Composition of IgA-containing circulating immune complexes in IgA nephropathy

Macromolecular IgA is found with a relatively high frequency in the sera of patients with IgA nephropathy (IgAN). This macromolecular IgA consists of polymeric IgA, IgA-containing immune complexes, or both. The presence of polymeric IgA antibodies reflects a recent IgA response. Vaccination data in patients with IgAN suggest that these patients respond more vigorously with their mucosal immune system than do controls. The association of exacerbations with upper respiratory tract infections suggests that the immunogenic stimuli probably are of microbial origin and are presented to mucosal surfaces. Analysis by sucrose density ultracentrifugation has shown that the macromolecular IgA may contain IgG, IgA rheumatoid factor, and C3. The search for the antigen or antigens specifically responsible for IgAN has been unsuccessful. Although IgG and IgA rheumatoid factor may contribute, they do not account for the pathogenesis of the disease in all patients. Alternative mechanisms have to be assumed for patients who do not have detectable levels of IgA-containing immune complexes. They could have polymeric IgA or IgA-containing immune complexes intermittently, as has been shown in children with relapsing IgAN. The binding of circulating IgA antibodies to antigens present in the mesangium can lead to the local formation of deposits in the absence of circulating IgA complexes.     

Immunoglobulin-antiimmunoglobulin interactions and immune complexes in IgA nephropathy

IgA nephropathy (IgAN) is characterized by mesangial co-deposition of IgA and C3. Elevated levels of circulating immune complexes containing these components in significant numbers of patients have been found in several studies; IgAN is therefore assumed by many investigators to be an immune complex-mediated disease. Our studies have shown that IgG is often co-complexed with IgA within circulating immune complexes, and we have begun to examine the potential mechanisms for these observations. In this regard, elevated levels of IgA rheumatoid factor and of IgG anti-IgA antibodies were found in some patients. Nevertheless, we were unable to correlate levels of circulating immune complexes with any clinical index of disease. Furthermore, many individuals with the acquired immune deficiency syndrome (AIDS) also have elevated levels of circulating immune complexes containing IgG and IgA, IgA rheumatoid factor, and IgG anti-IgA antibodies, although these patients apparently do not have mesangial IgA deposits. Therefore, the role of circulating IgA-containing immune complexes in the pathogenesis of IgAN requires further evaluation.     

Immunological aspects of IgA nephropathy

Summary: IgA nephropathy (IgAN) is one of the most common primary renal diseases, and can be readily diagnosed by finding glomerular IgA deposits as either the dominant or codominant immunoglobulin on immunofluorescence microscopy. Despite some contradictory results about the nature and origin of IgA, it is generally accepted that the deposited IgA is polymeric and belongs to the IgA, subclass and systemic compartment is the source of circulating polymeric-IgA in IgAN. Because IgAN presents with asymptomatic microscopic haematuria or with episodic gross haematuria following upper respiratory and gastrointestinal disturbance, various environmental respiratory or gastrointestinal infectious agents and dietary antigens are suggested. Until now, however, it has not been possible to unequivocally identify specific antigens that are responsible for the formation of mesangial IgA deposits in patients with IgAN. Overproduction or delayed clearance of IgA as observed in patients and in animal models and in those processes, polyclonal stimulation of immunoglobulin production, with structural abnormalities of IgA, seems to play an important role. The mechanism responsible for the mesangial deposition of IgA is still unclear. The codeposition of IgA, C3 and properdin without Clq and C4 suggested a possible activation of the alternative pathway by IgA-containing immune complexes. To sum up, in IgAN the predominant antibody appears to be composed of polymeric-IgA₁ originating in the systemic compartment. The deposition of polymeric-IgA₁ in the mesangium and the activation of the alternative pathway of complement are probably crucial in the induction of the inflammatory lesions in the glomeruli and the development of haematuria in IgAN.     

An increased polymeric IgA level is not a prognostic marker for progressive IgA nephropathy.

