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Pathogenesis of IgA nephropathy

Kar Neng Lai
Abstract | Since its first description in 1968, IgA nephropathy has remained the most common form of idiopathic glomerulonephritis leading to chronic kidney disease in developed countries. The exact pathogenesis of IgA nephropathy is still not well defined. Current data implicate an important genetic factor, especially in promoting the overproduction of an aberrant form of IgA1. The immunochemical aberrancy of IgA nephropathy is characterized by the undergalactosylation of Oglycans in the hinge region of IgA1. However, such aberrant glycosylation alone does not cause renal injury. The next stage of disease development requires the formation of glycanspecific IgG and IgA antibodies that recognize the undergalactosylated IgA1 molecule. These antibodies often have reactivity against antigens from extrinsic microorganisms and might arise from recurrent mucosal infection. Bcells that respond to mucosal infections, particularly tonsillitis, might produce the nephritogenic IgA1 molecule. With increased immunecomplex formation and decreased clearance owing to reduced uptake by the liver, IgA1 binds to the glomerular mesangium via an as yet unidentified receptor. Glomerular IgA1 deposits trigger the local production of cytokines and growth factors, leading to the activation of mesangial cells and the complement system. Emerging data suggest that mesangialderived mediators following glomerular deposition of IgA1 lead to podocyte and tubulointerstitial injury via mesangiopodocytictubular crosstalk. This Review summarizes the latest findings in the pathogenesis of IgA nephropathy.
Lai, K.N. Nat. Rev. Nephrol. 8, 275283 (2012); published online 20 March 2012; doi:10.1038/nrneph.2012.58

Introduction
Since its first description more than four decades ago, IgA nephropathy has been recognized as the most common form of primary glomerulonephritis in developed countries and remains an important cause of endstage renal disease.1,2 Epidemiological studies show that IgA nephropathy is found worldwide, but the frequency at which it is diagnosed varies, mostly in accordance with local policies regarding indications for renal biopsy.3 IgA nephropathy is less common in black individuals than in Asian or white individuals.4 Nephrologists now recognize that IgA nephropathy is a smoldering disease of a slowly progressive nature and that both familial and sporadic forms exist. Mesangial deposition of IgA1 is the defining hallmark of this disease although no obvious correlation between the extent of IgA1 deposition and the degree of glomerular and tubulointerstitial injury exists. Understanding the mechanisms that initiate mesangial deposition of IgA1, which induces glomerular inflammation and leads to tubulointerstitial injury, remains a prime target in this field. This Review provides a summary of the current understanding of the patho genesis of IgA nephropathy in humans. Based on the latest available evidence, several hypothetical pathological mechanisms can be proposed. complexes. Fundamental to the formation of immune complexes is the increased synthesis of aberrantly galactosylated IgA1. However, the presence of poorly galactosylated IgA1 O-glycoforms alone is insufficient to cause IgA nephropathy, and a second hit or even multiple hits are required. The second hit is the formation of glycan-specific IgG and IgA antibodies that recognize the undergalactosylated IgA1 molecule (Figure1). These antibodies often have reactivity against antigens from extrinsic microorganisms that form the subsequent hits and can arise following recurrent mucosal infection. Levels of glycan-specific IgG, which has a characteristic variable heavy-chain region that recognizes galactosedeficient IgA1, are elevated in patients with IgA nephropathy and correlate with proteinuria.5 Emerging evidence indicates that Bcells arising in response to mucosal infections, particularly tonsillitis, might produce the nephritogenic IgA1 molecule. 6 Genetic factors also heavily influence the production of undergalactosylated IgA1 and familial clustering of IgA nephropathy is well recognized. Another key area of interest is the effect of mesangial deposition of IgA1 immune complexes, which leads to injury of podocytes and renal tubular epithelial cells via a mesangiopodocytictubular crosstalk involving various mediators. Recent data from patients with IgA nephropathy have provided further insight into the initial development of this disease following mesangial deposition of IgA1 immune complexes and subsequent tubulointerstitial injury, leading to end-stage renal disease.

Disease pathogenesis
An important element in the pathogenesis of IgA nephropathy is the formation of IgA1 immune
Competing interests The author declares no competing interests.

