The gut kidney axis in IgA nephropathy. Rosanna Coppo. Fondazione Ricerca Molinette Torino

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1 The gut kidney axis in IgA nephropathy Rosanna Coppo Turin, Italy Fondazione Ricerca Molinette Torino

2 IgA nephropathy (IgAN): a disease originated from mucosal immunity dysregulation IgA: most prevalent Ig in mucosal secretions. Deposited IgAare polymeric (of mucosal origins

3 The tonsil-renal axis in IgAN IgA IgA immune complexes Mesangial deposits oral immunity activation

A potential treatment of IgAN: TONSILLECTOMY O Aimed at removing a source of pathogens reducing Mucosal Associated Lymphoid Tissue (MALT) decreasing polimeric mucosal IgA

4 A potential treatment of IgAN: TONSILLECTOMY O Aimed at removing a source of pathogens reducing Mucosal Associated Lymphoid Tissue (MALT) decreasing polimeric mucosal IgA synthesis. InAsia Asia, benefits of tonsillectomyhave been reported mostly in association with steroids In Western Countries no benefits of tonsillectomy in IgAN has been proven

5 GALT (gut associated lymphoid tissue) GALT intestinal immunity in IgAN: pathogenetical role and target for treatment

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

8 INTESTINAL MICROBIOTA

9 Modulated by diet, chemicals, host genes the gut microbiota shapes intestinal MALT in health and disease The gut-kidney axis in IgA nephropathy: the role intestinal dysbiosis Effect on maturation of lymphoid tissue with local and systemic modulation of innate and adaptive immunity June L.

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

12 Specific ligands for each TLR Medzhitov, Nat Rev Immunol

13 The LPS binding receptor CD14 and TLR4 initiate the response to microbes and influence various chronic inflammatory conditions a genetic modification of the membrane receptor for LPS may modulate the inflammatory response and the progression of IgAN

14 TLR-4 in circulating monocytes of IgAN patients Coppo et al in press Clin Exp Immunol 2009) a r y U n i t s A r b i t r TLR4 TLR 4 Healthy Controls TLR 4 IgAN A r b i t r a ry U nits TLR-4 mrna RQ TLR4 Healthy Controls RQ TLR4 IgAN FACS Taqman

15 Significant correlation in IgAN between TLR4 expression in PBMC and proteinuria ary U nits M F I - A rb itr TLR4 Log p= proteinuria g/day/1.73m 2 Pediatr Nephrol Sep;29(9):

16 Fab hinge region IgA1 Ser/Thr Cosmc C1GALT1 O GALNT2 &Cosmc GalNAc ß1-3 Gal ST6GalNAc II methylation and reduced activity induced by TLR4 -LPS ST3Gal sialic acid sialic acid Fc MALT dysregulation and MALT dysregulation and IgA1 defective galactosylation

17 LPS Endotoxin from Gram intestinal germ dysbiosis as a trigger for intestinal immunity response in IgAN

18 The gut kidney axis in IgA nephropathy High intestinal permeability in children and adults with IgAN (Davin & Nagy 1985) High levels of IgAanti alimentary antigens in IgAN Case reports of association between celiac disease and IgAN

19 Gluten induced experimental IgA glomerulopathy Coppo R, et al Mazzucco G, Martina G, Roccatello D, Amore A, Novara R, Bargoni A, Piccoli G, Sena LM. LbI Lab Invest.1989 ;60: gluten-free diet Oral immunization with gliadin

20 Spontaneous IgAN mouse model expressing human IgA1 and CD89 (double transgenic alpha1ki 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

21 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.

22 Correlation between anti-gliadin antibodies and proteinuria in experimental alpha1ki CD89 mice on gluten diet in patients with IgAN

23 Early gluten free diet abolishes IgAN development, hematuria and proteinuria i in alpha1ki CD89Tg mice

24 NEJM correspondence p Coppo R et al October 30, 1986

25 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 (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?

26 celiac disease Celiac type HLA HLA DQ2 HLA DQ8 Celiac AGA Anti TG2

27 In IgAN : increased risk of celiac disease (4% vs 0.5-1%) In celiac disease increased risk of IgAN (0.26% versus 0.08% ) Anti-gliadin AGA in 3-70% IgAN Negative 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%) In IgAN Duodenal inflammation of varying degree Ongoing small bowel inflammation with signs of stres,despite normal morphology. Increase in intestinal permeability

28 Can we target the GALT to treat IgAN?

30 Factors controlling the switch to IgA: TNF family members B cell activator factor BAFF (BlyS) APRIL Critical role for IgA production

31 IgAN in transgenic mice hyperexpressing BAFF IgA MICROBICAL AGENTS IFN γ and α TLRs B B cell B cell cell B cell B cell BR3 TACI BMCA Dendritic cell BAFF Blys

32 PATHOGENESIS of IgAN Genes B cell activity and IgA synthesis Intestinal immunity (GALT) Diet

33 Clinical data Experimental evidence BAFF promotes proliferation of mesangial cells Serum BAFF is increased in IgAN patients

34 Clinical Trials. Gov NCT BRIGHT-SC: Blisibimod Response in IgA Nephropathy p Following At-Home Treatment by Recruiting Subcutaneous Administration Target: BAFF Interventions drug: Blisibimod; drug: Placebo NCT Safety and Efficacity Study of Atacicept 25 mg to treat IgAN Recruiting Interventions drug: Atacicept 25 mg drug: Placebo Target:TACI

35 Activation of intestinal immunity in IgAN: subclinical i l intestinal ti mucosa inflammation leading to IgA dysregulated synthesis Sites of mucosal B cell induction: lower ileum and ascending colon with high density of Peyer s patches.

37 Genetic factors for the control of intestinal barrier & GALT response Epigenetic factors: exposure to alimentary components (gluten) and/or intestinal microbiota dysbiosis microbe products (LPS) Increased intestinal permeability GALT response subclinical inflammation CD4+ Dendritic cells IgA mesangial deposits IgAN inflammatory mediators antigen loaded dendritic cells Galactose deficient IgA1 (degal IgA1) IgAIC IgG anti degal IgA1 The gut-kidney connection in IgA nephropathy Coppo R Ped Nephrol 2018

38 Muchas gracias Thank you for your attention

39 50 years later

Pathogenesis of IgA Nephropathy. Shokoufeh Savaj MD Associate Professor of Medicine Firoozgar hospital- IUMS

Pathogenesis of IgA Nephropathy Shokoufeh Savaj MD Associate Professor of Medicine Firoozgar hospital- IUMS History Immunoglobin A nephropathy was first described by Berger and Hinglais in 1968 in Paris