PHYSIOPATHOLOGIE DES NEPHROPATHIES A DEPOTS D’IgA

Seminaire National de Néphrologie20-22 Juin 2010

Renato MonteiroInserm U699, Hôpital Bichat, Paris

« The disease was first described in 1801 by Heberden (of "Heberden's nodes" fame) in a 5-year old child with abdominal pain, hematuria, and purpura of the legs. Then in 1837, Johann Schonlein and Eduard Henoch built upon these discoveries by further characterizing the disease in pediatric populations. It was not until 1968 that the pathogenic role of IgA depositions was revealed, based on the work of French pathologist Jean Berger (left). Prior to his discovery that mesangial IgA deposits are present in these patients, many had believed IgG to be the sole nephritogenic immunoglobulin. »www.igan-world.org

Jean Berger et Nicole Hinglais Dépôts intercapillaires d’IgA-IgG. J Urol Nephrol (Paris). Sept 1968;

74:694-5.

Berger’s disease or IgA nephropathy

1968 1972-3 1975

Habib & Levy: Berger’s disease

French disease ? Food & environnement?

Severe disease. Recurrence after Tx

History

Descriptionat Necker Hosp,

Paris Descriptionby other groups:

- Netherlands (Maintz and coll)- USA (West & Burkholder)- UK (Davies and coll)- Australia (Woodroffe & Clarkson)- Japan (Ueda and coll)

1. Most of patients are asymptomatic

2. IgAN discovered during routine examination for jobs due

to the presence of hematuria with or without proteinuria

3. Macroscopic hematuria following upper respiratory tract

infection or after sport (back pain and hematuria).

4. Usually less than 40 years old

5. Definitive diagnosis is only made by kidney biopsy

DIAGNOSIS OF IgAN:

Immunofluorescence

• IgG in 30-50% of cases

• IgM in 5-10% of cases

(severity?)

• C3 in more than 60% of

cases

• more λ than κ chains

• mesangial electrodense

deposits IgA1 deposition in the mesangium

Heterogeneity of lesions

Morphology

Summary of four key pathological features

1. Mesangial Hypercellularity Score: ≤ 0.5 (M0) or < 0.5 (M1)

2. Segmental glomerulosclerosis: absent (S0) or present (S1)

3. Endocapillary hypercellularity: absent (E0) or present (E1)

4. Tubular atrophy/interstitial fibrosis : ≤ 25% (T0), 26-50% (T1), or > 50% (T2)

The Oxford classification of IgA nephropathy

Cattran et al Kidney Int 76, 534-545, 2009

International IgAN Network & Renal Pathology Society

Roberts et al Kidney Int 76, 546-556, 2009

Correlation between Oxford classification and disease severity (examples)

Glomerular lesions Definition Slope: ml/min per 1.73 m2 per year

Minimal mesangial hypercellularity Without segmental sclerosisWith segmental sclerosis

0.7 ± 2.5-1.5 ± 2.7

M0, S0, E0M0, S1, E0

1322

Mesangial hypercellularity Without segmental sclerosisWith segmental sclerosis

-2.2 ± 4.3-4.7 ± 7.6

M1, S0, E0M1, S1, E0

3188

Endocapillary proliferation Without segmental sclerosisWith segmental sclerosis

1.2 ± 1.2-4.9 ± 10.0

M0/1, S0, E1M0/1, S1, E1

2190

Glomerular lesions Tubular atrophy/interstitial fibrosis

Minimal mesangial hypercellularity ≤ 25%< 26%

-0.6 ± 3.0-1.0 ± 1.2

M0, E0, T0M0, E0,T1-2

305

Mesangial hypercellularity -2.7 ± 5.5-7.9 ± 9.1

M1, E0, T0M1, E0, T1-2

8930

Endocapillary proliferation -3.0 ± 1.9-6.9 ± 1.2

M0/1, E1, T0M0/1, E1, T1-2

8823

Criteria N° of patients

Slope: ml/min per 1.73 m2 per year

Criteria N° of patients

≤ 25%< 26%

≤ 25%< 26%

PREVALENCE:

1. South Europe, Asia, Australia, Finland: 20 to 40% of GN

2. UK, Canada, USA, Brazil: 5 to 15% of GN

• American indians (New Mexico): 38% of GN

3. Low prevalence in blacks

CHARACTERISTICS:

1. More frequent between the 2a or 3a decade.

2. More frequent in males than females : 2:1 Japan; 6:1 Europe.

• Familial cases• Several loci idenfied by genome-wide scan• No gene has been identified yet

