10.30hs Dra COPPO - sap.org.ara/NEF9-Nefro... · The gut-kidney axis in IgA nephropathy: the role...
Transcript of 10.30hs Dra COPPO - sap.org.ara/NEF9-Nefro... · The gut-kidney axis in IgA nephropathy: the role...
The gut‐kidney axis in IgA nephropathy
Rosanna CoppolTurin, Italy
Fondazione Ricerca MolinetteTorino
IgA nephropathy (IgAN):a disease originated from mucosal immunity dysregulationg y y g
IgA: most prevalent Ig in mucosal secretions.Deposited IgA are polymeric (of mucosal originsp g p y ( g
The The tonsiltonsil--renalrenal axisaxis in in IgANIgAN
IgA
IgA immune complexes
oral
complexes Mesangial deposits
oralimmunityactivation
A potential treatment of IgAN: ONSILL C O YTONSILLECTOMY
Aimed at removing a source of pathogens reducing Mucosal Associated Lymphoid Tissue (MALT)g y p ( )decreasing polimeric mucosal IgA synthesis.
In Asia benefits of tonsillectomy have been reportedIn Asia, benefits of tonsillectomy have been reported mostly in association with steroids
In Western Countries no benefits of tonsillectomy in IgAN has been proven
GALT intestinal immunity in IgAN:pathogenetical role and
target for treatment
GALT (GALT (gutgut associatedassociated lymphoidlymphoid tissuetissue))
g
the gut microbiota shapes intestinal MALT in health and disease
Modulated by diet, chemicals, host genes
the gut microbiota shapes intestinal MALT in health and disease
The gut-kidney axis in IgA nephropathy:The gut-kidney axis in IgA nephropathy: the role intestinal dysbiosis
Effect on maturation of lymphoid tissueJune L. with
local and systemic modulationof innate and adaptive immunity
The LPS binding receptor CD14 and TLR4 initiate the response to microbesand influence various chronic inflammatory conditions
a genetic modification of the membrane receptor for LPS may modulate the inflammatory response and the progression of IgAN
TLRTLR--4 4 in circulating monocytes in circulating monocytes of of IgANIgAN patientspatientsCoppo et al in press Clin Exp Immunol 2009)
32.5 TLR4 12TLR-4 mRNA
22 525.027.530.0
TLR4
91011
15.017.520.022.5
rary
Uni
ts
678
ary
Uni
ts7.5
10.012.515.0
Arb
itr
345
Arb
itra
TLR 4 Healthy Controls TLR 4 IgAN0.02.55.0
RQ TLR4 Healthy Controls RQ TLR4 IgAN012
y g RQ TLR4 Healthy Controls RQ TLR4 IgAN
FACSFACS TaqmanTaqman
Significant correlation in IgAN betweenTLR4 expression in PBMC and proteinuria
12.5
15.0
17.5p= 0.0312
rary
Uni
ts
7.5
10.0
MFI
- A
rbitr
0.0
2.5
5.0
TLR
4 Lo
g
0 1 2 3 4 5 6 7 8 9 100.0
proteinuria g/day/1.73m2
Pediatr Nephrol. 2014 Sep;29(9):1545-51.
IgA1 Cosmcg
C1GALT1Fab
methylation and reduced activityinduced by TLR4 -LPS
i li id
ST6GalNAc II
sialic acidST3Gal
Ser/Thr GalNAcOGALNT2
ß1-3 Gal& Cosmchinge
region
sialic acid
FcMALT dysregulation andMALT dysregulation and
IgA1 defective galactosylation
LPS Endotoxinfrom Gram –intestinal germ dysbiosisas a trigger for intestinal immunityresponse in IgANresponse in IgAN
The gut‐kidney axis in IgA nephropathy
High intestinal permeability in children and adults with IgAN (Davin & Nagy 1985)g ( gy )
High levels of IgA anti alimentary antigens in IgAN
Case reports of association between celiac disease and
g g y g g
IgAN
Gluten‐induced experimental IgA glomerulopathyCoppo R, et al Mazzucco G, Martina G, Roccatello D, Amore A, Novara R, Bargoni A,Pi li G S LM L b I t 1989 60 499 506Piccoli G, Sena LM. Lab Invest.1989 ;60:499‐506.
gluten-free dietOral immunization with
gliadin
Gluten free diet for 3 generations
reduction in • IgA1 mesangial deposition• glomerular inflammatory-cell infiltration • IgA1–sCD89 complexes in serum and kidney eluates• hematuria
Gluten diet for 30 days
Intestinal injury(inflammation and villous atrophy)Increase in• IgA1–sCD89 complexes• IgA1 mesangial deposition• IgA1 antigliadin Ab• correlation with proteinuria.
