Contribution in the understanding of the molecular ... · Heavy Chain Deposition Disease =HCDD...
Transcript of Contribution in the understanding of the molecular ... · Heavy Chain Deposition Disease =HCDD...
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Presented by Sébastien BENDER
Contribution in the understanding of the molecular mechanisms in Heavy Chain
Deposition Disease
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Disclosure of Conflict of Interest
Nature of relationship(s)Name of for-profit or not-for-profit organization(s)
Description of relationship(s)
Any direct financial payments including receipt of honoraria
Membership on advisory boards or speakers’ bureaus
Funded grants or clinical trials
Patents on a drug, product or device
All other investments or relationships that could be seen by a reasonable, well-informed participant as having the potential to influence the content of the educational activity
x I do not have a relationship with a for-profit and/or a not-for-profit organization to disclose
❑ I have a relationship with a for-profit and/or a not-for-profit organization to disclose
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Heavy Chain Deposition Disease =HCDD
Molecular mechanisms of HCDD
Healthy glomerulus Sclerotic glomerulus
▪ Deposition of a truncated heavy chain (HC), mainly in the kidney.▪ Non-organized/amorphous deposits along tubular and glomerular
basement membranes.▪ Proteinuria. ▪ Nodular glomerulosclerosis.
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VDJ CH1 CH2 CH3
Normal 1
H
γ1 case 1
CH1 deletion is always present in HCDD
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Molecular mechanisms of HCDD
= Binding Ig Protein
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Molecular mechanisms of HCDD
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Can CH1 deletion occur due to a problem with the light chain (LC)?
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Molecular mechanisms of HCDD
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Molecular mechanisms of HCDD
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Identification of 2 monoclonal components
Gamma heavy chain
Serum
The 2 components are produced by the same clone
@human gamma @human lambdaMerge
BM
Lambda light chain
BM Serum
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Molecular mechanisms of HCDD
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The lambda light chain has its V domain truncated
λmRNA atggcctgggctctgctgctcctcaccctcctcactcagggcacaggatcctgggctcagtctgccctgactcagcctccctccgtgtccgggtctcctggacagtcagtcaccatctcc
Prot M A W A L L L L T L L T Q G T G S W A Q S A L T Q P P S V S G S P G Q S V T I S
λmRNA tgcactggaatcagcagtgacgttggtcagcccaaggctgccccctcggtcactctgttcccaccctcctctgaggagcttcaagccaacaaggccacactggtgtgtctcataagtgac
Prot C T G I S S D V G Q P K A A P S V T L F P P S S E E L Q A N K A T L V C L I S D
λmRNA ttctacccgggagccgtgacagtggcctggaaggcagatagcagccccgtcaaggcgggagtggagaccaccacaccctccaaacaaagcaacaacaagtacgcggccagcagctacctg
Prot F Y P G A V T V A W K A D S S P V K A G V E T T T P S K Q S N N K Y A A S S Y L
λmRNA agcctgacgcctgagcagtggaagtcccacaaaagctacagctgccaggtcacgcatgaagggagcaccgtggagaagacagtggcccctacagaatgttcatag
Prot S L T P E Q W K S H K S Y S C Q V T H E G S T V E K T V A P T E C S -
Leader FR1
CDR1 Cλ3
Cλ3
Cλ3
VC junction
+22nt
-19nt
V J Cλ3L
Protein
gDNA
cDNA
L V Cλ3
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Molecular mechanisms of HCDD
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CH1 deletion of the heavy chain is genomic
VDJ CH1 CH2 CH3
Normal 1
H
γ1 case 1
B C
Protein
gDNA
cDNA
H CH2VDJ CH1 CH3Sµ-Sγ1L
L VDJ H CH2 CH3
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Molecular mechanisms of HCDD
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Is the truncated LC can associate with a HC ?
FL
+
FL
control +
0
2 0 0 0
4 0 0 0
6 0 0 0
[ I g G ] i n c u t u r e s u p e r n a t a n t s
[Ig
G
] in
n
g/m
L
ND
ɣFL
λcontrol Δλ
ɣFL
??
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Molecular mechanisms of HCDD
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Is the CH1 deletion beneficial to the plasma cell ?
ɣFL Δɣ
)
(+
)
FL(+
+)(
FL+)
(
0
20
40
60
80
0
5
10
15
20
HC secretion
**
ns
[ ]
intr
acell
ula
r/secre
ted
[] in
tracellu
laire
/sécré
té
+
FL+
0.0
0.5
1.0
1.5
2.0
2.5
*
Stress marker Xbp1-s expression in sp2/0 clones
Rela
tive
mR
NA
exp
ressio
n
Xbp1-s
Δλ+OR
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Molecular mechanisms of HCDD
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PROLIFERATION
Immunoglobulin
PLASMA CELL
Truncatedheavy chain
Truncated light chain
Oncogenics events
L VDJ CH1 H CH2 CH3
L VJλ Cλ+1
L VDJ CH1 H CH2 CH3
L Vλ Cλ+2
L VDJ H CH2 CH3
L Vλ Cλ+3
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Molecular mechanisms of HCDD
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A new model to mimic the loss of the light chain
L VJk Ck
LoxPLoxP
Light chain of Fanconisyndrome mouse model
Recombinase CRE induction
L VDJ H CH2 CH3CH1
Ck
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Molecular mechanisms of HCDD
Mouse heavy chain
Light chain of Fanconi syndrome mouse model (deleted)
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Conclusion
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▪ We showed that deletion of the LC could be the first event leading to the generation of a truncated heavy chain in HCDD
▪ Results must be confirmed in other HCDD patients
▪ Regarding the mouse model first tests are ongoing
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Thank you for your attention
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Pr Christophe Sirac Pr Arnaud Jaccard
Pr Frank Bridoux
Dr Vincent Javaugue Maria Victoria Ayala Amélie BONAUD
Pr Guy Touchard