GENETIC FACTORS IN IgAN

SusceptibilityLocus

LODScore

CandidateGenes

Reference

6q22-23

4q26-31

17q12-22

2q36

5.6

1.83

2.56

3.5

SGK, VNN3

TRPC3, IL-2, IL-21

HD5

CCL20

Gharavi, Nat Genet 2000

Bisceglia, Am J Hum Genet 2006

Paterson, J Am Soc Nephrol 2007

SUSCEPTIBILITY TO IgA NEPHROPATHY

Production of ‘pathogenic’

IgA complexes

Abnormal mesangial IgA handling

‘Inflammatory phenotype’

IgAN

Genetic influences

Physiopathogeny of IgA Nephropathy:

1. Abnormalities of IgA1 glycosylation and of immune system

2. Formation of IgA1 complexes: Role of IgA receptor type I

3. Defective clearance of IgA1 complexes

4. Mesangial deposition: Role of tranferrin receptor

5. Progression of IgAN towards renal failure

Monomeric IgA Polymeric IgA Secretory IgA

2 subclasses - IgA1 & IgA22 subclasses - IgA1 & IgA2

Circulation Mucosal fluids

J-chain

pIgA

IgA1 = IgA2IgA1 = IgA2

MUCOSAL

mIgA

IgA1 >> IgA1 >> IgA2IgA2

SYSTEMIC

BLOOD

95% mIgA1

SecretorySecretorycomponentcomponent

B cells

B cells

Human IgA SystemHuman IgA System

« Charge and size of mesangial IgA in IgA Nephropathy »Monteiro et al Kidney Int 1985

IgA complexes Negative charge

Study with kidney tissues

Award of the French Society of Nephrology in 1986

Composition of IgA-immune complexes

J-chain

Polymeric IgA Secretory IgA

IgA1 IgA2

Secretory IgA

- Polymeric IgA1

• Self-aggregated IgA1 (hypogalactosylated)• IgG anti-IgA antibodies (RF)• Antigens: collagen, fibronectin• soluble IgA receptors

- Components:

a

Aberrant glycosylation of IgA1 in IgAN

Gal

GalNac

NeuAc

b

c

d

ein IgAN

• Hypogalactosylation of IgA1 (Tomana et al Kidney Int 1997)

• IgA1 aggregates (Kokubo et al J Am Soc Nephrol 1997)

• Mesangial IgA1 is hypogalactosylated? (Allen et al Kidney Int 2001)

Ser/ThrIgA1

C1

VH

C2

C3

VL

CL

pIgA

MUCOSAL

pIgA1h

SYSTEMIC

IgA NephropathyIgA Nephropathy

BLOOD

pIgA1h

Is increase in pIgA enough? NO, myeloma IgA has no IgAN

STEP 1 STEP 2

IgA depositsNo disease?

Disease andProgression

Estimates from autopsies:10% of general population?

1 in 50 people with IgA deposits will have manifestations

Possible mechanisms of mesangial depositionPossible mechanisms of mesangial depositionAbnormally O-glycosylated IgA1Abnormally O-glycosylated IgA1

Complexformation

IgG-IgA1IgG-IgA1IgA1IgA1

as antigenas antigen

IgA1-IgA1IgA1-IgA1self-self-

aggregationaggregation

MesangialDeposition

IgA1-receptorIgA1-receptor

Complexformation

Co IgAN MCRA AC

4

2

Units

Soluble FcRI in IgA-N

Launay et al J Exp Med 2000

B Cell antibody

production

IgA

Fc receptors: Cell based Systems for Humoral Immunity

Mediators•TNF•IL-6•IL-1

•Regulation of immunity•Inhibitory functions

•ITIM vs ITAM

Cell effector function•Clearance •Phagocytosis•Antigen Presentation

IgA

CD89

IgA-N

Macrophages, PMN, EosinophilsDendritic cells,Platelets, Kupffer cells

FcαRI (CD89)

leukocyte

Humanized mouse model for IgAN

CD11bpromotor FcRI EGF

Stopcodon

Construct

83

96

73

LinesNon-Tg

Lt Tg

FcRI

CD11bHematuria - +

Launay et al J Exp Med 2000

Units

CoTg

0

5

10

Role of Soluble FcRI in IgAN

SerumFcRI Tg

IgAN

IgAN

Adoptive transfer

Rag2-/-

Rag2-/-

Hematuria +

Serum adsorbed byanti-FcRI mAbs

Rag2-/-

No disease

Man Mouse

Polymeric IgA

Monomeric IgA

10% 80%

90% 20%

FcRI (CD89) Yes No

Polymeric IgA binds better to CD89 than monomeric IgA

Can IgA/CD89 interaction induce IgAR expression on mesangial cells ?