BACKGROUND: Elution of IgA from renal biopsies of patients with primary IgA nephropathy (IgAN) has suggested that mesangial IgA deposits are mainly multimeric in nature. This macromolecular IgA consists of dimeric and polymeric IgA and may be derived from the circulation. In children with IgAN, circulating macromolecular IgA levels correlate with bouts of macroscopic haematuria, but in adults a correlation with disease activity is less clear. Therefore, we have designed a novel method to assess the levels of polymeric IgA (pIgA) in sera from patients and controls. METHODS: A novel precipitation assay using recombinant CD89 was developed to measure pIgA. Polymeric IgA levels were measured in serum samples obtained from healthy volunteers (n = 21) and patients with IgAN (n = 51). Subsequently, serum pIgA levels were correlated with clinical parameters of disease. RESULTS: Serum pIgA levels were significantly increased in patients with IgAN. However, pIgA concentrations relative to total IgA were significantly lower in sera of patients with IgAN. No correlation was found between serum pIgA levels and clinical parameters of IgAN, such as decline of glomerular filtration rate, haematuria or proteinuria. CONCLUSIONS: Although absolute levels of serum pIgA are increased in patients with IgAN as compared with controls, levels of pIgA relative to total serum IgA are lower. No significant correlation was found between serum concentrations of pIgA and clinical parameters of disease. These data support the notion that it is not the size alone, but the physicochemical composition of the macromolecular IgA that is the key factor leading to mesangial deposition.     

Both IgA nephropathy and alcoholic cirrhosis feature abnormally glycosylated IgA1 and soluble CD89-IgA and IgG-IgA complexes: common mechanisms for distinct diseases

Abnormalities of IgA arise in alcoholic cirrhosis, including mesangial IgA deposits with possible development of secondary IgA nephropathy (IgAN). Since little is known about circulating immune complexes in cases of secondary IgAN, we analyzed IgA-associated parameters in the serum of 32 patients with compensated or advanced alcoholic cirrhosis. Galactose deficiency and decreased sialylation of IgA1, as well as increased amounts of abnormally glycosylated polymeric IgA1, were detected in the serum of patients with advanced alcoholic cirrhosis. Moreover, aberrant IgA1 formed complexes with IgG and soluble CD89 in serum of patients with advanced alcoholic cirrhosis, similar to those found in primary IgAN. The IgA1 of alcoholic cirrhosis, however, had a modified N-glycosylation, not found in primary IgAN. In patients with alcoholic cirrhosis and IgAN, IgA deposits were associated with CD71 overexpression in mesangial areas, suggesting that CD71 might be involved in deposit formation. Although the IgA1 found in alcoholic cirrhosis bound more extensively to human mesangial cells than control IgA1, they differ from primary IgAN by not inducing mesangial cell proliferation. Thus, abnormally glycosylated IgA1 and soluble CD89-IgA and IgA-IgG complexes, features of primary IgAN, are also present in alcoholic cirrhosis. Hence, common mechanisms appear to be shared by diseases of distinct origins, indicating that common environmental factors may influence the development of IgAN.     

Structural features of IgA molecules which contribute to IgA nephropathy.

IgA nephropathy (IgAN) is characterised by the mesangial deposition of polymeric IgA1 (pIgA1). pIgA1 production is reduced in the mucosal immune system in IgAN and increased in the marrow; this switch may be secondary to a defect in gammadeltaT cell control of IgA production. However this does not explain the mechanism by which pIgA1 deposits in the mesangium. There is no direct evidence that classical immune complex deposition occurs in IgAN and alternative mechanisms resulting from physicochemical abnormalities of the IgA1 molecule, particular altered glycosylation, have been proposed. IgA1 has a distinctive hinge region which is a site for O-glycosylation. There is reduced terminal galactose on the hinge region O-glycans of circulating IgA1 in IgAN, perhaps due to a defect in B cell beta1,3 galactosyltransferase. A concomitant O-glycan defect in mesangial IgA1 has not yet been proven. Altered hinge O-glycosylation may have substantial impact on the quaternary structure of the IgA1 molecule influencing its capacity to interact with matrix proteins, IgA receptors on mesangial cells and leucocytes, and complement; it may therefore play a key role in the pathogenesis of mesangial deposition of IgA1 and subsequent glomerular injury in IgAN.     

Secondary IgA nephropathy

IgA nephropathy (IgAN) is the most common pattern of primary glomerulonephritis seen in the Western world. In the majority of cases the cause remains unknown. Cases of familial IgAN and secondary IgAN have been reported and these have provided insights into underlying genetic and environmental triggers for this common glomerular disease. Secondary IgAN is seen most commonly in patients with liver disease or mucosal inflammation, in particular affecting the gastrointestinal tract. A number of dietary and microbial antigens have been identified in circulating IgA immune complexes and mesangial IgA deposits, suggesting that environmental factors may play a role in the pathogenesis of IgAN. There is an increasing literature reporting associations between IgAN and other diseases. Whether these reports represent chance associations or genuine shared pathophysiology is discussed.     

