Pulmonary Sarcoidosis: Experimental Models and Perspectives of Molecular Diagnostics Using Quantum Dots

Abstract

Sarcoidosis is a complex inflammatory multisystem disease of unknown etiology that is characterised by epithelioid cell granulomatous lesions affecting various organs, mainly the lungs. In general, sarcoidosis is asymptomatic, but some cases result in severe complications and organ failure. So far, no accurate and validated modelling for clinical and pathohistological manifestations of sarcoidosis is suggested. Moreover, knowledge about disease-specific diagnostic markers for sarcoidosis is scarce. For instance, pulmonary granulomatosis is associated with the upregulated production of proinflammatory molecules: TNF-α, IL-6, CXCL1, CCL2, CCL18, CD163, serum angiotensin-converting enzyme (sACE), lysozyme, neopterin, and serum amyloid A (SAA). Quantum dots (QDs) are widely applied for molecular diagnostics of various diseases. QDs are semiconductor nanoparticles of a few nanometres in size, made from ZnS, CdS, ZnSe, etc., with unique physical and chemical properties that are useful for the labelling and detection in biological experiments. QDs can conjugate with various antibodies or oligonucleotides, allowing for high-sensitivity detection of various targets in organs and cells. Our review describes existing experimental models for sarcoidosis (in vitro, in vivo, and in silico), their advantages and restrictions, as well as the physical properties of quantum dots and their potential applications in the molecular diagnostics of sarcoidosis. The most promising experimental models include mice with TSC2 deletion and an in silico multiscale computational model of sarcoidosis (SarcoidSim), developed using transcriptomics and flow cytometry of human sarcoid biopsies. Both models are most efficient to test different candidate drugs for sarcoidosis.

Keywords: experimental models of sarcoidosis; molecular diagnostics; quantum dots; sarcoidosis.

Figure 1

Schematic representation of the in vitro sarcoidosis model to study human lung cells. Cells are isolated from lung tissue biopsy, BAL, or blood of sarcoidotic patients and healthy donors. In healthy controls without pulmonary pathology, bacterial agents (Mycobacterium protein particles, P. acnes) or carbon nanoparticles (MWNCTs) are added to initiate granulomas and pulmonary fibrosis as major signs of sarcoidosis.

Figure 2

A scheme for the creation of sarcoidosis models in animals. For this purpose, animals are sensitised by preliminary administration of bacterial antigens (Mycobacterium protein particles, P. acnes) or carbon nanoparticles (MWNCTs), which initiate granulomas and pulmonary fibrosis as the main signs of sarcoidosis. Mice with deletion of the Tsc2 gene, a regulator of the mTOR signalling pathway, are also used to simulate sarcoidosis. Abbreviations: BAL—bronchoalveolar lavage, IHC—immunohistochemistry, PBMCs—peripheral blood mononuclear cells, GSEA—gene set enrichment analysis, GWAS—genome-wide association studies, WES—whole-exome sequencing, MWNCTs—multi-walled carbon nanotubes.

Figure 3

The main signalling molecules and pathways involved in the pathogenesis of sarcoidosis.