Home > Publications database > Human desmocollin 3-specific IgG antibodies are pathogenic in a humanized HLA-class II transgenic mouse model of pemphigus. > print

001     169841
005     20240408152048.0
024 7 _ |a 10.1016/j.jid.2021.06.017
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024 7 _ |a 0022-202X
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024 7 _ |a 1523-1747
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037 _ _ |a DKFZ-2021-01584
041 _ _ |a English
082 _ _ |a 610
100 1 _ |a Hudemann, C.
|b 0
245 _ _ |a Human desmocollin 3-specific IgG antibodies are pathogenic in a humanized HLA-class II transgenic mouse model of pemphigus.
260 _ _ |a Amsterdam
|c 2022
|b Elsevier
336 7 _ |a article
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500 _ _ |a Volume 142, Issue 3, Part B, March 2022, Pages 915-923.e3
520 _ _ |a Pemphigus is a potentially lethal autoimmune bullous skin disorder, which is associated with IgG autoantibodies against desmoglein 3 (Dsg3) and Dsg1. Notably, a subset of pemphigus patients presents with a similar clinical phenotype in the absence of anti-Dsg IgG, suggesting the presence of serum IgG reactive with desmosomal components other than Dsg1 or Dsg3. We and others have previously shown that such patients have serum IgG autoantibodies against desmocollin 3 (Dsc3), a component of desmosomes, that induce loss of keratinocyte adhesion ex vivo. Moreover, Dsc3 hypomorphic mice show a severe blistering phenotype of the mucous membrane which is highly characteristic in pemphigus. These findings prompted us to study induction and regulation of anti-human Dsc3 IgG in humanized mice transgenic for HLA-DRB1*04:02, which is a highly prevalent haplotype in pemphigus. We show that IgG from sera of immunized mice induce acantholysis in a dispase-based keratinocyte dissociation assay via the activation of p38 mitogen-activated protein kinases and epidermal growth factor receptor. Passive IgG transfer from mice immunized with recombinant human Dsc3 into neonates did not induce intraepidermal loss of adhesion presumably due to the lack of homology between human and mouse Dsc3. Ex vivo stimulation of splenocytes from Dsc3-immunized mice with human Dsc3 leads to a significant proliferative interferon-γ and interleukin 4 T cell response, which is restricted by HLA-DR/DQ. These findings suggest that induction of pathogenic anti-Dsc3 IgG is associated with Dsc3-specific T cells that recognize Dsc3 in association with HLA-DRB1*04:02.
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650 _ 7 |a HLA
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650 _ 7 |a antibodies
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650 _ 7 |a autoimmunity
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650 _ 7 |a desmocollin
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650 _ 7 |a pemphigus vulgaris
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700 1 _ |a Maglie, R.
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700 1 _ |a Llamazares, M.
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700 1 _ |a Beckert, B.
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700 1 _ |a Didona, D.
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700 1 _ |a Tikkanen, R.
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700 1 _ |a Schmitt, T.
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700 1 _ |a Hashimoto, T.
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700 1 _ |a Waschke, J.
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700 1 _ |a Hertl, M.
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700 1 _ |a Eming, R.
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773 _ _ |a 10.1016/j.jid.2021.06.017
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