IgAN recurs frequently in renal allografts.²²,²³,²⁴,²⁵,²⁶ Moreover, in isolated instances in which a kidney was transplanted from a donor with subclinical IgAN into a patient with non-IgAnephropathy renal disease, the immune deposits cleared from the affected kidney within several weeks.²⁷ These clinical observations suggest that the cause of IgAN is extrarenal and there is considerable evidence indicating that the mesangial deposits originate from circulating IgA-containing immune complexes. It is well established that patients with IgAN frequently have elevated circulating levels of IgA and IgA-containing immune complexes.²⁸,²⁹,³⁰ Idiotypic determinants are shared between the circulating complexes and the mesangial deposits³¹; however, a disease-specific idiotype has not been identified.³² Circulating immune complexes in patients with IgAN contain IgA1,²⁸,³³,³⁴ the only IgA subclass in the mesangial immunodeposits.

Analysis of the glycosylation of IgA1 in patients with IgAN has yielded novel insights into the mechanisms underlying immune complex formation and mesangial deposition.³⁰,³⁴,³⁵,³⁶,³⁷,³⁸,³⁹,⁴⁰ Specifically, galactose deficiency in IgA1 O-glycans appears to be a key pathogenetic factor.³⁶ Circulating complexes in patients with IgAN contain IgA1 with galactose-deficient hinge-region O-linked glycans.³⁰,³⁴,³⁷,⁴¹ Notably, galactose-deficient IgA1 is the predominant glycosylation variant of IgA1 in the mesangial deposits, as determined by analyses of IgA1 eluted from glomeruli of nephrectomized kidneys or biopsy specimens from patients with IgAN.⁴²,⁴³ A relationship between galactose deficiency and nephritis also has been underscored by two other observations: (1) galactose-deficient IgA1⁴⁴ and IgA-IgG circulating complexes⁴⁵ are found in sera of patients with HSPN but not in sera of patients with HSP and (2) patients with IgA1 myeloma have high circulating levels of IgA1, but only those with aberrantly glycosylated IgA1 develop immune-complex glomerulonephritis.⁴⁶,⁴⁷

IgA1 and IgA2 represent two structurally and functionally distinct subclasses of IgA in humans.⁴⁸ IgA1 contains a unique hinge-region segment between the first and second constant-region domains of the heavy chains (Fig. 49.2A), with a high content of proline, serine, and threonine, that is the site of attachment of O-glycans. Up to six of the nine possible sites are occupied in each hinge region. These IgA1 O-glycans consist of N-acetylgalactosamine with a β1,3-linked galactose that may be sialylated.⁴⁹,⁵⁰,⁵¹,⁵²,⁵³,⁵⁴ Sialic acid can be attached to N-acetylgalactosamine also
by an α2,6 linkage. The carbohydrate composition of the O-linked glycans in the hinge region of normal human serum IgA1 is variable (Fig. 49.2B). The prevailing glycans include galactose-N-acetylgalactosamine disaccharide and its mono- and di-sialylated forms.³⁰,⁵¹,⁵⁴,⁵⁵,⁵⁶,⁵⁷,⁵⁸ Galactose-deficient variants with terminal N-acetylgalactosamine or sialylated N-acetylgalactosamine are rarely found in the O-glycans of normal serum IgA1.⁵¹

The first step in the O-glycosylation of the IgA1 hinge region, with selection of the sites to be modified and the control of the sequence in this process, is accomplished by one of the few enzymes of the UDP-N-acetylgalactosamine:polypeptide N-acetylgalactosaminyltransferase family. In the second step, N-acetylgalactosamine is then modified by addition of β1-3-linked galactose, as detailed in Figure 49.2C. Lastly, one or both sugars can be further modified by the addition of sialic acid.⁵⁹

In patients with IgAN, the basis of the aberrant O-glycosylation of IgA1 has been determined by using immortalized IgA1-secreting cell lines generated from circulating mononuclear cells. The galactose deficiency develops due to changes in expression and activity of key enzymes involved in O-glycosylation in the IgA1-producing cells (Fig. 49.2C).⁶⁰ These changes in expression corresponded to decreased enzymatic activity of galactosyltransferase and elevated activity of sialyltransferase. Moreover, studies by other investigators identified mucosal, but not systemic, immune responses as the integral part of the aberrant O-glycosylation of IgA1.⁶¹,⁶² However, mechanisms involved in these pathways and their regulation remain to be elucidated.

