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dc.contributor.author
Ravasio, Sara
dc.contributor.supervisor
Sallusto, Federica
dc.contributor.supervisor
Lanzavecchia, Antonio
dc.contributor.supervisor
Picotti, Paola
dc.contributor.supervisor
Merlini, Giampaolo
dc.date.accessioned
2019-09-30T05:55:37Z
dc.date.available
2019-09-29T10:27:17Z
dc.date.available
2019-09-30T05:55:37Z
dc.date.issued
2019
dc.identifier.uri
http://hdl.handle.net/20.500.11850/367098
dc.identifier.doi
10.3929/ethz-b-000367098
dc.description.abstract
It is well established that immunoglobulin Light (L) chains dimers, also known as Bence-Jones (BJ) proteins, are secreted by normal and malignant plasma cells (PCs) and, when produced in large amounts, can aggregate into amyloid fibrils in target tissues leading to organ failure and to the clinical manifestation of Immunoglobulin Light Chain amyloidosis (AL amyloidosis). The unique identity of the pathogenic L chain belonging to each AL amyloidosis patient, which originates from the mechanisms of generation of antibody diversity, has considerably hindered the identification of the structural determinants of L chains aggregation and consequent clinical manifestations. The aim of my thesis is to examine AL amyloidosis from the B cell perspective, considering that in developing B cell clones, L chain variable (VL) domains undergo a process of somatic mutation and are selected for pairing with variable Heavy (H) chain (VH) domains to form a functional B cell receptor (BCR). Therefore, by comparing the effect of L chains hetero-dimerization with H chains to L chains homo-dimerization, I could show that free L chains, which are not subject to antigen-driven selection, are intrinsically unstable and are characterized by the exposure of hydrophobic patches and free thiols; their instability is substantially increased by somatic mutations, leading to aggregation into Congo Red (CR)- and Thioflavin T (ThT)- positive amyloid fibers. I could also show that free L chains have unique specificities and can bind to cells and to the extracellular matrix, a property that may increase their local concentration and drive the nucleation phase of amyloid aggregation in the target tissues. Taken together, these findings demonstrate that, in the absence of a negative selection mechanism, L chain dimers develop through somatic mutations into rogue proteins, leading to their concentration-dependent aggregation and organ accumulation. Consequently, these results suggest that a plausible explanation of AL amyloidosis pathogenesis could be represented by the deleterious combination of a break of tolerance with a break of protein homeostasis.
en_US
dc.format
application/pdf
en_US
dc.language.iso
en
en_US
dc.publisher
ETH Zurich
en_US
dc.title
Light Chain Dimers Acquire Amyloidogenic Properties in the Absence of Selection
en_US
dc.type
Doctoral Thesis
dc.date.published
2019-09-30
ethz.size
106 p.
en_US
ethz.code.ddc
DDC - DDC::6 - Technology, medicine and applied sciences::610 - Medical sciences, medicine
ethz.code.ddc
DDC - DDC::5 - Science::570 - Life sciences
ethz.identifier.diss
25870
en_US
ethz.publication.place
Zurich
en_US
ethz.publication.status
published
en_US
ethz.leitzahl
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02030 - Dep. Biologie / Dep. of Biology::02520 - Institut für Mikrobiologie / Institute of Microbiology::09604 - Sallusto, Federica / Sallusto, Federica
en_US
ethz.date.deposited
2019-09-29T10:27:29Z
ethz.source
FORM
ethz.eth
yes
en_US
ethz.availability
Embargoed
en_US
ethz.date.embargoend
2022-09-30
ethz.rosetta.installDate
2019-09-30T05:55:58Z
ethz.rosetta.lastUpdated
2020-02-15T21:48:52Z
ethz.rosetta.versionExported
true
ethz.COinS
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