FcRI/CD89on

Blood monocytes

Mesangial cells

?

protease ?

IgA binding induces triggering of human mesangial cells:

• enhanced proliferation• IL6, IL8, TNF and TGF

• enhanced production of ECM

Evidences in favor of IgA receptor(s) in the mesangium:

(Gomes-guerrero et al 1994, Chen et al 1994, van den Dobbelsteen et al 1994, Lopez-Armada et al 1996, Amore et al 2001, Lai et al 2003)

• Ca++ mobilization, activation of PLCγ

Absence of classical IgA receptors on mesangial cells

Monteiro & Van de Winkel Ann. Rev. Immunol. 2003

Fc/R ASGP-R

IgA/IgM ASGP/IgA

Poly IgR

IgA/IgM

FcRI(CD89)

IgA

Transferrin Receptor (TfR, CD71) binds IgA1

Genes: Chromosome 3

Proteins: TfR1 and TfR2

Expression: All cells but heterogeneous Mesangial cells +++Immature cells

Ligands: Low density: Transferrin, HFE High density : pIgA1

Functions: Transferrin: Iron uptake IgA1: deleterious?

from Lawrence et al Science 1999

Upregulation of transferrin receptor in the mesangium of patients with IgAN and HSP

Normal

IgAN HSP

Haddad et al J Am Soc Nephrol 2003

Haddad et al J Am Soc Nephrol 2003

Enhanced expression of TfR is associated with disease severity.A new biomarker for diasese progression?

Can aberrantly glycosylated IgA1 bind to TfR?

Fluorescence Intensity (log)

Ce

ll N

um

be

r

desialylated & degalactosylated

desialylated

Non treated

desialylated & Degalactosyl ated+ sTfR1

IgG

Degalactosylation of pIgA1 promotes enhanced binding to transferrin receptor

Moura et al J Am Soc Nephrol 2004

controls IgAN

Med

ian

Flu

ores

cenc

e In

tens

ity

p<0.001

0

2

4

6

8

10

12

Myeloma IgA1 Patient IgA

Can IgA1-TfR interaction explain inflammation ?

IgA1-induced cytokine production through TfR

IL-6 TGF-β

0

20

40

60

80

100

120

140

160

TG

F

(p

g/m

l)

0.5% FCS A24 30.9

pIgA1

P < 0.05

-0.5% FCS0

100

200

300

400

IL-6

(p

g/m

l)

A24 30.9

pIgA1

-

P < 0.05

Aberrant IgA1 complexes

Enhanced TfR expression

Proliferation IgA1 depositson mesangial TfR

CytokinesChemokines

Mesangiopathy

FibrosisInflammation

TfR = transferrin receptor

Proposed role of transferrin receptor in IgAN

A possible explanation for recurrence of IgA deposits after transplantation

Cell activation Inhibition

Soluble FcRI

IgA complexes

IgA complexes

IgA recycling

chain (ITAM)

Inflammation

Role of transmembrane FcRI-

SHP-1Syk

IgA bound to FcRI is correlated with glomerulosclerosis in IgAN patients

Monocytes

Anti-IgA Ab (FI)

Controls IgAN MC

1

2

3

4

5 p < 0.001

1.1

2.9

0.9

Glomerulosclerosis

Grossetete et al Kidney Int 1998Lai et al J Am Soc Nephrol 2002

-less FcRI Tg

days4 75210 3 6

Pro

tein

uria

(m

g/dl

)

500

250

0

*

FcRI Tg

days7510 3 62 4

Crosslinking of FcRI- induces proteinuria and macrophage infiltration

L

Mutant R209LTg

A77A77

IgA

mac1

R

Wild typeTg

chain

Kanamaru et al, Eur J Immunol 2007

* *

* anti-FcRI F(ab’)2

(Balb/c)

C57/BL6

Moura et al Sem Nephrol 2008

Circulation Glomerulus R

en

al in

ters

titiu

m

1.

3.

FcR adaptor

Transmembrane FcRI

IgA

TfR (CD71)

Soluble FcRI

2.

GBM

Fenestratedendothelium

ActivatedMesangial cells

Monocytes

Priming

Chemotaxis

Renal tubule

Cytokines/chemokines

Endothelium

ActivatedMonocytes

Defectiveclearance

pIgA

MUCOSAL

pIgA1

SYSTEMIC

Future treatments for IgA NephropathyFuture treatments for IgA Nephropathy

BLOOD

pIgA1

Leukocytes

- Anti-CD20 ?- Proteases ?

- Anti-CD71 (A24) Developped by InatherYs- Rapamycin

- Anti-CD89