Research Article: Single-cell sequencing reveals dynamic immune features of paraneoplastic pemphigus in a patient with follicular lymphoma

Abstract:
Paraneoplastic pemphigus (PNP) is a highly fatal autoimmune blistering disease that commonly occurs in patients with underlying benign or malignant neoplasms. It poses significant challenges for diagnosis and treatment. To date, the cellular and molecular mechanisms underlying the pathogenesis of PNP remain largely unclear. This study aims to elucidate the cellular and molecular mechanisms of PNP, particularly when it occurs secondary to lymphoma, by analyzing the dynamic immune landscape throughout the course of treatment. We performed single-cell transcriptome sequencing and single-cell T cell receptor (TCR) analysis on peripheral blood mononuclear cells (PBMCs) and bone marrow cells (BMCs) obtained from a patient with follicular lymphoma (FL) accompanied by PNP. Samples were collected at three critical time points: before treatment, during treatment, and after successful treatment. Using public datasets as a qualitative reference, we exploratorily compared patient cell frequencies to published healthy controls. In these exploratory contrasts, we observed an apparent relative abundance of ITGAL + T cells, TRDV1 -biased ??T-cell clusters, and BCL2 + B cells in PBMCs. In BMCs, we noted apparent differences including naïve T cell and certain B cell clusters. The single-cell transcriptome results described the lymphoma-associated tumor microenvironment and revealed post-treatment immune remodeling. This reconstitution involved activated DNA damage and T cell immune responses, which was further supported by the observation of a gradually expanded TCR clone as the treatment progressed. Our study delineates the dynamic immune landscape in a patient with FL-associated PNP throughout treatment. This is a descriptive, hypothesis-generating single-patient study; findings are exploratory, not generalizable, and do not establish causality. The observed changes are compatible with post-treatment immune remodeling involving specific T cell responses and TCR clone expansion. This longitudinal single-cell analysis describes the immune landscape observed in a patient with FL-associated PNP and reveals dynamic features associated with treatment response, providing a resource and generating hypotheses for future study.

Introduction:
Paraneoplastic pemphigus (PNP) is a highly fatal autoimmune blistering disease that commonly occurs in patients with underlying benign or malignant neoplasms. It poses significant challenges for diagnosis and treatment. To date, the cellular and molecular mechanisms underlying the pathogenesis of PNP remain largely unclear.

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