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

Pediatr Nephrol 2018 Jan;33(1):53-61.

INTESTINAL MICROBIOTA

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

Pilot study in 34 IgAN patients:different microbiota in progressive IgAN

Specific ligands for each TLR

Medzhitov, Nat Rev Immunol

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

Spontaneous IgAN mouse model expressinghuman IgA1 and CD89 (double transgenicalpha1KI‐CD89Tg mice)

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

NEJM correspondence pCoppo R et al October 30, 1986

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 ?

celiac disease

C li

HLA DQ2

Celiac‐typeHLA

HLA DQ2HLA DQ8

CeliacAGA 

Anti TG2

• 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

Can we target the GALT to treat IgAN?Can we target the GALT  to treat IgAN? 

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

PATHOGENESIS of IgANg

Genes

B cell activity and IgA synthesis

Intestinal immunity(GALT)

Diet

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

Muchas graciasg

Thank you for your attention

50 yearslater

https://