Pathogenicity of autoantibodies in anti-p200 pemphigoid - impact of anti-laminin β4 IgG

• Applicant: Privatdozentin Stephanie Goletz, Ph.D.
• Subject Area: Dermatology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 548023977

Anti-p200 pemphigoid is a subepidermal blistering autoimmune dermatosis characterized by autoantibodies against a 200 kDa protein in the dermoepidermal junction zone, identified in 2009 as laminin γ1 (lamγ1). However, IgG antibodies against lamγ1 have shown neither in vitro nor in vivo pathogenic potential. Recently, we identified a new antigen in anti-p200 pemphigoid, namely laminin β4 (lamβ4). Based on this discovery, studies are proposed to better understand the pathophysiology of anti-p200 pemphigoid and the significance of anti-lamβ4 antibodies in this process. The results aim to contribute to the development of more specific therapeutic strategies for anti-p200 pemphigoid patients. The objectives of this planned DFG proposal include: I. in vitro investigations of potential Fcγ receptor-independent effects of anti-lamβ4 IgG compared to anti-lamγ1 IgG in human keratinocytes. This will be achieved through comprehensive analyses, including transcriptomics, proteomics, and kinomics. II. validation of newly identified target proteins for therapeutic interventions in anti-p200 pemphigoid within primary keratinocytes. This validation will be carried out using "single-nuclei RNA-sequencing" in skin biopsies from patients. III. establishment of an in vivo passive IgG transfer model replicating the characteristic clinical and immunopathological features of anti-p200 pemphigoid. Since rodents do not express lamβ4, SCID mice with human skin transplants will be utilized, followed by the injection of purified antibodies. These approaches are crucial for exploring disease mechanisms and testing new treatment options. The developed in vitro model contributes to reducing animal experiments and identifying potential targets for the development of novel therapeutics.

• DFG Programme: Research Grants