and epidermal

263 tibility complex class II alleles restricted Dsg3 specific T cell responses.

264 expand, persist, and specifically eliminate Dsg3-specific B cells in vivo.

265 iated HLA-DRB1*04:02 induce the secretion of Dsg3-specific IgG in vivo.

266 e inhibitory antibody against Ecad but not a Dsg3-specific PV antibody interfered with stimulated lip

267 Two CD4+ Dsg3-specific T cell lines and 12 T cell clones from two

268 Dsg3-specific T cell lines and clones were developed and

269 toantibodies is presumably T cell dependent, Dsg3-specific T cell reactivity was investigated in 14 P

270 T cell epitope(s) and TCR genes utilized by Dsg3-specific T cells.

271 immunoreactive segments of the ectodomain of Dsg3 specifically induced proliferation of T cells from

272 is sera have IgG reactivity to both Dsg1 and Dsg3, suggesting that Dsg1 may also participate in the a

273 ent on the plakoglobin-binding domain of the Dsg3 tail.

274 is patients exhibit T cell responses against Dsg3 that may serve as a target to modulate the producti

275 gainst the desmosomal cadherin desmoglein 3 (Dsg3), the major autoantigen in PV, cause loss of epider

276 Desmoglein 3 (Dsg3), the pemphigus vulgaris antigen, has recently been

277 bly can be prevented by expressing exogenous Dsg3, thereby driving Dsg3 biosynthesis and desmosome as

278 es and the turnover of cell surface pools of Dsg3 through endocytic pathways.

279 autoantibody-mediated direct interference of DSG3 transinteraction, as revealed by atomic force micro

280 By limiting loss of DSG3 transinteraction, p38 MAPK activation, and keratin

281 -46 B cell populations may be predisposed to Dsg3-VP6 cross-reactivity, but multiple mechanisms preve

282 whether VH1-46 B cells may be predisposed to Dsg3-VP6 cross-reactivity.

283 wever, somatic mutations only rarely promote Dsg3-VP6 cross-reactivity; most mutations abolish VP6 an

284 Depletion of Dsg3 was inhibited by DP-S2849G-GFP in the cytoskeletal

285 Remarkably, binding to DSG3 was lost when somatic mutations were reverted to th

286 DSG3 was over-expressed in SQCCs but had very limited ex

287 ordance, immunostaining for Dsg1 but not for Dsg3 was reduced after 24 h of Ca(2+) chelation in an ex

288 oth endosomes and lysosomes, suggesting that Dsg3 was targeted for degradation.

289 T cell recognition of Dsg3 was thus not only restricted by the pemphigus vulga

290 T cell responses to Dsg3 were also observed in four of 12 healthy individual

291 sg2) were expressed throughout, but Dsc3 and Dsg3 were confined to the limbus and conjunctiva, and Ds

292 orescence analysis indicated that PV IgG and Dsg3 were rapidly internalized from the cell surface in

293 stronger in superficial layers, but Dsc3 and Dsg3 were stronger basally, fading suprabasally.

294 Antibodies against BP180, Dsg1, and Dsg3, when injected into neonatal mice, induce the BP, P

295 atients showed reactivity with both Dsg1 and Dsg3, whereas the remaining four reacted only with Dsg3.

296 taining the extracellular portion (EC1-5) of Dsg3, whereas two of seven PV patients in remission or u

297 DRbeta1*0402+ patient PV9 was stimulated by Dsg3 with DRbeta1*0402+ L cells as antigen-presenting ce

298 donor C11 were differentially stimulated by Dsg3 with L cells expressing one of several DR11 alleles

299 iagnosis of SQCCs of the lung and to compare DSG3 with p63, CK5, and CK6, as markers of squamous cell

300 tion constructs, we find that PKP-1 clusters Dsg3 with the desmosomal plaque protein desmoplakin in a