Dataset Information

Development of a Desmocollin-3 Active Mouse Model Recapitulating Human Atypical Pemphigus.

ABSTRACT: Pemphigus vulgaris (PV) is a life-threatening mucocutaneous autoimmune blistering disease. It is often associated with autoantibodies to the desmosomal adhesion proteins Desmoglein 3 (DSG3) and Desmoglein 1 (DSG1). Recently, auto-antigens, such as desmocollins and others have been described in PV and in atypical pemphigus forms such as Pemphigus Herpetiformis (PH), Pemphigus Vegetans (PVeg), and Paraneoplastic Pemphigus (PP). Desmocollins belong to a cadherin subfamily that provides structure to the desmosomes and play an important role in cell-to-cell adhesion. In order to verify the pathogenic activity of anti-Desmocollin 3 (DSC3) antibodies, we developed an active disease model of pemphigus expressing anti-DSC3 autoantibodies or anti-DSC3 and anti-DSG3 antibodies. This approach included the adoptive transfer of DSC3 and/or DSG3 lymphocytes to Rag2-/- immunodeficient mice that express DSC3 and DSG3. Our results show that the presence of anti-DSC3 auto-antibodies is sufficient to determine the appearance of a pathological phenotype relatable to pemphigus, but with features not completely super-imposable to those observed in the DSG3 active model, suggesting that the DSC3 active model might mimic the atypical pemphigus. Moreover, the presence of both anti-DSC3 and anti-DSG3 antibodies determines a more severe phenotype and a slower response to prednisolone. In conclusion, we have developed an adult DSC3 pemphigus mouse model that differs from the DSG3 model and supports the concept that antigens other than desmogleins may be responsible for different phenotypes in human pemphigus.

SUBMITTER: Lotti R

PROVIDER: S-EPMC6593104 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Development of a Desmocollin-3 Active Mouse Model Recapitulating Human Atypical Pemphigus.

Lotti Roberta R Atene Claudio Giacinto CG Marconi Alessandra A Di Rocco Giulia G Reggiani Bonetti L L Zanocco Marani Tommaso T Pincelli Carlo C

Frontiers in immunology 20190619

Pemphigus vulgaris (PV) is a life-threatening mucocutaneous autoimmune blistering disease. It is often associated with autoantibodies to the desmosomal adhesion proteins Desmoglein 3 (DSG3) and Desmoglein 1 (DSG1). Recently, auto-antigens, such as desmocollins and others have been described in PV and in atypical pemphigus forms such as Pemphigus Herpetiformis (PH), Pemphigus Vegetans (PVeg), and Paraneoplastic Pemphigus (PP). Desmocollins belong to a cadherin subfamily that provides structure to ...[more]

PMID: 31275323

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Project description:Crimean-Congo hemorrhagic fever virus (CCHFV) is a cause of severe hemorrhagic fever. Its tick reservoir and vector are widely distributed throughout Africa, Southern and Eastern Europe, the Middle East, and Asia. Serological evidence suggests that CCHFV can productively infect a wide variety of species, but only humans develop severe, sometimes fatal disease. The role of the host adaptive immunity in control or contribution to the severe pathology seen in CCHF cases is largely unknown. Studies of adaptive immune responses to CCHFV have been limited due to lack of suitable small animal models. Wild-type mice are resistant to CCHFV infection, and type I interferon-deficient mice typically develop a rapid-onset fatal disease prior to development of adaptive immune responses. We report here a mouse model in which type I interferon-deficient mice infected with a clinical isolate of CCHFV develop a severe inflammatory disease but ultimately recover. Recovery was coincident with development of CCHFV-specific B- and T-cell responses that were sustained for weeks postinfection. We also found that recovery from a primary CCHFV infection could protect against disease following homologous or heterologous reinfection. Together this model enables study of multiple aspects of CCHFV pathogenesis, including convalescence, an important aspect of CCHF disease that existing mouse models have been unsuitable for studying.IMPORTANCE The role of antibody or virus-specific T-cell responses in control of acute Crimean-Congo hemorrhagic fever virus infection is largely unclear. This is a critical gap in our understanding of CCHF, and investigation of convalescence following severe acute CCHF has been limited by the lack of suitable small animal models. We report here a mouse model of CCHF in which infected mice develop severe disease but ultimately recover. Although mice developed an inflammatory immune response along with severe liver and spleen pathology, these mice also developed CCHFV-specific B- and T-cell responses and were protected from reinfection. This model provides a valuable tool to investigate how host immune responses control acute CCHFV infection and how these responses may contribute to the severe disease seen in CCHFV-infected humans in order to develop therapeutic interventions that promote protective immune responses.

Dataset Information

Development of a Desmocollin-3 Active Mouse Model Recapitulating Human Atypical Pemphigus.

Publications

Development of a Desmocollin-3 Active Mouse Model Recapitulating Human Atypical Pemphigus.

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