Abstract
Background
Paraneoplastic autoimmunity develops as consequences of immune reactions to cancer and exhibits a wide range of clinical manifestations. The autoimmune signs are often visible before the underlying malignancy is diagnosed, and a prompt diagnosis of paraneoplasia is crucial to enable early tumor detection. We characterized the immune responses underlying the severe mucocutaneous blistering disease paraneoplastic pemphigus.
Methods
We used a two-step approach to proteome-wide autoantibody repertoire analysis and independent validation in patients with paraneoplastic pemphigus (n = 84) and non-paraneoplastic autoimmune blistering diseases (n = 103).
Results
Our findings reveal that paraneoplastic pemphigus features a broad repertoire of disease-specific autoantibodies that mainly target tissue-specific proteins in the skin and mucous membranes. Importantly, we identify SERPINB3 as a major autoantibody target with an expression pattern and clinical association suggesting a role in bronchiolitis obliterans. Autoantibody profiles are similar across neoplasias, except in thymoma patients, who additionally express multiple cytokine autoantibodies.
Conclusions
Our findings reveal a disease-defining autoantibody repertoire in paraneoplastic pemphigus that corresponds with clinical manifestations and holds high potential for early cancer detection in patients with blistering disease.
Plain language summary
When the immune system reacts against cancer cells, it can sometimes mistakenly attack self-tissues in a process called autoimmunity. In some patients, these autoimmune symptoms present even before the cancer is detected, making early diagnosis of cancer-associated autoimmunity very important. In this study, we characterized the proteins targeted by the immune system in paraneoplastic pemphigus, a severe cancer-associated autoimmune disease that causes blisters on the skin and mucous membranes. To achieve this, we tested blood samples from the patients against thousands of human proteins to determine which ones were recognized by their antibodies. The findings provide new insights into how the immune system responds to cancer and can serve as early diagnostic markers to help detect cancer in patients with autoimmune blistering diseases.
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Data availability
The data that support the findings of this study are available through the ArrayExpress collection in BioStudies under accession number E-MTAB-14920. Source data for all Figures can be accessed from Supplementary Data 1. RNA-seq expression data for healthy subjects were retrieved from the Human Protein Atlas18 version 23.0 (https://www.proteinatlas.org/), accessed 2023-12-13 (rna_single_cell_type.tsv, and rna_single_cell_cluster_description.tsv), and the GTEx portal (v6p.v1.1.8), accessed 2022-12-05. The GTEx database was queried using the top 42 autoantibody targets identified in Fig. 2d (Supplementary Fig. S6). From these, tissue-specific proteins were selected for further emphasis in Fig. 3a. RNA-seq summary statistics for hematological malignancies were retrieved from the CGCI Data Matrix (https://ocg.cancer.gov/programs/cgci/data-matrix), accessed 2022-12-09 (datasets BLGSP, HTMCP-CC, NHL-DLBCL, and NHL-FL). Frequent neoantigens were retrieved from the Tumor-specific Neoantigen Database22, version 2, accessed October 2023.
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Acknowledgements
We thank the National Facility for Autoimmunity and Serology Profiling at SciLifeLab for excellent technical support. The study was supported by the Swedish Cancer Society (21 1513 Pj 01 H), the Swedish Research Council (2021-03118), and the ALF-agreement between the Swedish government and the county councils. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The results published here are in part based upon data generated by the Cancer Genome Characterization Initiative (phs000235): Non-Hodgkin Lymphoma project, HIV+ Tumor Molecular Characterization Project, and Burkitt Lymphoma Genome Sequencing Project, developed by the NCI. Information about CGCI projects can be found at https://www.cancer.gov/ccg/.
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Open access funding provided by Uppsala University.
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D.E. and N.L. conceived the study, and D.E., M.A.G., O.K., T.H., and N.L. planned the work. D.E., M.A.G., A.C., A.B., F.A., J.K., S.Ö., J.O., R.S., P.N. performed or contributed to experiments. D.E., M.A.G., A.C., A.B., F.A., J.K., S.Ö., and J.O. performed the data analysis. N.I., D.S., and T.H. characterized the patient cohorts. D.E., M.A.G., and N.L. wrote the manuscript with contributions from all coauthors.
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Communications Medicine thanks Gilles F. H. Diercks, Kelly N. Messingham and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
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Eriksson, D., Aranda-Guillén, M., Ishii, N. et al. Autoantibody repertoire analysis in paraneoplastic pemphigus reveals novel targets linked to mucocutaneous blistering and bronchiolitis obliterans. Commun Med (2026). https://doi.org/10.1038/s43856-025-01335-2
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DOI: https://doi.org/10.1038/s43856-025-01335-2