Normal circulatory IgA has a relatively short half-life (˜5 days) due to its rapid catabolism by hepatocytes.⁶³ Hepatocytes express the asialoglycoprotein receptor⁵²,⁶⁴ that binds glycoproteins through terminal galactose or N-acetylgalactosamine residues.⁵²,⁶⁴,⁶⁵ Because the structural prerequisite for binding is a terminal galactose or N-acetylgalactosamine, the absence or enzymatic removal of the otherwise terminal sialic acid is essential for effective binding.

Galactose-deficient IgA1 is retained in the circulation for prolonged intervals.⁶⁶ Galactose deficiency in itself should not hinder disposal of IgA1 molecules because the asialoglycoprotein receptor recognizes terminal N-acetylgalactosamine as well as galactose.⁶⁵ However, if the N-acetylgalactosamine is linked to sialic acid or is occupied by an antibody, it cannot be recognized by the receptor.⁴¹,⁶⁷ Because galactose-deficient IgA1 is present primarily within immune complexes, it is plausible to speculate that this IgA1 does not effectively reach the hepatic asialoglycoprotein receptor. The larger size of the complexes, compared to that of uncomplexed IgA1, precludes binding to this receptor because the relatively small endothelial fenestrae block entry into the space of Disse. It is thus quite possible that immune complexes containing aberrantly glycosylated IgA1 are not efficiently cleared from the circulation and eventually deposit in the mesangium after passing through larger fenestrae in the glomerular capillaries.⁶⁹,⁷⁰,⁷¹,⁷² In animals, highmolecular-mass immune complexes induce more severe glomerular lesions than do small complexes.⁶⁸

Immune complexes containing aberrantly glycosylated IgA1 can activate human mesangial cells in vitro, resulting in a proliferative response and overproduction of extracellular matrix components and cytokines/chemokines.³⁷,⁴¹,⁷³,⁷⁴,⁷⁵ Multiple studies have pointed to activation through an IgAspecific receptor(s) on mesangial cells. However, none of the known IgA receptors (CD89, asialoglycoprotein receptor, and polymeric immunoglobulin receptor) are expressed on human mesangial cells.³⁷,⁴¹,⁷⁶ Among the candidate receptors that may mediate binding of IgA1 and IgA1 complexes are CD71 (transferrin receptor)⁷³,⁷⁷,⁷⁸ and the Fcα/µ receptor.⁷⁹ CD71 appears to be the major IgA1 receptor on proliferating human mesangial cells.⁷³,⁷⁸,⁸⁰ Notably, expression of CD71 is enhanced in the mesangia of IgAN patients and it colocalizes with IgA1 deposits.⁸¹ Engagement of CD71 by IgA1 induces cellular proliferation and cytokine production (e.g., interleukin [IL]-6, tumor growth factor [TGF]-β).⁸⁰ This induction of cellular proliferation and cytokine production by IgA1 is inhibited completely by anti-CD71 antibody.⁸⁰ It is not clear, however, whether CD71 is the only receptor or if any other receptor(s) plays a role in the activation of mesangial cells.

Although the signaling pathways and detailed mechanisms of the activation of mesangial cells by IgA1-containing immune complexes remain to be elucidated, it is generally agreed that mesangial cells represent the primary target in IgAN. There are two hypotheses for mechanisms leading to activation of mesangial cells by IgA1 in IgAN (Fig. 49.3). Both theories propose multiple hits and involvement of aberrantly glycosylated IgA1 and antiglycan antibodies. The first assumes formation of immune complexes in the circulation and their subsequent mesangial deposition and activation of mesangial cells (Fig. 49.3, solid lines).³⁴,³⁷,⁶⁰,⁸² The other theory proposes that some of the aberrantly glycosylated IgA1 molecules are in the mesangium as lanthanic deposits, and later bound by newly generated antiglycan antibodies to form immune complexes in situ (Fig. 49.3, broken lines).⁸³

Mesangial cells activated by immune complexes containing galactose-deficient IgA1 proliferate and overproduce extracellular matrix proteins, cytokines, and chemokines.³⁷,³⁹,⁷³,⁷⁴,⁷⁸,⁸⁴,⁸⁵,⁸⁶,⁸⁷ These processes, when unchecked for substantial periods of time, may lead to expansion of the glomerular mesangium and, ultimately, glomerular fibrosis with loss of glomerular filtration function. Furthermore, humoral factors (e.g., tumor necrosis factor [TNF]-α and TGF-β)³⁸,⁸⁶,⁸⁸,⁸⁹ are released from mesangial cells activated by IgA1-containing immune complexes and alter podocyte gene expression and may thus increase glomerular permeability (Fig. 49.3). This mesangio-podocyte communication may be a mechanism to explain the occurrence of proteinuria and segmental glomerular sclerosis and tubulointerstitial injury in IgAN.¹⁴,⁸⁶ Moreover, pathogenicity of IgA1 immune complexes may be enhanced in the presence of systemic signs of oxidative stress, and it has been hypothesized that oxidative stress may affect expression and progression of the disease.⁹⁰

