Autoantibody repertoire analysis in paraneoplastic pemphigus reveals novel targets linked to mucocutaneous blistering and bronchiolitis obliterans

TL;DR

This study identifies new autoantibody targets in a cancer-related autoimmune disease, offering potential for early cancer detection.

Contribution

The study reveals SERPINB3 as a novel autoantibody target linked to lung complications in paraneoplastic pemphigus.

Findings

Paraneoplastic pemphigus involves a broad repertoire of autoantibodies targeting tissue-specific proteins.

SERPINB3 autoantibodies are associated with bronchiolitis obliterans in these patients.

Autoantibody profiles are consistent across cancers, except in thymoma patients who show additional cytokine autoantibodies.

Abstract

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.

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).

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.

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.

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.

Eriksson, Aranda-Guillén et al., conduct a comprehensive analysis of autoantibodies in paraneoplastic pemphigus and identify that autoantibodies against SERPINB3 are associated with the life-threatening lung condition bronchiolitis obliterans. These discoveries provide new diagnostic biomarkers that could also allow for earlier detection of the underlying cancer.

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