Nephrology Center, 10th floor, Li Shu Pui Block, Hong Kong Sanatorium and Hospital, 2 Village Road, Happy Valley, Hong Kong. knlai@hkucc.hku.hk

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Key points
IgA nephropathy is mediated by the deposition of IgA1 immune complexes Increased synthesis of aberrantly galactosylated IgA1 is the first step in disease pathogenesis and remains fundamental to the formation of immune complexes The formation of glycanspecific IgG and IgA antibodies that recognize the undergalactosylated IgA1 is required for the development of disease Genetic factors heavily influence the production of undergalactosylated IgA1 and familial clustering of IgA nephropathy is well recognized The initial event of mesangial deposition of IgA1 immune complexes induces injury to podocytes and renal tubular epithelial cells via a mesangiopodocytic tubular crosstalk involving various mediators The tubulointerstitial injury that follows chronic inflammation subsequently leads to endstage renal disease

Bacterial/viral infection

Somatic mutation

Genetic factor

Bacterial/viral infection

Autoimmune dysregulation Second or multiple hits Production of antiglycan antibodies

Inherited defect in IgA1-producing B cells

Mucosabone marrow axis

First hit

Production of IgA1 in bone marrow Tonsils

Production of galactose-de cient IgA1

Immune-complex formation Decreased clearance of IgA1 by hepatocytes or reticuloendothelial system Abnormality in mucosal immune system and/or abnormal systemic response to mucosal antigens

Glomerular IgA1 deposition

Figure 1 | Proposed pathways involved in the mesangial deposition of IgA1 in IgA nephropathya multihit mechanism. Fundamental to immunecomplex formation is the increased synthesis of poorly galactosylated IgA1 (first hit). Genetic factors heavily influence the production of undergalactosylated IgA1 and familial clustering is well recognized. However, the presence of these IgA1 Oglycoforms alone is insufficient to cause IgA nephropathy. The second hit is the formation of glycan specific IgG and IgA antibodies that recognize the aberrantly galactosylated IgA1 molecule. These antibodies, often with reactivity against antigens from extrinsic microorganisms, might arise from recurrent mucosal infection (subsequent hits). Emerging evidence indicates that Bcells that arise in response to mucosal infections, particularly tonsillitis, may produce the nephritogenic IgA1 molecule. With increased immunecomplex formation and decreased clearance, IgA1 (mainly polymeric in nature) binds to the glomerular mesangium via an as yet unidentified receptor. Glomerular IgA1 deposits trigger the local production of cytokines and growth factors, leading to mesangial cell activation and complement activation.

Production of IgA1 immune complexes

Aberrant structure of the IgA1 molecule The primary defect of IgA nephropathy lies in the structure of the IgA1 molecule. Human IgA1 is a functionally and structurally distinct molecule that differs from other immunoglobulins, including IgA2, IgM and IgG.7 The attachment site of three to six O-linked glycan chains is located in the unique hinge region
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segment between the first and second constant-region domains of the heavy chains of IgA1. O-glycans in circulating IgA1 are characterized by the presence of N-acetylgalactosamine (GalNAc) with a 1,3-linked galactose; these residues can be attached to a sialic acid. O-glycans in normal serum IgA1 exhibit microheterogeneity in their carbohydrate composition (Figure2). They exist as galactoseGalNAc disaccharides in their monosialylated and disialylated forms. IgA nephropathy is characterized by the overproduction of galactose-deficient IgA1 variants with terminal GalNAc or sialylated GalNAc. The glomerular deposits of IgA1 immune complexes in patients with IgA nephropathy mainly contain these aberrantly glycosylated galactose-deficient forms.810 The synthesis of O-linked glycans of circulatory IgA1 occurs in a step-wise manner. O-Glycosylation of protein is initiated by the addition of GalNAc to serine or threonine residues through the activity of poly peptide N-acetylgalactosaminyltransfer ase2 (GalNAc-T2) followed by -galactosylation by glycoprotein-N-acetylgalactosamine 3--galactosyltransferase1, also known as core1 1,3galactosyltransferase1 or core1 O-glycan T-synthase (C1GALT1). GalNAc bound to serine or threonine residues is galactosylated in the 1,3 configuration by C1GALT1, which requires the presence of the C1GALT1-specific chaperone (COSMC). 11 The formation of the glycan structure is accomplished by -N-acetylgalactosaminide -2,6-sialyltransferase2 (ST6GALNAC2) and -2,3-sialyltransferase (ST3GAL), which attach sialic acid to the GalNAc and galactose residues, respectively. Sialic acid can also be added to terminal GalNAc by ST6GALNAC2. This addition represents a terminal step in O-glycan formation as it prevents any further modification of the molecule.12,13 G e n e s e n c o d i n g C 1 G A LT 1 , C O S M C a n d ST6GALNAC2 are located on chromosome 7p21.3, chromosome Xq24 and chromosome 17q25.1, respectively. Early Chinese and Italian studies reported risk haplotypes in ST6GALNAC2 and C1GALT1 for IgA nephropathy.1416 However, later studies revealed that galactose-deficient IgA1 is derived from IgA1-producing cells and that serum levels of galactose-deficient IgA1 correlated with that of levels in supernatants of IgA1producing cells isolated from the peripheral blood of patients with IgA nephropathy. 13 These data suggest that the aberrant glycosylation in IgA nephropathy is an intrinsic and specific defect originating from IgA1-producing cells rather than from modification of IgA1 during the formation of immune complexes. The expression and enzymatic activity of C1GALT1 does not seem to correlate with O-glycosylation in IgA nephropathy 17 and such aberrant glycosylation does not exist in other glycoproteins with O-linked glycans, such as IgD.18 These observations indicate that the IgA1 glycosylation defect lies in the upstream regulatory pathway(s) rather than in the glycosylation activities of enzymes located downstream of IgA synthesis. However, Suzuki etal.13 studied Epstein Barr virus-immortalized
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1,3

