Internalisation of immunoglobulin light chains by cardiomyocytes in AL amyloidosis: what can biopsies tell us?

Abstract

Background

Cardiac involvement in systemic light chain amyloidosis (AL) leads to chronic heart failure and is a major prognosis factor. Severe cellular defects are provoked in cardiac cells by tissue-deposited amyloid fibrils of misfolded free immunoglobulin light chains (LCs) and their prefibrillar oligomeric precursors.

Objective

Understanding the molecular mechanisms behind cardiac cell cytotoxicity is necessary to progress in therapy and to improve patient management. One key question is how extracellularly deposited molecules exert their toxic action inside cardiac cells. Here we searched for direct evidence of amyloid LC uptake by cardiomyocytes in patient biopsies.

Methods

We immunolocalized LCs in cardiac biopsies from four AL cardiac amyloidosis patients and analysed histopathological images by high resolution confocal microscopy and 3D image reconstruction.

Results

We show, for the first time directly in patient tissue, the presence of LCs inside cardiomyocytes, and report their proximity to nuclei and to caveolin-3-rich areas. Our observations point to macropinocytosis as a probable mechanism of LC uptake.

Conclusions

Internalisation of LCs occurs in patient cardiomyocytes. This event could have important consequences for the pathogenesis of the cardiac disease by enabling interactions between amyloid molecules and cellular organelles inducing specific signalling pathways, and might bring new insight regarding treatment.

Keywords:

• Cardiac biopsies
• cardiomyocytes
• caveolin-3
• immunoglobulin light chains
• light chain (AL) cardiac amyloidosis
• high resolution confocal microscopy

Acknowledgments

We thank Dr Domitille Callon (Forensic and Pathology Departments, Academic Hospital of Reims, Reims, France) for critical reading of the manuscript and scientific discussion.

Disclosure statement

The authors have no conflict of interests related to this publication to declare.

Additional information

Funding

This work was supported by recurrent funding from Sorbonne Université, CNRS and INSERM. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.