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. 2025 May;155(5):1521-1535.
doi: 10.1016/j.jaci.2025.02.014. Epub 2025 Feb 19.

Molecular mimicry-driven autoimmunity in chronic rhinosinusitis with nasal polyps

Tomoaki Asamori  1 , Hiroto Katoh  2 , Mikiya Takata  3 , Daisuke Komura  3 , Miwako Kakiuchi  3 , Itaru Hashimoto  3 , Madoka Sakurai  3 , Asami Yamamoto  3 , Takeshi Tsutsumi  4 , Takahiro Asakage  5 , Yasushi Ota  6 , Shumpei Ishikawa  7
Affiliations
Free article

Molecular mimicry-driven autoimmunity in chronic rhinosinusitis with nasal polyps

Tomoaki Asamori et al. J Allergy Clin Immunol. 2025 May.
Free article

Abstract

Background: The pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP) remains a subject of discussion. Although both microbial infection and autoimmunity have been proposed as potential contributors to CRSwNP pathobiology, their respective roles and intricate interactions in disease progression remain unclear owing to the limited knowledge regarding dysregulated humoral immunity in CRSwNP.

Objective: To deepen understanding of CRSwNP, we sought to identify the precise humoral antigens targeted by dominant B-cell clones within the disease environments.

Methods: Immunoglobulin repertoire sequencing was performed to identify dominant B-cell clones in CRSwNP tissues. These immunoglobulin clones were reconstructed as antibodies, which were then used in immunoprecipitation and antigen array experiments for hypothesis-free global antigen profiling of autogenous and exogenous antigens.

Results: From analysis of 13 patients with CRSwNP, 31 antibodies were reconstructed from dominant B-cell clones identified in 9 patients. Seven novel protein autoantigens were identified, 5 of which were nucleic acid-binding proteins, and all were associated with autoimmune diseases. Additionally, 9 microbial antigens, including various viruses, bacteria, and fungi, were discovered. Notably, 2 antibodies demonstrated dual reactivity, simultaneously recognizing both microbial and human proteins. For example, 1 antibody targeted cytomegalovirus, Clostridium tetani, and human PLEC, whereas another recognized Aspergillus niger and human DLAT, through molecular mimicry of shared amino acid homologies.

Conclusion: Our data indicate the possibility that the pathobiology of CRSwNP involves autoreactive humoral immunity, with a subset of cases potentially exhibiting molecular mimicry-driven autoimmune features triggered by microbial infections. Nevertheless, this hypothesis requires further investigation.

Keywords: CRSwNP; autoimmunity; humoral antigen; immunoglobulin; microbial immunity; molecular mimicry; repertoire sequencing.

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Conflict of interest statement

Disclosure statement This study was supported by the Japan Society for the Promotion of Science (JSPS) Grant-in-Aid for Scientific Research (A) (grant number JP19H01032) to H.K., the Japan Agency for Medical Research and Development (AMED) Science and Technology Platform Program for Advanced Biological Medicine (grant number JP23am0401010) to S.I., and the Japan Initiative for World-leading Vaccine Research and Development Centers, University of Tokyo Pandemic Preparedness, Infection, and Advanced Research Center (UTOPIA) from AMED (grant number JP243fa627001). Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.