C1GALT1 + COSMC GalNAc-T2 Fab CH1 CL Hinge region

1,3 Ser/Thr 1,3 Ser/Thr

Tn antigen

Ser/Thr

GalNAc

C1GALT1 C1GALT1C1 Tn antigen Ser/Thr Core 1 structure 1,3 GalNAc 1,3 Gal

CH1 Val Pro Ser Thr 225 Pro Pro Thr 228 Pro Ser 230 Pro Ser 232 Thr Pro Pro Thr 236 Pro Ser Pro Ser Cys

Sialyl-T

Ser/Thr

1,3

GalNAc 2,6 NeuNAc

CH2

Monosialyl-T

Ser/Thr

1,3

GalNAc

1,3

Gal NeuNAc 2,3

CH3 Fc

Monosialyl-T

Ser/Thr

1,3

GalNAc NeuNAc

1,3 2,6

Gal

CH2

NeuNAc Disialyl-T Ser/Thr 1,3 GalNAc NeuNAc 1,3 2,6 Gal 2,3

Figure 2 | Microheterogeneity of the Oglycans in the hinge region of IgA1. OGlycosylation of protein is initiated by the addition of GalNAc to serine or threonine residues through the activity of polypeptide Nacetylgalactosaminyltransferase2 (GalNAcT2), which is followed by galactosylation through glycoproteinNacetylgalactosamine 3galactosyltransferase1, also known as core1 1,3galactosyltransferase1 or core1 Oglycan Tsynthase (C1GALT1). The moiety is galactosylated in the 1,3 configuration by C1GALT1, which requires the presence of C1GALT1specific chaperone1 (COSMC). Abbreviations: CH, constant heavy chain region; CL, constant light chain region; Gal, galactose; GalNAc, Nacetylgalactosamine; NeuNAc, Nacetylneuraminic acid.

cells from patients with IgA nephropathy and demonstrated a decrease in C1GALT1 activity and an increase in ST6GALNAC2 activity, which favors the notion of premature sialylation. Undergalactosylated IgA1 molecules are prone to self-aggregate and to form complexes with IgG antibodies.5,9,10 Epitopes at the hinge region that are exposed in the absence of galactose are recognized by IgG and IgA antibodies with antiglycan specificities.5 IgA1 immune complexes are formed following the binding of glycanspecific IgG to undergalactosylated IgA1. Formation of mesangial IgA1 immune complexes insitu following the initial deposition of IgA1 alone has also been suggested as a mechanism of disease.

