Disease relevance of Dsg3

• Pemphigus is a life-threatening blistering disorder of the skin and mucous membranes caused by pathogenic autoantibodies to desmosomal adhesion proteins desmoglein 3 (Dsg3) and Dsg1 [1].
• PVMAB786 will be a valuable tool in identifying the role of Dsg3 in epithelial cell adherence and acantholysis, mechanisms of Dsg3 processing/presentation and V gene and isotype usage in PV pathogenesis [2].
• CONCLUSION: The cDNA sequence and the baculovirus recombinant protein of canine Dsg3 will be useful to characterize the serum autoantibodies in canine PV [3].
• BACKGROUND: Pemphigus vulgaris (PV) is a blistering skin disease caused by IgG autoantibodies against desmoglein 3 (Dsg3) [4].
• These findings indicate that the CD40/CD154 interaction is essential for the induction of pathogenic anti-Dsg3 IgG antibodies and that antigen-specific immune-regulatory cells induced by anti-CD154 mAb would hold a therapeutic option for autoimmune diseases [5].

High impact information on Dsg3

• Protection against pemphigus foliaceus by desmoglein 3 in neonates [6].
• Antibodies against BP180, Dsg1, and Dsg3, when injected into neonatal mice, induce the BP, PF, and PV disease phenotypes, respectively [7].
• Splenocytes from the immunized Dsg3(-/-) mice were then adoptively transferred into Rag-2(-/-) immunodeficient mice expressing Dsg3 [8].
• This IgG bound to Dsg3 in vivo and disrupted the cell-cell adhesion of keratinocytes [8].
• We injected into Dsg 3-lacking mice the PV IgGs that did not cross-react with the 160-kDa Dsg 1 or its 45-kDa immunoreactive fragment and that showed no reactivity with recombinant Dsg 1 [9].

Chemical compound and disease context of Dsg3

• To address these questions we used transgenic mouse technology to produce an NH2-terminally truncated desmoglein (Pemphigus Vulgaris Antigen or Dsg3) in cells known to express its wild-type counterpart [10].

Biological context of Dsg3

• Collectively, the recipient mice developed the phenotype of PV due to the pathogenic anti-Dsg3 IgG [8].
• CONCLUSIONS: In PV model mice the antibodies were dominantly raised against the middle to C-terminal extracellular domains of mouse Dsg3 where amino acid sequences are less conserved among desmoglein isoforms and that those antibodies may also be involved in the blister formation [4].
• Thus, the anti-desmoglein antibody profiles in pemphigus sera and the normal tissue distributions of Dsg1 and Dsg3 determine the sites of blister formation [11].
• Loss of cell adhesion in Dsg3bal-Pas mice with homozygous deletion mutation (2079del14) in the desmoglein 3 gene [12].
• The mouse desmoglein 3 gene consisted of 15 exons in chromosome 18 [13].

Anatomical context of Dsg3

• Intraperitoneal inoculation of the AK23 hybridoma, but not the other AK hybridomas, induced the virtually identical phenotype to that of PV model mice or Dsg3(-/-) mice with typical histology of PV [14].
• These results suggest that loss of tolerance against Dsg3 in both B and T cells is important for the development of autoimmune state of PV [15].
• These results indicate that the N-terminal regions of Dsg3 from opposing cells interact at the dense mid-line of desmosomes where EC1 overlaps [16].
• We demonstrate that, although a Dsg3 mRNA transcript was detectable in Dsg3bal-Pas skin, the corresponding protein for desmoglein 3 was completely absent in the oral mucosal epithelium of homozygous Dsg3bal-Pas compared with that of +/Dsg3bal-Pas mice [12].
• Three different hybridoma cell lines producing anti-Dsg3 monoclonal antibodies (mAb) were intraperitoneally injected into immunodeficient mice and the precise ultrastructural location of bound IgG between the mucosal epithelial cells in vivo was statistically measured and analyzed [16].

Associations of Dsg3 with chemical compounds

• Our results contrast markedly with those recently obtained by expressing Dsg3 in epidermis under the involucrin promoter [17].
• This hypothesis has been confirmed by another group who demonstrated that the bal(J) mutation is due to the insertion of a thymidine in the desmoglein 3 gene, resulting in a premature stop codon [18].

Enzymatic interactions of Dsg3

• IgG binds to desmoglein 3 in desmosomes and causes a desmosomal split without keratin retraction in a pemphigus mouse model [19].

Regulatory relationships of Dsg3

• To address this issue, we engineered transgenic mice with desmoglein 3 under the control of the involucrin promoter [20].

Other interactions of Dsg3

• Several murine models of skin inflammation were found to develop autoantibodies to Dsg3 tightly correlated with disease aggravation, especially in MRL lpr/lpr mice [21].
• We have recently developed an active disease mouse model for PV by adoptive transfer of splenocytes from immunized or naive Dsg3-/- mice into Rag2-/- recipient mice [4].
• We characterized their epitopes using domain-swapped and point-mutated Dsg1/Dsg3 molecules and examined their pathogenic activities in blister formation in three different assays [22].
• Intracellular domain of desmoglein 3 (pemphigus vulgaris antigen) confers adhesive function on the extracellular domain of E-cadherin without binding catenins [23].
• DSG3 -/- mice had no DSG3 mRNA by RNase protection assay and no Dsg3 protein by immunofluorescence (IF) and immunoblots [24].

Analytical, diagnostic and therapeutic context of Dsg3

• ELISA using baculovirus-expressed recombinant Dsgs (rDsg3, rDsg1) has revealed that 25 out of 25 PNP sera tested were positive against Dsg3 and 16 of 25 were positive against Dsg1 [25].
• Previously, we have generated an active mouse model for PV by adoptive transfer of Dsg3(-/-) splenocytes [14].
• To solve this controversy, we performed immunoelectron microscopy to map the Dsg3 epitopes in desmosomes [16].
• To date, in mouse, only Dsg3 has been characterized by molecular cloning [26].
• CONCLUSIONS: Dsg3-specific naive lymphocytes in Dsg3(-/-) mice can be primed and activated by the endogenous Dsg3 in recipient mice to produce pathogenic anti-Dsg3 IgG without active immunization [27].

References