Transcriptional heterogeneity of clonal plasma cells and immune evasion in immunoglobulin light chain amyloidosis

Abstract

Immunoglobulin light chain amyloidosis (AL amyloidosis) is characterized by the presence of B cells producing amyloidogenic immunoglobulin light chains (LCs). The low frequency of aberrant B cells in AL is often masked by a polyclonal B cell background, making it difficult for treatment. We analyzed the single-cell RNA sequencing data from GEO database to compare the plasma cell (PCs) in four individuals with AL amyloidosis, one AL subject after treatment, and six healthy controls. High interindividual variability in AL-derived PCs in their expression pattern of known overexpressed genes in multiple myeloma and their usage of V regions in LCs was demonstrated. We also found overexpression of MHC class I molecules as one of the common features of clonal PCs in individuals with AL amyloidosis. Significantly reduced frequencies of circulating natural killer (NK) cells were also observed in a small cohort of AL patients when compared to healthy controls. These data demonstrate that aberrant PCs in AL has a highly diverse transcriptome, an upregulation of MHC, and a dampened capability of immunosurveillance by reduction of circulating NK frequencies. The analysis of clonal PCs at single cell level may provide a better approach for precise molecular profiling and diagnosis of AL amyloidosis. Keywords Immunoglobulin light chain amyloidosis • Single-cell RNA sequencing • Plasma cells • Natural killer cells Abbreviations AL Immunoglobulin light chain BM Bone marrow DEG Differentially expressed gene ER Endoplasmic reticulum LC Light chain MGUS Monoclonal gammopathy of undetermined significance MM Multiple myeloma NK Natural killer PC Plasma cell scRNA-seq Single-cell RNA sequencing UMAP Uniform manifold approximation and projection Yujia Wang and Lushuang Xu have contributed equally to this work.

T cell landscape and dynamics in immunoglobulin light chain amyloidosis before and after daratumumab‐based therapy

“…1 The pathogenesis of AL remains less well understood. [2][3][4] Less than 25% of AL patients with the current mainstay chemotherapy such as a combination of bortezomib, cyclophosphamide and dexamethasone (BCD or CyBorD), and hematopoietic stem cell transplantation achieves a complete and long-lasting haematological remission and survive for more than 10 years. 5,6 In particular, AL patients with the most common chromosomal abnormality (t (11;14)) had a poor haematologic response and shorter survival when treated with BCD.…”

“… 8 , 9 Recently, high counts of monocytes and reduced frequencies of NK cells in peripheral blood were found in AL patients and the circulating monocyte counts were associated with an increased risk for AL. 10 , 11 The changes in T cells, however, are not clear. The patients with AL had similar frequencies of circulating CD3 + , CD4 + and CD8 + cells when compared to healthy controls, 12 increased ratios of BM CD4 + subsets (CCR5 + and CD28 + subsets) when compared to MM patients.…”