Aging-associated cutaneous IgM autoreactivity identifies acquired anti-collagen XVII IgM alongside lifelong anti-collagen VII natural IgM in mice
Abstract Aging is a major risk factor for bullous pemphigoid (BP), but aging-induced cutaneous self-tolerance failure remains largely unclear. We examined skin and sera from mice across an age range using direct immunofluorescence (DIF), indirect immunofluorescence (IIF), immunoblotting against recombinant proteins of the dermal–epidermal junction (DEJ), and super-resolution microscopy. Although aged mice developed no blisters or inflammation, they displayed age-dependent linear IgM deposits at the DEJ. Circulating IgM targeted both epidermal and dermal DEJ components and comprised two specificities: age-acquired anti–type XVII collagen (COL17, autoantigen in BP) IgM and lifelong anti–type VII collagen (COL7, autoantigen in epidermolysis bullosa acquisita) IgM. Anti-COL7 IgM persisted across diverse immunopathological models and was reduced in B-1a–deficient mice, supporting a natural antibody origin. We propose a model in which lifelong anti-COL7 natural IgM coexists with aging-driven emergence of anti-COL17 IgM, suggesting a subclinical pre-BP state.
Authors
- Yoichiro Fujioka (ORCID: https://orcid.org/0000-0002-5760-9357)
- Yoshinori Hasegawa (ORCID: https://orcid.org/0000-0003-2904-6611)
- Takamasa Ito (ORCID: https://orcid.org/0009-0001-5972-6186)
- Ken Muramatsu (ORCID: https://orcid.org/0000-0001-6212-0751)
- Ken Natsuga (ORCID: https://orcid.org/0000-0003-3865-6366)
- Norihiro Yoshimoto (ORCID: https://orcid.org/0000-0002-9599-1251)
- Takuya Kawamura (ORCID: https://orcid.org/0000-0001-6256-6964)
- Sho Katayama (ORCID: https://orcid.org/0000-0003-0188-3717)
- Yosuke Mai (ORCID: https://orcid.org/0000-0001-6356-7192)
- Hiroaki Iwata (ORCID: https://orcid.org/0000-0002-8781-2735)
- Utano Tomaru (ORCID: https://orcid.org/0000-0001-7929-9874)
- Yusuke Ohba (ORCID: https://orcid.org/0000-0003-2461-8289)
- Chihiro Shiiya (ORCID: https://orcid.org/0000-0003-4802-2623)
- Hideyuki Ujiie (ORCID: https://orcid.org/0000-0002-3489-5418)
- Shoko Mai (ORCID: https://orcid.org/0000-0001-5468-6851)
- Hiroyuki Kitahata (ORCID: https://orcid.org/0000-0003-3453-9883)
- Kentaro Izumi (ORCID: https://orcid.org/0000-0001-8221-9644)
- Kentaro Saito
Institutions
- Chiba University (JP)
- Hokkaido University (JP)
- Hokkaido University Hospital (JP)
- Kazusa DNA Research Institute (JP)
- Gifu University (JP)
Publication Details
- Journal
- Research Square
- Published
- 2026-11-02
- DOI
- https://doi.org/10.21203/rs.3.rs-10549604/v1
- Primary Topic
- Autoimmune Bullous Skin Diseases
- Type
- preprint