Circulating Tcells and Bcells

Patients with IgA nephropathy have increased numbers of circulating IgA1-positive Bcells and activated T helper (TH) cells, with increases in both circulating TH1 and TH2 lymphocyte subsets.21 The cytokine profile expressed by these cells is characterized by a predominance of IL-4, IL-5, IL-10 and IL-13, released by TH2 cells.21,22 The increased production of IL-4 could explain the overproduction of IgA1 whereas the increased production of IL-5 favors the IgA isotype switch and differentiation.23 The proportion of Tcells in peripheral blood mononuclear cells is high in patients with IgA nephropathy and correlates well with the number of surface IgA1-positive Bcells. Both Tcells and CD4-positive Tcells produce a large amount of transforming growth factor1 (TGF-1), which induces IgA class switching by Bcells.24,25 The equilibrium between the rate of IgA1 synthesis, uptake by leukocytes and removal by hepatocytes determines the plasma level of IgA1. In one study, binding of endogenous IgA1 to circulating granulocytes and monocytes was increased in patients with IgA nephropathy.26 Expression of the IgA Fc receptor (FCAR, also known as CD89) was increased independently of plasma IgA1 levels. As a result of IgA1 internalization after uptake by leukocytes, FCAR was not saturated. Inhibition studies revealed the presence of a binding mechanism other than FCAR for polymeric IgA1 uptake by leukocytes.26
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Charge of the IgA1 molecule The binding of serum polymeric IgA1 to human mesangial cells depends heavily on the charge of the molecule. Human mesangial cells bind more strongly to anionic than cationic polymeric IgA1 from patients with IgA nephropathy.19 Preincubation of mesangial cells with polyanion (heparin) decreases the binding of polymeric IgA1 to mesangial cells, which indicates that the anionic charge of IgA1 has an important role in mesangial deposition.19 The oversialylation of IgA1 increases the negative charge of the molecule and also increases steric hindrance to hepatic removal.20
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Bone marrowmucosa axis
Most patients with IgA nephropathy have an increased repertoire of IgA1-positive memory Bcells in their bone marrow. Mucosal Bcells are displaced to systemic lymphoid organs and bone marrow following the abnormal trafficking of B lymphocytes along the mucosabone marrow axis in a process that involves chemokines and adhesion molecules.27 The connection between the bone marrow compartment and the mucosal immune system involves the trafficking of antigen-presenting cells and/or antigen-specific lymphocytes. An increased synthesis of both monomeric and polymeric IgA1 occurs in patients with IgA nephropathy with increased numbers of IgA1-producing plasma cells.28,29 A shift in IgA subclass towards IgA1 has been found in immunoglobulins produced by peripheral blood lympho cytes and by plasma cells in the bone marrow and tonsils of patients with IgA nephropathy.3032 These patients also have high levels of circulating IgA1 and IgA1 immune complexes and hyper-responsive lymphocytes to antigens both invitro and invivo. An abnormal systemic response to tetanus toxoid immunization has also been demonstrated.33 Animal studies suggest that TH1 cells derived from the bone marrow initiate disease activity, and that mucosal IgA1 responses to antigens are altered by a TH2-biased background or dysregulation of innate immunity in this disease.34,35 These data suggest that the excess IgA1 derived from bone marrow may be mucosal-type polymeric IgA1, yet has gained abnormal access to the circulation and hence resulting in mesangial deposition. An increased number of IgA1-positive cells are found in tonsillar tissues of patients with IgA nephropathy.36 Germinal centers in the tonsils of these patients are constituted by follicular dendritic cells with preferential IgA1 localization.37 A reduced expression of Jchain mRNA in duodenal IgA1-secreting plasma cells is also present in patients.38 Clinical exacerbation of the disease with macrohematuria is frequently associated with mucosal infection. The crosstalk between the mucosa and bone marrow during a mucosal infection, mediated by continued trafficking of antigen- presenting cells and antigen-specific cells, might increase the generation of nephritogenic IgA1 and thus lead to macrohematuria.6 polymorphisms in a cohort of Japanese patients with IgA nephropathy.42

