Post-graduate theses
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Identifier |
000376188 |
Title |
Functional analysis of innate immunity receptors in chronic lymphocytic leukemia |
Author
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Vardi, Anna
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Author
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Βαρδή, Άννα
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Thesis advisor
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Παπαδάκη Ελένη
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Reviewer
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Σταματόπουλος, Κώστας
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Abstract |
Background: Mature B cells recognize antigens through the B cell receptor (BCR)
in a specific way and through Toll-like receptors (TLRs) and Nod-like receptors
(NLRs) in a costimulatory manner. Plenty of evidence supports a role for antigenic
stimulation in the natural history of chronic lymphocytic leukemia (CLL). While
BCR signaling has extensively been studied, little is known regarding the function
of TLRs and NLRs in CLL cells.
Design and methods: We used a series of 67 patients, selected with an
intentional bias for cases assigned to two different subsets with stereotyped BCRs,
namely subsets #1 and #4. We stimulated negatively isolated CLL cells with
specific ligands for all TLRs/NLRs found to be expressed in B cells and measured
by flow cytometry the upregulation of CD25 and CD86 expression as a marker of
NF-κB activation. We compared our findings among CLL subgroups based on
IGHV mutational status, IGHV gene usage and BCR stereotypy.
Results: TLR9 was functional in practically all cases. TLR1/2, TLR2/6 and NOD2
were functional in most cases with concordant functionality in different cases.
TLR7 was functional in fewer cases and responded only to imiquimod, but not
loxoribine. Moreover, TLR9 upregulated CD86 expression only in “mutated” CLL
cases while TLR7 upregulated CD25 expression only in “unmutated” CLL cases.
Finally, TLR1/2, TLR2/6 and NOD2 stimulation had a much stronger effect in
CD25/86 upregulation in subset #4 cases when compared to all other “mutated”
cases or cases carrying the IGHV4-34 gene in heterogeneous rearrangements.
When subset #4 was compared to subset #1, we found that TLR9, TLR1/2, TLR 2/6
and NOD2 stimulation had no effect in CD86 expression in subset #1. Instead,
TLR7 stimulation strongly induced CD25 upregulation, in sharp contrast with
subset #4.
Conclusions: TLRs and NLRs are functional in CLL cells, yet in a heterogeneous
fashion. Their stimulation has a pleiotropic effect on the upregulation of
costimulatory molecules, depending on the IGHV mutational status. Patterns of
TLR/NLR functionality can be recognized among CLL subsets with distinct
stereotyped BCRs, offering hints for the nature of the antigenic drive.
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Language |
Greek |
Subject |
Immunity,Innate |
Issue date |
2010-07-20 |
Collection
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School/Department--School of Medicine--Department of Medicine--Post-graduate theses
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Type of Work--Post-graduate theses
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Permanent Link |
https://elocus.lib.uoc.gr//dlib/d/e/3/metadata-dlib-1351843062-974372-673.tkl
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Views |
229 |