Correlation between anti-gliadin antibodies and proteinuria
in experimentalalpha1KI‐CD89 mice
on gluten diet
in patients with IgAN
Early gluten‐free diet abolishes IgAN development, hematuriad t i i i l h 1KI CD89T iand proteinuria in alpha1KI‐CD89Tg mice
Conclusion of early studies (30 years ago)to target gluten for treating patients with IgAN
• Gluten-free diet was of some benefit in our exploratory study (29Gluten free diet was of some benefit in our exploratory study (29 patients without evidence of celiac disease) with reduction of proteinuria, but without effect on renal function decline after 4 years.
• The gluten-free diet is difficult to be followed by patients without GI symptoms
A next RCT testing gluten-free diet in IgAN ?
• In IgAN : increased risk of celiac disease (4% vs 0.5-1%) • In celiac disease increased risk of IgAN (0.26%° versus 0.08%°)In celiac disease increased risk of IgAN (0.26% versus 0.08% )
• Anti-gliadin AGA in 3-70% IgANNegative anti-endomisium /tissue transglutaminase antibodies inNegative anti-endomisium /tissue transglutaminase antibodies in IgAN
• No association with HLA DQ2-DQ8
In inflammatory bowel diseases IgAN is more frequent than other glomerular diseases (24% vs 8%)g ( )
In IgAN• Duodenal inflammation of varying degree• Ongoing small bowel inflammation with signs of stres,despite
normal morphology. • Increase in intestinal permeabilityp y
Factors controlling theFactors controlling the switch to IgA:
TNF family membersB cell activator factorB cell activator factor
BAFF (BlyS)APRIL
Critical role forIgA production
IgAN in transgenic micehyperexpressing
MICROBICAL AGENTS
IFN γ and αhyperexpressingBAFF
IgATLRs
DendriticcellB
B
cellBAFFBlysBR3
TACI
B cell B
cellB
cellB B
cellyTACI
BMCAB cell
Clinical data Experimental evidence
BAFF promotes proliferationof mesangial cells
Serum BAFF is increasedin IgAN patientsg p
ClinicalClinical Trials. Trials. GovGov
NCT02062684 BRIGHT-SC: Blisibimod Response in IgANephropathy Following At-Home Treatment by p p y g ySubcutaneous Administration
_______________________________________________________
drug: Blisibimod;
Recruiting Target: BAFF
drug: Blisibimod;drug: Placebo
Interventions
NCT02808429 Safety and Efficacity Study of Atacicept 25 mg to treat IgAN
____________________________________drug: Atacicept 25 mg
Recruiting
I t tiTarget:TACIdrug: Atacicept 25 mg
drug: PlaceboInterventions
g
Activation of intestinal immunity in IgAN:b li i l i t ti l i fl tisubclinical intestinal mucosa inflammationleading to IgA dysregulated synthesis
Sites of mucosal B cell induction: lower ileum and ascending colon
with high density of Peyer’s patches.
CD4+
Genetic factorsfor the control of intestinal barrier
Epigenetic factors:exposure to alimentary
components (gluten)
Increasedintestinalpermeability
Dendriticcells
intestinal barrier& GALT response
components (gluten) and/or
intestinal microbiotadysbiosis
microbe products
GALT response subclinical
permeability
microbe products(LPS)
antigen loaded
inflammation
Galactose deficient IgA1
antigen loaded
dendritic cellsIgA mesangialdepositsIgAN g
(deGal IgA1)
IgG anti deGal IgA1IgAIC
inflammatory mediators
IgG anti deGal IgA1
Coppo RPed Nephrol 2018
The gut-kidney connectionin IgA nephropathy