The pathogenetic potential of environmental antigens in IgA nephropathy

Patients with IgA nephropathy (IgAN) can be considered high responders for IgA production; data which indicate a generalized hyperreactivity of the immune system include autoantibody production, increased response to viral vaccination, and high titers of antibodies to various common respiratory and gastrointestinal microbes. From clinical and experimental observations, two types of antigen seem to be most involved in the pathogenesis of IgAN, ie, environmental respiratory or gastrointestinal infectious agents and dietary antigens. A role played by microbes has been suggested because macroscopic hematuria shortly follows a pharyngitis or a gastrointestinal disturbance. Antibodies to a wide spectrum of viral and bacterial infectious agents have been detected in sera from patients with IgAN. The possible role of dietary antigens has been demonstrated experimentally in animal models. In human IgAN, antibodies to various dietary antigens have been detected in sera; antibodies have also been found in IgA immune complexes and renal eluates. In human IgAN, a significant decrease in serum levels of IgA-containing circulating immune complexes after a gluten-free diet has been observed. The present experience accounts for 27 IgAN patients followed for 6 months to 3 years on a gluten-free diet. A decrease in serum levels of IgA-containing circulating immune complexes was observed in 64% of the patients whose initial levels were high during a period of unrestricted diet. Patients with basal high levels also had significantly high levels of IgA antibodies to dietary antigens, including bovine serum albumin, ovalbumin, and various gluten fractions. After 1 year of gluten-free diet the levels significantly decreased. A disappearance of antigliadin IgA, observed in 80% of the cases, was paralleled by a decrease in titers of the other antibodies to dietary components. These data support the hypothesis that in patients with IgAN, gluten may act as a toxic lectin, increasing the permeability of the intestinal mucosa to various dietary antigens.     

Glycosylation and size of IgA1 are essential for interaction with mesangial transferrin receptor in IgA nephropathy

Transferrin receptor (TfR) has been identified as a candidate IgA1 receptor expressed on human mesangial cells (HMC). TfR binds IgA1 but not IgA2, co-localizes with mesangial IgA1 deposits, and is overexpressed in patients with IgA nephropathy (IgAN). Here, structural requirements of IgA1 for its interaction with mesangial TfR were analyzed. Polymeric but not monomeric IgA1 interacted with TfR on cultured HMC and mediates internalization. IgA1 binding was significantly inhibited (>50%) by soluble forms of both TfR1 and TfR2, confirming that TfR serves as mesangial IgA1 receptor. Hypogalactosylated serum IgA1 from patients with IgAN bound TfR more efficiently than IgA1 from healthy individuals. Serum IgA immune complexes from patients with IgAN containing aberrantly glycosylated IgA1 bound more avidly to TfR than those from normal individuals. This binding was significantly inhibited by soluble TfR, highlighting the role of TfR in mesangial IgA1 deposition. For addressing the potential role of glycosylation sites in IgA1-TfR interaction, a variety of recombinant dimeric IgA1 molecules were used in binding studies on TfR with Daudi cells that express only TfR as IgA receptor. Deletion of either N- or O-linked glycosylation sites abrogated IgA1 binding to TfR, suggesting that sugars are essential for IgA1 binding. However, sialidase and beta-galactosidase treatment of IgA1 significantly enhanced IgA1/TfR interaction. These results indicate that aberrant glycosylation of IgA1 as well as immune complex formation constitute essential factors favoring mesangial TfR-IgA1 interaction as initial steps in IgAN pathogenesis.     

IgA serology in recurrent and non-recurrent IgA nephropathy after renal transplantation