IgA receptors
Five IgA receptors exist in humans, namely, the FCAR, asialoglycoprotein receptor (ASGR), polymeric immuno globulin receptor, transferrin receptor and Fc/ receptor. The FCAR binds IgA1 of monomeric or dimeric form and IgA2 but not IgG. 4345 FCAR is expressed by neutrophils, monocytes, macrophages, eosinophils, dendritic cells and Kupffer cells.46 FCAR was considered to have a key role in the removal of IgA1 immune complexes from the circulation47 and earlier work suggested that Fc receptors for IgA1 were present in mesangial cells.48,49 Moura etal.50 proposed that activation of the classic FcR-associated transmembrane FCAR expressed on circulating myeloid leukocytes takes place. Crosslinking transgenic mice expressing human FCAR with transgenic mice expressing FcR2 led to FCARFcR2 interaction and promoted disease progression by increasing leukocyte chemotaxis and cytokine production.50 Of note, rodent IgA1 is more like human IgA2 than human IgA1 in structure as it lacks a structure that corresponds to the human IgA1 hinge region. Other investigators failed to demonstrate FCAR expression in human mesangial cells,51,52 despite the fact that mesangial cells showed dose-dependent and saturable Fc-dependent IgA1 binding. One study suggested that a soluble form of the 30 kDa monocyte-derived FCAR complexed with polymeric IgA1 is a prognostic indicator of disease progression.53 Notably, FCAR gene polymorphisms influence the production of the 30 kDa soluble FCAR isoform.53 ASGR, an integral transmembrane glycoprotein, recognizes GalNAc and galactose residues of desialylated glycoproteins and mediates endocytosis of serum glycoproteins. 54 Human ASGR is composed of two units, H1 and H2. Rat hepatic lectin1 (rHL-1; also known as Asgr1) and rHL-2 (also known as Asgr2) mRNAs are expressed widely in various tissues and cell lines despite the fact that ASGR was initially thought to be present exclusively in hepatocytes.55,56 The absence of galactose in galactose-deficient IgA1 with its anionic charge reduces the hepatic clearance of IgA1, which leads to increased serum levels of IgA1 in patients with IgA nephropathy.20 Gmez-Guerrero etal.57 demonstrated binding and degradation of I125-labeled asialo-orosomucoid rich in terminal galactose by human and rat mesangial cells. They also detected rHL-1 and rHL-2 RNA transcripts in rat mesangial cells. Based on these indirect observations, the researchers concluded that human mesangial cells express ASGR. Polymeric immunoglobulin receptor is an integral membrane secretory component that mediates the transepithelial transport of polymeric immunoglobulins including polymeric IgA1.58 The receptor is localized on the basolateral surface of secretory epithelial cells and is detected in most human secretory epithelia.59 The polymeric immunoglobulin receptor acts as a barrier to extracellular and intracellular pathogens in mucous
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Toll-like receptors
Mucosal surfaces have an important role in innate immunity and mucosal immunity with their continuous exposure to pathogen-associated molecular patterns. Expression of Toll-like receptor4 (TLR4) is increased in patients with IgA nephropathy. Ligation of B-cell TLR4 by bacterial lipopolysaccharide induces methylation of C1GALT1C1, leading to reduced activity of COSMC and to undergalactosylation of IgA1. 39 Circulating monocytes from patients with active IgA nephropathy have increased expression of TLR4.40 The increased expression of TLR4 might be a consequence of increased systemic exposure to antigens, possibly as a result of impaired mucosal antigen exclusion in IgA nephro pathy. 41 Disease progression has also been associated with TLR9
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membranes by forming complexes between polymeric IgA1 and pathogens before they are excreted via epithelial transcytosis.49 The transferrin receptor binds to IgA1 but not IgA2 and co-localizes with mesangial IgA1 deposits. This receptor has been suggested as a possible IgA receptor in IgA nephropathy.60,61 However, the transferrin receptor is ubiquitously expressed in various kidney cells. The Fc/ receptor has also been examined as a novel IgA receptor in mesangial cells, on the basis of invitro studies.62 Subsequent in-depth studies have failed to detect these five IgA receptors in mesangial cells, podocytes or renal tubular epithelial cells.52,63,64 Thus, the uptake of IgA1 by human mesangial cells is mediated by mechanisms yet to be identified. IgA nephropathy who had common ancestors in previous generations.73,74 No familial clustering was found in nearby villages that shared a similar environment, lifestyle and culture, which indicates an inherited mechanism of disease. The clinical features of familial and sporadic forms of IgA nephropathy are very similar and little difference in histological findings, nature of the immunoglobulin and complement C3 deposition in renal tissue exists between the two forms of disease at first presentation. Some studies suggest a worse prognosis and a more severe histopathology for familial IgA nephropathy than for sporadic IgA nephropathy, resulting in a renal survival rate of 41% (15years from the time of renal biopsy) versus 94%, respectively.75,76 However, findings that show no difference in prognosis between familial and sporadic IgA nephropathy have also been reported.77,78 In families in which IgA nephropathy aggregate, other types of glomerulonephritis including IgM nephropathy, thin basement membrane nephropathy, and most importantly, HenochSchnlein purpura have been reported.71,79

Genetic factors
Most IgA nephropathies are sporadic rather than familial and IgA nephropathy is generally considered to be a complex disorder. That is, it is multifactorial with both genetic and environmental factors that are likely to contribute to disease in the majority of patients. Studies suggest that genes responsible for sporadic and familial IgA nephropathy might differ and that the genetic contribution to the disease is heterogeneous, and can lie anywhere in the spectrum from monogenic through to oligogenic or polygenic, differing between individual cases and families. However, in some families the disease segregates in an obviously autosomal dominant fashion.

