A mouse model of pemphigus vulgaris by adoptive transfer of naive splenocytes from desmoglein 3 knockout mice

Aoki-Ota, Miyo; Tsunoda, Kazuyuki; Ota, Takayuki; Iwasaki, Tadaaki; Koyasu, Shigeo; Amagai, Masayuki; Nishikawa, Takeji

doi:10.1111/j.1365-2133.2004.06056.x

Cited by 49 publications

(58 citation statements)

References 20 publications

(49 reference statements)

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“…All four recipient mice, which received a single Dsg3-reactive T cell clone and unprimed Dsg3 Ϫ/Ϫ B cells, produced IgG1 together with IgG2a, IgG2b, and IgG3 (Table II). The predominance of the IgG1 subclass is consistent with the predominant IgG1 subclass found in PV model mice (17). This finding provides further evidence that single Dsg3-reactive T cell clones interact with polyclonal naive B cells that produce at least two different IgG subclasses.…”

Section: Induction Of Two or More Igg Subclasses By Dsg3-reactive T Csupporting

confidence: 72%

A Single Helper T Cell Clone Is Sufficient to Commit Polyclonal Naive B Cells to Produce Pathogenic IgG in Experimental Pemphigus Vulgaris

Takahashi¹,

Kuwana

Amagai³

2009

The Journal of Immunology

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The development of naive B cells into IgG-producing memory B cells requires cognate T cell-B cell interaction in Ag-specific immune responses. It is unknown whether a single T cell clone is sufficient or whether multiple clones are necessary to induce polyclonal IgG production in vivo. We addressed this issue using a mouse model of pemphigus vulgaris, a fatal autoimmune blistering skin disease caused by IgG autoantibodies against desmoglein (Dsg) 3. We previously isolated several Dsg3-reactive T cell clones from Dsg3−/− mice. Among these, two pathogenic T cell clones induced anti-Dsg3 IgG production and the development of a pemphigus phenotype when adoptively transferred with unprimed B cells from Dsg3−/− mice. IgG Abs harvested from recipient mice reacted with at least three parts of the extracellular domain of Dsg3, as determined using domain-swapped Dsg3/Dsg1 molecules. The anti-Dsg3 IgGs included at least two subclasses among IgG1, IgG2a, IgG2b, and IgG3 in each mouse. The anti-Dsg3 IgG induced by Dsg3-reactive T cell clones with primed B cells from Dsg3−/− mice also showed reactivity against different parts of the molecule, with a similar epitope distribution. Together, these results indicate that a single potent Dsg3-reactive T cell is sufficient to commit polyclonal naive B cells to produce pathogenic anti-Dsg3 IgG Abs and induce the PV phenotype. These findings provide an important framework for examining immunological mechanisms in Ab-mediated autoimmune diseases.

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Section: Induction Of Two or More Igg Subclasses By Dsg3-reactive T Csupporting

confidence: 72%

A Single Helper T Cell Clone Is Sufficient to Commit Polyclonal Naive B Cells to Produce Pathogenic IgG in Experimental Pemphigus Vulgaris

Takahashi¹,

Kuwana

Amagai³

2009

The Journal of Immunology

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“…In experimental autoimmune encephalomyelitis, a myelin-reactive T cell-dependent multiple sclerosis model, natural resolution correlates with the accumulation of myelin-reactive Tregs expanded during the course of experimental autoimmune encephalomyelitis in the inflamed CNS (31,32 (33,34). In experimental pemphigus vulgaris, an autoimmune blistering disease caused by anti-desmoglein 3 Abs, the production of autoantibodies required both CD4 + T cells and B cells from naive desmoglein 3 knockout mice (35). To further investigate the pathogenic role of CD4 + T cells, we administered CsA, an immunosuppressant that inhibits T cell function, to the Rag-2 2/2 / COL17-humanized recipients after the adoptive transfer of immunized splenocytes.…”

Section: Discussionmentioning

confidence: 99%

A Novel Active Mouse Model for Bullous Pemphigoid Targeting Humanized Pathogenic Antigen

Ujiie

Shibaki

Nishie

et al. 2010

The Journal of Immunology

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Bullous pemphigoid (BP), the most common autoimmune blistering disease, is caused by autoantibodies against type XVII collagen (COL17). To establish an active stable BP animal model that demonstrates the persistent inflammatory skin lesions initiated by the anti-human COL17 Abs, we used COL17-humanized (COL17m−/−,h+) mice that we recently produced. First, we generated immunodeficient Rag-2−/−/COL17–humanized mice by crossing Rag-2−/− mice with COL17-humanized mice. Then, splenocytes from wild-type mice that had been immunized by grafting of human COL17-transgenic mouse skin were transferred into Rag-2−/−/COL17–humanized mice. The recipient mice continuously produced anti-human COL17 IgG Abs in vivo and developed blisters and erosions corresponding to clinical, histological, and immunopathological features of BP, although eosinophil infiltration, one of the characteristic histological findings observed in BP patients, was not detected in the recipients. Although the depletion of CD8+ T cells from the immunized splenocytes was found to produce no effects in the recipients, the depletion of CD4+ T cells as well as CD45R+ B cells was found to inhibit the production of anti-human COL17 IgG Abs in the recipients, resulting in no apparent clinical phenotype. Furthermore, we demonstrated that cyclosporin A significantly suppressed the production of anti-human COL17 IgG Abs and prevented the development of the BP phenotype in the treated recipients. Although this model in an immunodeficient mouse does not exactly reproduce the induction mechanism of BP in human patients, this unique experimental system targeting humanized pathogenic Ag allows us to investigate ongoing autoimmune responses to human molecules in experimental animal models.

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“…Passively transferred Dsg3-specific and Dsg1-specific IgG into mice results in loss of epidermal cell-cell adhesion and typical lesions found in pemphigus [17]. A mouse model that produces pathogenic anti-Dsg3 IgG and induces the PV phenotype has also been developed by transferring naive splenocytes from Dsg3 (-/-) mice into Rag2 (-/-) mice that expressed Dsg3 [18]. The 113 NH2-terminal residues of Dsg1 and Dsg 3, part of the first two portions of five extracellular domains (EC1-5), are integral for the binding of autoantibodies in pemphigus.…”

Section: Pemphigusmentioning

confidence: 98%

What’s new in blistering disorders?

Chaudhari¹,

Marinkovich

2007

Curr Allergy Asthma Rep

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From the characterization of new animal models for the study of disease pathogenesis, to the demonstration of new therapeutic modalities, many developments have revolutionized the field of autoimmune bullous diseases in the past several years. This review highlights many of the significant advances that have taken place in the diagnosis, pathogenesis, and treatment options for pemphigus, pemphigoid, epidermolysis bullosa acquisita, and immunoglobulin (Ig) A-mediated bullous disorders.

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A mouse model of pemphigus vulgaris by adoptive transfer of naive splenocytes from desmoglein 3 knockout mice

Cited by 49 publications

References 20 publications

A Single Helper T Cell Clone Is Sufficient to Commit Polyclonal Naive B Cells to Produce Pathogenic IgG in Experimental Pemphigus Vulgaris

A Single Helper T Cell Clone Is Sufficient to Commit Polyclonal Naive B Cells to Produce Pathogenic IgG in Experimental Pemphigus Vulgaris

A Novel Active Mouse Model for Bullous Pemphigoid Targeting Humanized Pathogenic Antigen

What’s new in blistering disorders?

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