BACKGROUND: This study investigated whether abnormal circulation of macromolecularIgA and IgA with altered glycosylation or electrical chargeplays a role in the recurrence of IgA nephropathy (IgAN) aftertransplantation. STUDY DESIGN: A total of 92 renal transplant patients were enrolled; 52 IgANpatients and 40 with other non-IgAN. The IgAN group included10 patients showing IgA mesangial deposits in the grafted kidneys(recurrent group) and 10 who did not (immunohistochemicallyproven non-recurrent group). In addition another 22 IgAN transplantpatients were clinically free of recurrent disease. METHODS: The analyses included macromolecular IgA (IgAIC) detected bythe conglutinin assay (K), heavy IgA precipitated in 2.5% polyethyleneglycol (PEG), IgA-fibronectin aggregates (IgA/F Aggr), mixedIgA/IgGIC, IgA binding to mesangial matrix components (fibronectin,laminin, type IV collagen) or polycations (poly-L-lysine) andIgA with altered glycosylation (Jacalin-binding assay). RESULTS: After transplantation, IgAN patients displayed significantlyhigher mean levels for each variable measured than non-IgAN(ANOVA, P <0.05). By stepwise regression analysis, the bindingof IgA to fibronectin had the highest coefficient. By comparingdata in recurrent and clinically non-recurrent IgAN, we observedthat two groups could be distinguished by the results of thetwo assays for macromolecular IgA (conglutinin IgAIC and IgA-fibronectinaggregates) and IgA with increased affinity for type IV collagen(P <0.05). When the selected group of immunohistochemicallyproven non-recurrent IgAN was compared to the recurrent one,a statistically significant difference was found only for thebinding of IgA to type IV collagen (P<0.05). Data from thistest were significantly related with proteinuria (P<0.05)and microscopic haematuria (P <0.04). CONCLUSION: Even though the IgA serology of renal transplant IgAN patientsshows peculiar features and recurrent and non-recurrent IgANdiffer in many aspects, the prevalence of positive data in thetwo groups had no predictive value. This suggests that the recurrenceof IgAN is modulated by factors affecting the interaction betweencirculating abnormal IgA and mesangial cells and/or matrix.     

Differential glycosylation of polymeric and monomeric IgA: a possible role in glomerular inflammation in IgA nephropathy

IgA nephropathy (IgAN) is characterized by mesangial deposition of polymeric IgA1 (pIgA1) and complement. Complement activation via mannose-binding lectin and the lectin pathway is associated with disease progression. Furthermore, recent studies have indicated a possible role for secretory IgA. IgAN is associated with abnormalities in circulating IgA, including aberrant O-linked glycosylation. This study characterized and compared functional properties and N-linked glycosylation of highly purified monomeric IgA (mIgA) and pIgA from patients with IgAN and control subjects. Total serum IgA was affinity-purified from patients (n = 11) and control subjects (n = 11) followed by size separation. pIgA but not mIgA contained secretory IgA, and its concentration was significantly higher in patients with IgAN than in control subjects. Both in patients with IgAN and in control subjects, IgA binding to the GalNAc-specific lectin Helix Aspersa and to mannose-binding lectin was much stronger for pIgA than for mIgA. Furthermore, binding of IgA to mesangial cells largely was restricted to polymeric IgA. Binding of pIgA to mesangial cells resulted in increased production of IL-8, predominantly with IgA from patients with IgAN. Quantitative analysis of N-linked glycosylation of IgA heavy chains showed significant differences in glycan composition between mIgA and pIgA, including the presence of oligomannose exclusively on pIgA. In conclusion, binding and activation of mesangial cells, as well as lectin pathway activation, is a predominant characteristic of pIgA as opposed to mIgA. Furthermore, pIgA has different N-glycans, which may recruit lectins of the inflammatory pathway. These results underscore the role of pIgA in glomerular inflammation in IgAN.     

Sequential occurrence of IgA nephropathy and Henoch-Schönlein purpura: support for common pathogenesis

We report a patient who developed Henoch-Schönlein purpura (HSP) 13 years after he presented with IgA nephropathy (IgAN). In both HSP and IgAN renal biopsy most commonly reveals focal proliferative glomerulonephritis on light microscopy and immunofluorescence displays mesangial IgA deposits. In addition, patients with HSP or IgAN have elevated serum IgA levels, circulating IgA immune complexes, IgA-bearing lymphocytes, immunoglobulin-producing cells, and binding of IgG to glomerular components of similar molecular weight. The occurrence of both diseases in the same patient or the same families and the presence of immune abnormalities compatible with HSP or IgAN in relatives of patients with these diseases suggest a common pathogenesis.     