Familial studies Familial clustering of a disease often suggests a genetic effect. IgA nephropathy is sometimes identified when screening for prospective kidney donors within a family.65 The prevalence of familial IgA nephropathy or sibling recurrence risk ratio is not known as the associated urinary abnormalities are often intermittent and definitive diagnosis requires a renal biopsy. A detailed family history focusing on unexplained hematuria in first-degree and second-degree relatives, presence of consanguinity and potential environmental exposures often provides clues for a familial renal disorder. Familial aggregation of IgA nephropathy was first reported in the late 1970s.66 In two European studies, 410% of patients with IgA nephropathy had a family history of kidney disease.67,68 Schena etal.69 detected urinary abnormalities in 61 of 269 asymptomatic firstdegree relatives from 48 families of patients with IgA nephropathy. In another Italian survey lasting 25years, 14% of the 185 patients with IgA nephropathy were related to at least one other patient, forming 10 multiplex pedigrees. 70 Levy 71 reported 40 families with no less than two members having IgA nephropathy. Familial IgA nephropathy has also been found in Asia and North America, 65,72 indicating that familial IgA nephropathy is not uncommon, but probably underdiagnosed as urinalysis is not routinely performed and microhematuria is intermittent. Epidemiological studies of patients with IgA nephropathy in isolated geographical areas identified individuals with sporadic
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Relatives of patients with IgA nephropathy Relatives of patients with IgA nephropathy demonstrate abnormalities in their IgA1 immune system with increased circulating IgA1-positive Bcells and T4 cells. Peripheral blood mononuclear cells isolated from these relatives overproduce IgA1, T cells, other immunoglobulins and IgA1 immune complexes upon stimulation by mitogen invitro.80 First-degree relatives of both pediatric and adult patients with IgA nephropathy have elevated serum levels of undergalactosylated IgA1, which suggests a predominantly unilineal transmission of the trait.81 Gharavi etal.82 detected undergalactosylated IgA1 in 47% and 25% of first-degree relatives of patients with familial IgA nephropathy and patients with sporadic IgA nephropathy, respectively. Tam etal.72 also demonstrated elevated serum levels of undergalactosylated macromolecular IgA1 in first-degree relatives of adult patients with familial IgA nephropathy. An invitro study using macromolecular IgA1 isolated from asymptomatic relatives showed that IgA1 upregulated mesangial cell activation leading to increased expression of cytokines.72 Renal tubular cells cultured with conditioned medium from relatives of patients with familial IgA nephropathy exhibit increased expression of chemokines and proinflammatory cytokines, with prominent synthesis of IL-6, IL-8 and tumor necrosis factor (TNF). 76 The conditioned medium from mesangial cells cultured with macromolecular IgA1 isolated from relatives of familial IgA nephropathy induced chemotaxis of lymphocytes expressing receptor-type tyrosineprotein phosphataseC (also known as CD45) and activated monocytes expressing IL-2 receptor subunit- (also known as CD25). These invitro findings suggest that macromolecular IgA1 from relatives of patients with familial IgA nephropathy induces proinflammatory changes in cultured renal tubular cells through a glomerulotubular interaction.
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Familial IgA nephropathy and linked loci The most clearcut report of familial IgA nephropathy and linkage is from a study of a four-generation Canadian family of GermanAustrian origin with 14 affected and 11 unaffected members. 83 The pedigree is consistent with autosomal dominant inheritance. Parametric and nonparametric linkage analysis produced a significant logarithm of the odds ratio (LOD) score of 3.47 according to standard criteria for Mendelian disease. A LOD score of three indicates 1,000:1 odds that linkage between the marker and the disease exists and is of significance. The first loci identified in a linkage analysis of 24 Italian families and six American families with IgA nephropathy were 6q22q23 and 3p23p24, with a LOD score of 5.6 for 6q22q23, which was named IGAN1.84 Although the locus at 3p23p24 was the other interval with a LOD score >1 in this study (LOD score 2.8), this interval did not reach statistical significance. The European IgA Nephropathy Consortium identified suggestive loci at 4q26q31 (LOD score 1.8) and 17q12q22 (LOD score 2.6) in 22 Italian families with 59 affected and 127 unaffected members.85 The loci were named IGAN2 and IGAN3.85 These four loci have not been revealed in patients with familial IgA nephropathy of other ethnicities.86 Most intriguingly, in a preliminary report using genome-wide linkage scan to study a large four-generation Singaporean Chinese family and 23 smaller Chinese IgA nephropathy kindreds from Hong Kong, Hsu etal.87 identified a novel locus on chromosome 8p2223 with a maximum multipoint LOD score of 3.89. This locus contributes a large genetic effect in 50% of these kindreds, which suggests a novel susceptibility gene for familial IgA nephropathy in Southeast Asian Chinese patients. Genome-wide association studies In one genome-wide association study, a strong signal of association on chromosome 6p in the region of the MHC (P = 1 10 9) was identified in 533 European patients with IgA nephropathy recruited from the UK Glomerulonephritis DNA Bank.88 The strongest association signal was detected in a combination of DQ loci, with a weaker signal in the HLA-B loci, indicating that the susceptibility alleles for IgA nephropathy in European patients are located in the HLA region. Using a similar approach in 1,194 patients of Chinese Han ethnicity, Gharavi etal.89 identified five loci that surpassed genome-wide significance: three of these loci were in the HLA region, as well as a common deletion in CFHR1 and CFHR3 at chromosome 1q32 and in a locus at chromosome 22q12. However, only 47% of the disease variance can be accounted for by these five loci.89 Complex selective pressure is suggested by the close correlation between the IgA nephropathy risk allele frequencies and the variation of disease prevalence among different ethnic populations. Genes in sporadic IgA nephropathy Numerous association studies have reported various frequencies of genetic variants but none of these candidate
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genes are unique to IgA nephropathy. In an analysis of 123 candidate-gene association studies of IgA nephropathy, Kiryluk etal.90 found 31%, 32% and 35% were associated with disease susceptibility, disease progression, or both, respectively. One-third of the studies examined gene polymorphisms of the reninangiotensin system. Cohorts in these studies were underpowered with inadequate cover of the number of single nucleotide polymorphisms. Which of the reported genes truly confer susceptibility is therefore unclear.

