Update on immunoglobulin A nephropathy, Part I: Pathophysiology

Table 1 Common genetic determinants for immunoglobulin A nephropathy

Genetic locus	Genes	Function
6q21	HLA-DRB1, HLADQA1 and HLA-DQB1	Class II major histocompatibility complex
	PSMB8/9 and TAP/2	Regulators for antigen processing and presentation
1q32	CFHR1/3	Modulators for complement activation and inflammation
22q12	HORMAD2	Unknown
17q13	TNFSF13	Important for B cell development and IgA isotype switching
8p23	DEFA1	Encoding a-defensins as a type of endogenous antimicrobial mediators
1p13	VAV3	Regulators for lymphocyte development and antigen presentation
9q34	CARD9	Participant in antigen-induced signalosome formation (CARD9-BCL 10-MALT1) and NF-κB activation
16p11	ITGAM and ITGAX	Mediators for immune cell adhesion and phagocytosis

IgA: Immunoglobulin A.

Table 2 Summary of the four hits involved in the pathogenesis of immunoglobulin A nephropathy with distinction of the pathogenetic process (putative environmental factors involved, putative genetic factors involved, potential clinical biomarkers and potential novel therapeutic approaches)

Hit	Pathogenic process	Putative environmental factors involved	Putative genetic factors involved	Potential clinical biomarkers	Potential novel therapeutic approaches
1	Hereditary increase in circulating galactose-deficient IgA1	Potential role of mucosal exposure to infectious of dietary antigens	Strong evidence for high heritability of serum galactose-deficient IgA1 level Potential role of chromosome 22q12.2	Serum galactose-deficient IgA1 level (HAA-based ELISA)	Suppression of synthesis of galactose-deficient IgA1 Enzymatic boost of galactose transfer to IgA1 hinge- region O-glycans Suppression of sialylation of galactose-deficient O-glycans
2	Circulating antibody directed against galactose-deficient IgA1	Potential role of mucosal exposure to infectious or dietary antigens	Potential role of three MHC-II loci in antigen presentation and humoral response to galactose-deficient IgA1 O-glycans	Serum anti-glycan antibodies (dot blot assay)	Alteration of processing and presentation of galactose-deficient IgA1 O-glycopeptides Specific B-cell depletion therapy
3	Formation of pathogenic IgA1-containing immune complexes	Unknown	Unknown	Circulating and/or urinary immune complexes	Competitive blockade of immune complex formation by non-cross-linking anti-glycan antibodies or specific glycopeptides
4	Mesangial deposition of IgA1 containing immune complexes, cell activation and initiation of glomerular injury	Unknown	Protective effect of common deletion in CFHR1 and CFHR3	Circulating and/or urinary complement degradation products, or novel markers of glomerular injury	Suppression of the alternative complement pathway Targeted CFHR1/3 depletion Blocking mesangial cell signaling induced by nephritogenic IgA1-containing immune complexes

HAA: Helix Aspersa; ELISA: Enzyme-linked immunosorbent assay; CFHR3: Complement factor H receptor 3; IgA: Immunoglobulin A.