1. What’s new for IgA Nephropathy. Part 1: Epidemiology and Pathogenesis
Professor of Nephrology
University of Florence

2. AGENDA
DEFINITION
EPIDEMIOLOGY
PATHOPHYSIOLOGY

3. AGENDA
DEFINITION
EPIDEMIOLOGY
PATHOPHYSIOLOGY

4. DEFINITION AND MAIN CHARACTERISTICS
IgAN represents the most frequent glomerulonephritis
Typical histological sign is a proliferation of glomerular mesangial cells with different aspects on light microscopy
The hallmark is the deposition of IgA and complement principally in the mesangial area
Characterized by extremely different clinical signs

5. DIFFERENT HISTOLOGICAL ASPECTS

6. TYPICAL IgA DEPOSITION

7. AGENDA
DEFINITION
EPIDEMIOLOGY
PATHOPHYSIOLOGY

8. EPIDEMIOLOGY
Estimated frequency of about 2.5 cases/year per adults
Prevalence of IgA mesangial deposits in necropsy studies from 4% to 16%
Clear West-to-East gradient (32-54% in east Asia vs 10-35% in Europe
Unequal gender distribution
Genetics play a significant role to explain geographic differences
Incidence of ESRD because of IgAN ranges from 18 to 264 cases per million population (USRDS, 2009)

9. Percentage of patients primary glomerular disease
15-21%
4.7%
<5%
Percentage of patients
with
primary glomerular disease

10. Male > Female Male = Female
15-21%
Male > Female
Male = Female
4.7%
<5%

11. Genetic Risk Map of IgAN

12. AGENDA
DEFINITION
EPIDEMIOLOGY
PATHOPHYSIOLOGY

13. PATHOPHYSIOLOGY (four hits theory)
Hit 1 Generation of aberrantly galactosylated IgA1 (Gd-IgA1)
Mucosal antigens as trigger
Plasma cells (tonsils, marrow) produce ↑ Gd-IgA1 (genetic risk)
Hit 2 Autoantibodies form against Gal-deficient hinge region
Hit 3 Circulating immune complexes of polymeric Gd-IgA1 + autoantibodies, get trapped in the mesangium
Hit 4 Glomerular damage

14. GENETICS OF IgA NEPHROPATHY
Linkage studies on familial aggregation of IgAN
Genome-wide association studies

15. PATHWAYS IMPLICATED BY THE GENETIC STUDIES
Antigen processing and presentation
MHC region
Complement system
CFHR1/3 ; ITGAM-ITGAX loci
Regulation of mucosal IgA production
TNFSF13 and LIF/OSM loci
Innate immunity against pathogens
DEFA, CARD9, ITGAM-ITGAX, VAV loci

16. COMMON GENETIC DETERMINANTS FOR IgA NEPHROPATHY

17. RELATIONSHIP BETWEEN PATHOGENETIC PROCESSES AND KNOWN GENETIC FACTORS
Hit
Pathogenic process
Genetic factors involved 1
Hereditary increase in circulating galactose-deficient IgA1
Strong evidence for high heritability of serum galactose-deficient IgA1 levels
Potential role of chromosome 22q12.2 2
Circulating antibody directed against galactose-deficient IgA1
Potential role of three MHC-II loci in antigen presentation and humoral response to galactose-deficient IgA1 O-glycans 3
Formation of pathogenic IgA1 containing immune complexes
Unknown 4
Mesangial deposition of IgA1 containing immune complexes, cell activation and initiation of glomerular injury
Protective effect of common deletion in CFHR1 and CFHR3

18. Hit 1 Generation of aberrantly galactosylated IgA1 (Gd-IgA1)

19. DEFECT IN THE REGULATION OF IgA1 PRODUCTION AND GLYCOSYLATION
Human IgA are composed of two subclasses: IgA1 and IgA2
IgA1 is the predominant form in the circulation of healthy individuals, while IgA2 prevails in the mucosa
The IgA1 molecule is normally O-glycosylated in the site of attachment of O-linked glycan moieties
In IgAN patients abnormal quantities of IgA1 underglycosylated are found in circulation and in the glomeruli

20. Normal IgA1 molecule with magnification of the hinge region

21. IgA1 ABNORMAL GLYCOSYLATION IN IgAN

22. Dagalactosylated serum IgA1 in IgAN

23. Aberrant glycosylation of IgA1 in patients and their relatives

24. Hit 1: Consideration I
In IgAN, the glycosylation defects involve principally polymeric IgA1, which is normally produced by mucosal IgA1 secreting cells
Is not clear how polymeric Gd-IgA1 finds its way to the circulation in IgAN patients
An intriguing possibility is that mucosal IgA1 secreting cells may migrate to the bone marrow because of faulty expression of surface homing receptors (mis-homing)

25. Hit 1: Consideration II IgAN patients have ↑↑circulating Gd-IgA1
Predisposed to immune complex formation
Makes up minority of circulating IgA, but virtually all the mesangial IgA
Recognized by naturally occurring Ig’s
Insufficient alone to cause disease

26. OPEN QUESTIONS FOR HIT 1
Is there a tropism of abnormally glycosylated IgA for the kidney mesangium?
Comparing IgA glycosylation from serum and nephrectomy specimens, Gal deficient IgA was enriched in kidney compared to serum samples
Is abnormal IgA glycosylation sufficient for IgA onset?
Abnormal IgA glycosylation is present both in IgAN patients and their relatives who do not develop disease.Abnormal IgA1 glycosylation alone is not sufficient to trigger disease onset