Glomerulopodocytictubular crosstalk
IgA nephropathy is characterized by the mesangial deposition of pathogenic polymeric IgA1 with limited deposits in podocytes or tubular epithelial cells. 63,65 Three pathogenetic mechanisms may operate independently or synergistically to induce renal injury in IgA nephropathy: tubulointerstitial infiltration by monocytes or macrophages, tubulointerstitial injury as a result of luminal exposure to albumin in proteinuria, and glomerulo podocytictubular crosstalk (Figure3).63,64,91 Proinflammatory cytokines and angiotensinII are released by mesangial cells following binding to pathogenic IgA1.91 Inflammatory cells infiltrating the tubulointerstitium have an important role in mediating tubulointerstitial injury and renal fibrosis in a variety of renal pathologies. Tubular epithelial cells are activated by mediators released by infiltrating leukocytes and this process initiates and amplifies an inflammatory cascade through increased local release of chemotactic mediators, which attract further proinflammatory immunocompetent cells. 92 A positive feedback loop of activation is then established leading to increased matrix formation, tubulointerstitial fibrosis and ultimately renal failure. Proteinuria stimulates chemotaxis and migration of immunocompetent cells in various glomerular diseases.63,93,94 However, proteinuria has a minor contributory role in IgA nephropathy as heavy proteinuria is uncommon. With the absence of known IgA1 receptors in podocytes or tubular epithelial cells, an invitro study indicated that altered glomerular permeability and tubulointerstitial injury in patients with IgA nephropathy are mediated by humoral factors (predominantly TNF, TGF- and angiotensinII) derived from mesangial cells.63 First, mesangial-derived humoral factors and mediators activate podocytes that synthesize TNF in an autocrine fashion. An invitro study revealed that activation of the TNF receptor1 (TNFR1) in podocytes by mesangial-derived TNF leads to synthesis of IL-6 and apoptosis.64 TNF, TNFR1, and TNF receptor2 (TNFR2) in podocytes are upregulated in patients with IgA nephropathy. Upregulation of TNFR1 favors apoptotic cell death whereas the upregulation of TNFR2 maintains a chronic proinflammatory state.64 Expression of podocyte proteins, including nephrin, ezrin and podocin, is reduced in patients with IgA nephropathy and this downregulation is mediated by mesangial-derived TNF and TGF-.95 The clinical relevance of this finding is that the expression of nephrin, ezrin and podocin correlates with the
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IgA1 Glomerulotubular crosstalk via TNF, IL-6 and Ang II AGTR1 Glomerulopodocytic crosstalk via TNF and TGF-

AGTR2 Tubular epithelial cell

AGTR1

Glomerulotubular crosstalk favoring glomerulosclerosis Aldosterone Ang II

Mesangial cell

Podocyte

MR AGTR2 Apoptosis

TNFR1

TNF

TNFR2

Proteinuria Tubular atrophy TNF IL-6 Apoptosis Bcl-2 BAX Proin ammatory cellular response

Figure 3 | Proposed pathways leading to glomerular damage, podocyte dysfunction and tubulointerstitial injury in IgA nephropathy. Mesangial deposition of IgA1 immune complexes leads to activation of mesangial cells, which triggers mesangial cell proliferation and release of proinflammatory and profibrotic mediators, including TNF, TGF, IL6 and angiotensinII. Deposition of IgA1 immune complexes is limited on podocytes and tubular epithelial cells. TNF released from the mesangium induces TNF synthesis by podocytes. Podocytederived TNF further upregulates production of TNF in an autocrine manner, which also upregulates the expression of TNF receptors. The binding of TNF to TNFR1 leads to IL6 synthesis and apoptosis whereas binding to TNFR2 maintains proinflammatory cellular responses. Podocytes increase interstitial damage by amplifying the activation of tubular epithelial cells with increased TNF synthesis. In the renal tubulointerstitium the interaction of angiotensinII and AGTR1 leads to inflammatory responses through the upregulation of protein kinaseC and MAPK pathways. The activation of AGTR2 leads to apoptosis through downregulation of the MAPK pathway. Aldosterone released from mesangial cells following IgA1 immunecomplex deposition acts synergistically with angiotensinII to induce apoptosis in renal tubular epithelial cells. The mesangialderived angiotensinII maintains the tubulointerstitial injury. Abbreviations: AngII, angiotensinII; AGTR, angiotensin receptor; IL6, interleukin 6; MAPK, mitogen activated protein kinase; MR, mineralocorticoid receptor; TGF, transforming growth factor; TNF, tumor necrosis factor; TNFR, TNF receptor.