Genetic factors are known to play an important role in susceptibility to IgAN, as indicated by worldwide reports of extended multiplex pedigrees.⁹¹,⁹²,⁹³,⁹⁴,⁹⁵,⁹⁶,⁹⁷,⁹⁸ Familial IgAN has offered a convenient tool for genetic studies and provided insight into the mechanism of inheritance. In some families, segregation of IgAN has been consistent with an autosomal-dominant transmission with incomplete penetrance. The incomplete penetrance, consistent with a complex-disease model, may reflect a requirement for additional genetic or environmental factors for clinical manifestation of the disease.

Gene mapping studies of diseases with complex determination are difficult and, thus far, no single mutation has been conclusively demonstrated to cause IgAN. Several genome-wide studies of familial IgAN have linked various loci with disease, including chromosomes 6q22-23 (named IGAN1), 4q26-31, 3p24-23, and 2q36.⁹⁵,⁹⁹,¹⁰⁰ In contrast to the linkage studies, association studies involve a collection of sporadic cases and a group of unrelated controls. These studies can be performed for specific preselected genes (candidate-gene association studies) or on a genome-wide
scale to provide an unbiased examination of the genome, with the ability to detect and correct for population stratification. Replication of findings in independent cohorts is necessary for validation of both approaches.¹⁰¹

A single, unreplicated genome-wide association study (GWAS) in a small European cohort (533 cases) has reported association of IgAN with a human leukocyte antigen (HLA) locus.¹⁰² A recent replicated GWAS of a cohort of 3,144 IgAN cases of Chinese and European ancestry identified five loci.¹⁰³ These loci explained up to a tenfold variation in interindividual risk and cumulatively accounted for 4% to 7% of the disease variance and included three independent loci in the major histocompatibility complex, a common deletion of CFHR1 and CFHR3 at chromosome 1q32 (complement factor H-related genes) and chromosome 22q12. The risk allele frequencies also strongly paralleled the prevalence of IgAN in the different populations. Furthermore, many of the IgAN-protective alleles imparted increased risk for other autoimmune or infectious diseases, suggesting complex selective pressures on allele frequencies.¹⁰³ It is likely that studies with larger cohorts, and thus higher power, will define additional genetically influenced components in the pathogenesis of IgAN.

Recent studies of the glycosylation abnormalities of IgA1 offered prospects for a phenotypic biomarker for IgAN.¹⁰⁴,¹⁰⁵,¹⁰⁶,¹⁰⁷,¹⁰⁸,¹⁰⁹ A new quantitative lectin-binding assay enabled investigation of the inheritance of galactose-deficient IgA1 in familial and sporadic forms of IgAN.¹¹⁰ A high serum galactose-deficient IgA1 level was present in most index cases, as well as many of their first-degree relatives, whereas levels in spouses were indistinguishable from those in controls, eliminating an environmental effect. Segregation analysis of galactose-deficient IgA1 suggested inheritance of a major dominant gene with an additional polygenic component. The inheritance of galactose-deficient IgA1 has been confirmed in Chinese patients with familial and sporadic adult IgAN³⁹,¹¹¹ and in pediatric patients with IgAN and HSPN.⁹⁴ Thus, aberrant IgA1 glycosylation is a common inherited defect that provides a unifying link in the pathogenesis of HSPN and familial and sporadic IgAN in many populations worldwide. GWAS studies using this new phenotype will likely provide information about the genetic and biochemical pathways leading to production of galactose-deficient IgA1 by IgA1-secreting cells.⁶⁰ Furthermore, elevated circulatory levels of galactose-deficient IgA1 are antecedent to disease. However,
as most family members with elevated levels are asymptomatic, IgA1 glycosylation abnormalities are not sufficient to produce IgAN and additional cofactors, such as antiglycan antibodies,⁸² are required to trigger formation of pathogenic immune complexes (Fig. 49.3).

The reported incidence and prevalence of IgAN varies widely, and depends, to some degree, on variations in criteria for renal biopsy in different countries. Studies from Europe have estimated the incidence at 15 to 40 new cases per million population per year. The incidence is higher in Japan and Korea,¹¹²,¹¹³ where screening for urinary abnormalities is routinely performed in school-aged children. Prevalence rates, expressed as a percentage of renal biopsy diagnoses, are reported to be 20% to 40% in Asia, Australia, Finland, and southern Europe. In the United States, the rate may be as low as 2% but in a large nephropathology referral practice IgAN accounted for 14% of nontransplant renal biopsies in adults aged 20 to 39 years.¹¹⁴

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