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Bone Marrow Interstitial Light-chain Amyloid and its Microenvironment

ABSTRACT: Bone Marrow Interstitial Light-chain Amyloid and its Microenvironment

PROVIDER: PRJNA1000614 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25469356.fastq.gz	Fastqsanger.gz
	SRR25469357.fastq.gz	Fastqsanger.gz
	SRR25469358.fastq.gz	Fastqsanger.gz
	SRR25469359.fastq.gz	Fastqsanger.gz
	SRR25469360.fastq.gz	Fastqsanger.gz

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Bone Marrow Interstitial Light-chain Amyloid and its Microenvironment

Project description:Amyloid deposition and neighboring tissue responses remain poorly understood. Twenty percent of patients with systemic light-chain amyloidosis (AL) have interstitial marrow amyloid containing clonal Ig light-chain fibrils and apolipoprotein chaperone proteins. We compared CD138-depleted aspirate mononuclear cells (MNC) from marrows of AL patients with (+MA) and without (-MA) interstitial amyloid by gene expression profiling (GEP) and single-cell RNA-sequencing (scRNA seq). GEP showed no differential expression of genes for proteolytic enzymes or apolipoproteins between the groups but +MA cases had significantly up-regulated erythroid genes involved in oxygen transport, including transmembrane and coiled-coil domain family 2 (TMCC2). In +MA marrows at the single-cell level, CD14+ monocytes were increased by 22%, granulocyte-monocyte progenitors decreased by 66%, and erythroid-megakaryocyte progenitors and early and late erythroid progenitors increased up to five-fold. Gene enrichment studies showed that in +MA marrows pathways for TNFα signaling, immune activation, monocyte hypoxia and erythropoiesis were significantly enriched. We also compared peripheral blood and marrow plasma by immunoprecipitation and immunoblot with respect to apolipoproteins and light chains in complex with the erythroid protein TMCC2, and by ELISA for marrow apolipoprotein E and J levels. Apolipoprotein J is strongly associated with light chains in blood and E is not, while in +MA marrow plasma J and E are strongly present in association with light chains. There is also significantly more apolipoprotein E and J in +MA marrow plasma. In summary, marrows with interstitial amyloid provide opportunities to study amyloid’s impact on cellular and regenerative activity and chaperone involvement in amyloid formation.

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Project description:Bone Marrow Interstitial Light-chain Amyloid and its Microenvironment

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Insight into the protein composition of immunoglobulin light chain deposits of eyelid, orbital, and conjunctival amyloidosis.

Project description:Amyloidosis is a disorder characterized by the formation of extracellular amyloid deposits. Immunoglobulin light-chain amyloidosis the most common form of amyloidosis can appear as a local disorder presented with mild symptoms or as a life threatening systemic disease. Identification of the proteins forming amyloid fibrils is essential for the diagnosis of the disease and knowledge about the overall protein composition of the deposits may lead to a larger understanding of the deposition events thereby facilitating a more detailed picture of the molecular pathology. In this study, we investigated the protein composition of AL amyloid deposits isolated from human eyelid, conjunctival and orbital specimens. Deposits and internal control tissue (patient tissue without apparent deposits) were procured by laser capture microdissection. Proteins in the captured amyloid and control samples were identified by liquid chromatography tandem mass spectrometry and subsequently quantified using the label-free mass spectrometry quantification method exponential modified Protein Abundance Index. Immunoglobulin light chain kappa or lambda was revealed to be the most predominant protein in the amyloid deposits. In addition, the protein profiles identified apolipoprotein E and serum amyloid P component to be associated with the immunoglobulin light chain deposits across all three tissues analyzed. The method used in this study provides high sensitivity and specificity of typing amyloidosis and may provide additional information on the pathology of amyloidosis.

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A conservative point mutation in a dynamic antigen-binding loop of human immunoglobulin λ6 light chain promotes pathologic amyloid formation

Project description:Immunoglobulin light chain (LC) amyloidosis (AL) is a life-threatening human disease wherein free monoclonal LCs deposit in vital organs. To determine what makes some LCs amyloidogenic, we explored patient-based amyloidogenic and non-amyloidogenic recombinant LCs from the λ6 subtype prevalent in AL. Hydrogen-deuterium exchange mass spectrometry, structural stability, proteolysis, and amyloid growth studies revealed that the antigen-binding CDR1 loop is the least protected part in the variable domain of λ6 LC, particularly in the AL variant. N32T substitution in CRD1 is identified as a driver of amyloid formation. Substitution N32T increased the amyloidogenic propensity of CDR1 loop, decreased its protection in the native structure, and accelerated amyloid growth in the context of other AL substitutions. The destabilizing effects of N32T propagated across the molecule increasing its dynamics in regions ~30Å away from the substitution site. Such striking long-range effects of a conservative point substitution in a dynamic surface loop may be relevant to Ig function. Comparison of patient-derived and engineered proteins showed that N32T interactions with other substitution sites must contribute to amyloidosis. The results suggest that CDR1 is critical in amyloid formation by other λ6 LCs.

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