degree of proteinuria, the increase in serum creatinine levels and the decrease in creatinine clearance. Another invitro study indicated that platelet-activating factor mediated nephrin loss in patients with IgA nephropathy when cultured podocytes were preincubated with TNF.96 Mesangial-derived mediators (TNF, IL-6 and angiotensinII) reach the tubulointerstitium by two separate routes: glomerular filtration and transportation via the postglomerular capillaries. These mesangial-derived inflammatory cytokines activate tubular epithelial cells, which induce the migration of inflammatory competent cells by amplifying an inflammatory cascade through the production of chemotactic mediators.76 The inflammatory mediators produced by tubular epithelial cells, including IL-6, TNF, TGF-, soluble intercellular adhesion molecule1 and angiotensinII, generate a positive feedback loop of activation leading to the overproduction of extracellular matrix components that result in fibrosis and renal failure. The reninangiotensin system is heavily involved in renal injury in many renal diseases, including IgA nephropathy, and angiotensinII is the prime culprit. Type1 angiotensinII receptor (AGTR1) and type2 angiotensinII receptor (AGTR2) are present in mesangial cells,97 podocytes98 and tubular epithelial cells.99 Invitro studies have shown that mesangial expression of AGTR1 is reduced after acute exposure to polymeric IgA1 from patients with IgA nephropathy, which supports a local downregulation of AGTR1 resulting from negative feedback involving increased intraglomerular reninangiotensin system activity and, hence,
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angiotensinII activity.97,100102 Interestingly, such adaptive changes in mesangial cells are gradually lost with prolonged exposure to polymeric IgA1. Laboratory data suggest that failure to suppress the increased AGTR1 expression in the presence of defective AGTR2 activation enables the development of proliferative and inflammatory processes in the glomerular mesangium.99 The continuous synthesis of mesangial-derived mediators perpetuates glomerulotubular crosstalk, which potentiates the progression of renal deterioration in IgA nephropathy. In addition, IL-6 upregulates expression of AGTR1 and increases the production of angiotensinII in tubular epithelial cells.99 The tubulointerstitial inflammation may be mediated through protein kinaseC and mitogen-activated protein kinase pathways following interaction of angiotensinII and AGTR1.99 Most recently, aldosterone synthesis and aldosterone synthase expression by mesangial cells were shown to be upregulated by polymeric IgA1 isolated from patients with IgA nephropathy.103 Mineralocorticoid receptors are constitutively expressed in renal tubular epithelial cells. AngiotensinII and aldosterone act synergistically to induce apoptosis in renal tubular epithelial cells. Apoptosis is inhibited by AGTR2 blockade and aldosterone antagonists, which suggests that crosstalk between angiotensinII and aldosterone could participate in determining the tubular pathology of IgA nephropathy.

Conclusions
IgA nephropathy is a glomerular disease that is caused by increased circulating levels of IgA1 with
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galactose-deficient hinge-region O-glycans and deposition of immune complexes. However, aberrant glycosylation is not able to induce renal injury on its own. Additional insults, including the formation of glycanspecific IgG and IgA antibodies that recognize the undergalactosylated IgA1 molecule, are required to establish permanent renal injury. These antibodies may arise following recurrent mucosal infection. Although the underlying mechanism of glomerular IgA1 deposition in IgA nephropathy remains unknown, recent studies indicate that mesangial-derived mediators lead to podocyte and tubulointerstitial injury via mesangio podocytictubular crosstalk. A greater understanding of
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the pathogenesis will provide a better approach for noninvasive diagnosis, amelioration of renal deterioration and prevention of allograft IgA nephropathy.

Review criteria
The PubMed database was searched for articles published from 1981 to 31 October 2011 using the search terms IgA nephropathy, pathogenesis, IgA1 molecule, etiology, IgA1 binding and pathophysiology. The search was limited to human studies and the references of these papers were searched for further relevant material.

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