27. Hit 2 Antibody production towards the abnormal IgA1

28. Antibody production towards the abnormal IgA1
The galactose-deficient hinge region of IgA1 contains N-acetylgalactosamine (GalNac) residues. Exposed GalNac may represent an epitope recognized by specific anti-glycan antibodies
Bacteria and viruses might express GalNac on their surfaces that could act as a trigger for the formation of cross-reacting autoantibodies (molecular mimicry)
Presence of anti-glycan antibodies correlates with proteinuria, severe histopathologic injury and faster progression of kidney disease

29. IgA1 ABNORMAL GLYCOSYLATION IN IgAN AND AUTOANTIBODY FORMATION

30. ANTI IgA1 AUTOANTIBODIES AND DEVELOPMENT OF IgAN
Autoantibodies recognizing the abnormally glycosylated IgA1s are essential in the pathogenesis of the disease
Accordingly, IgAN is an autoimmune disease due to the mesangial deposition of immunocomplexes containing GdpIgA1
Other molecules such as sCD89, fibronectin, collagen and laminin are also found

31. The two-hit hypothesis for IgA-IC formation in IgAN

32. PATHOGENESIS OF IgAN: FROM DEFECTIVE IgA1 TO GLOMERULAR DEPOSITION
SOME POLYMERIC IgA1 IS GALACTOSE DEFICIENT
IS RECOGNIZED BY ANTI GLYCAN IgG OR IgA1 ANTIBODIES
THE RESULTANT IMMUNE COMPLEXES DO NOT REACH THE ASIALOGLYCOPROTEIN RECEPTOR IN THE LIVER
CONSEQUENTLY REACH THE GLOMERULAR CAPILLARIES AND INDUCE GLOMERULAR INJURY

34. OPEN QUESTIONS CONCERNING HIT 2
Are the autoantibodies the result of a molecular mimicry triggered by infections?
Additionally, these autoantibodies are the result of a Toll-like receptor polymorphisms (TLR4/TLR9) ?
Is there a genetically determination induced by somatic mutations in the IgG heavy chain ?

35. Hit 3 Binding of the anti-glycan antibodies to the abnormal IgA1 and consequent production of immunocomplexes

36. TWO HYPOTHESES FOR HIT 3
Formation in circulation of immune complexes and subsequent deposition on the glomeruli
By Novak/Mestecky/Suzuki
Immune complexes are formed in situ by reacting with “planted” abnormally glycosylated IgA1 (lanthanic deposition)
By Glassock

37. ADDITIONAL COMPONENTS TO EXPLAIN IMMUNE COMPLEXES PATHOGENICITY
Complement
IgA receptors

38. COMPLEMENT
Complement activation is essential to induce the immune complexes pathogenicity
Complement is present on the glomeruli of IgAN patients with a deposition pattern similar to IgA
Genetic variants of complement regulatory functions may have a protective role towards the disease

39. ICAM-2 ICAM-3 Bacterial and viral motifs/SIgA
IgA RECEPTORS
Receptors
Ligands
FcαRI (CD89)
IgA
Polymeric IgR
IgA/IgM
Fcα/μR
ASGP-R
ASGP IgA
DC-SIGN
ICAM-2 ICAM-3 Bacterial and viral motifs/SIgA
β1,4-GT
IgA/IgG/IgM/Tf
TfR (CD71)
Tf, HFE, IgA1

40. ROLE OF RECEPTORS CD 89 is the only IgA-R which exclusively binds IgA
In the IgAN pathogenesis, two IgA-R compartments have been mainly implicated
Mesangial cells
Myeloid cells essentially kidney infiltrating macrophages
TfR1 has been identified as a mesangial IgA1 receptor and pIgA1 binding to TfR1 induces mesangial cell activation
sCD89 might have a different role

41. Hypothesis for a role of CD89
The IgA receptor CD89 is expressed on myeloid cells.
Interaction with altered polymeric IgA1 consecutively induces CD89 shedding, leading to formation of circulating IgA-soluble (s) CD89 complexes.
The released sCD89-pIgA complexes amplify the molecular size of circulating IgA-IC and promote mesangial IgA deposition

42. Hit 4 INDUCTION OF RENAL DAMAGE

43. RENAL DAMAGE IN IgAN Mesangial Cell Activation Podocyte Injury
Tubulo-interstitial scarring

44. INDUCER FACTORS IN MESANGIAL DAMAGE
Platelet derived growth factor (PDGF)
Involved in mesangial cell proliferation
Intracellular mediation involves inositol triphosphate, diacylglycerol, protein kinase C
Trasforming growth factor β (TGFβ)
Involved in the fibrotic response
Promotes transcription of extracellular matrix,
Promotes differentiation of tubular epithelial cells to myofibroblast
Renin-Angiotensin-Aldosterone system (RAAS)
Pathogenic IgA1 activates the system intrarenally

45. PODOCYTE INJURY
Podocyte necrosis and podocyte detachment are present in IgAN
Nephrin expression is reduced in IgAN
IgA1-IC upregulate the production of CXCL1 and TGFβ in IgAN
CXCL1 and TGFβ exert a synergistic effect, inducing podocyte dysfunction and podocyte death

46. TUBULOINTERSTITIAL SCARRING
TGFβ favors the transformation of the tubular cells into a fibrotic phenotype
Mesangial cell derived TNFα activates tubular cells inducing pro-inflammatory mediators (glomerular-tubular cross-talk)
Filtered mesangial cell-derived mediators cause a proinflammatory and profibrotic transformation of proximal tubular epithelial cells

47. PATHWAYS TO RENAL DAMAGE IN IgAN

48. THANK YOU if you like go to the second part !!!