A pathogenic role for secretory IgA in IgA nephropathy

IgA nephropathy (IgAN) is characterized by deposits of IgA in the renal mesangium. It is thought that deposits of IgA mainly involve high molecular weight (HMW) IgA1. However, there is limited information on the exact composition of HMW IgA in these deposits. In this study, we investigated the presence of secretory IgA (SIgA) in human serum and in the glomerular deposits of a patient with IgAN. Furthermore, we analyzed the interaction of SIgA with mesangial cells. With enzyme-linked immunosorbent assay, SIgA concentrations in the serum of IgAN patients and healthy controls were measured. Both patients and controls had circulating SIgA that was restricted to the HMW fractions. Patients tended to have higher levels of SIgA, but this difference was not significant. However, in patients with IgAN, high serum SIgA concentrations were associated with hematuria. Binding of size-fractionated purified serum IgA and SIgA to mesangial cells was investigated with flow cytometry. These studies showed stronger binding of SIgA to primary mesangial cells compared to binding of serum IgA. Importantly, after isolation and elution of glomeruli from a nephrectomized transplanted kidney from a patient with recurrent IgAN, we demonstrated a 120-fold accumulation of SIgA compared to IgA1 in the eluate. In conclusion, we have demonstrated that SIgA strongly binds to human mesangial cells, and is present in significant amounts in serum. Furthermore, we showed that SIgA is accumulated in the glomeruli of an IgAN patient. These data suggest an important role for SIgA in the pathogenesis of IgAN.     

IgA肾病诊疗进展

IgA肾病是全球最常见的原发性肾小球肾炎,亚洲人群中发病率高于其他人种。IgA肾病是目前导致终末期肾病的重要原因之一。临床上以血尿为特点,常伴随蛋白尿、高血压。其病理表现主要为IgA免疫复合物在肾小球系膜区的沉积、系膜细胞增生、毛细血管内皮细胞增生等。其发病机制可能为血液循环中半乳糖缺乏的IgA1增多,在內外界环境刺激下,产生过多的、能沉积于肾小球系膜区的免疫复合物。目前,对IgA肾病的诊断主要依靠病理检查。治疗方面,以肾素-血管紧张素系统阻断剂、控制血压为基础,恰当联合免疫抑制剂、细胞毒性药物、鱼油等或能延缓IgA肾病的进展。本文的目的是对IgA肾病的诊疗现状进行总结和分析,为临床工作及进一步科研提供指导和参考。     

The pathogenic role of IgA1 O-linked glycosylation in the pathogenesis of IgA nephropathy

Numerous abnormalities of the IgA immune system have been reported in IgAN but the most consistent finding remains aberrant IgA1 O-linked glycosylation of the IgA1 hinge region. The defect comprises reduced galactosylation of O-linked N-acetylgalactosamine residues with or without changes in the terminal sialylation of the O-linked sugars. Aberrant O-galactosylation has been found in serum IgA1, in IgA1 isolated from tonsillar lymphocytes, and in IgA1 eluted from mesangial deposits. There is evidence that changes in IgA1 O-galactosylation lead to IgA immune complex formation and mesangial IgA deposition. Mesangial cells exposed to these IgA immune complexes proliferate and adopt a pro-inflammatory phenotype; they secrete cytokines, chemokines, growth factors and extracellular matrix components promoting glomerular inflammation and glomerulosclerosis. Recent evidence suggests that the control of IgA1 O-glycosylation is linked to class switching from IgD to IgA1 synthesis and that the pattern of IgA1 O-glycosylation may be programmed at the time of initial antigen encounter. IgA1 glycosylation varies between systemic and mucosal sites and the association of aberrant IgA1 galactosylation with low affinity, polymeric IgA1 antibodies against mucosal antigens suggests undergalactosylated IgA1 may in fact be a mucosal glycoform of IgA1. Although suited to the mucosal compartment, when these IgA1 glycoforms enter the systemic circulation in appreciable quantities they deposit in the mesangium and trigger glomerular inflammation. This review will discuss the evidence for the role of IgA1 O-glycosylation in the pathogenesis of IgAN and propose an explanation for the presence of aberrantly O-glycosylated IgA1 in the circulation of patients with IgAN.     

Pathogenetic significance of aberrant glycosylation of IgA1 in IgA nephropathy

IgA nephropathy (IgAN), the most common form of primary glomerulonephritis worldwide, is defined by predominant IgA1 deposits in the glomerular mesangium. Among abnormalities of the IgA immune system reported so far in IgAN, aberrant O-linked glycosylation in the hinge region of IgA1 is the most consistent finding. IgA1 molecules bearing abnormal glycosylation have been found in serum, in tonsillar lymphocytes, and in eluate from mesangial deposits, and characterized by decreased O-linked N-acetylgalactosamine residues with or without alteration in the terminal sialylation of the O-linked sugars. IgA1 with incomplete galactosylation has a tendency to accumulate in glomerular mesangium by self-aggregation or immune complex formation. Glomerular mesangial cells exposed to immune complexes of these IgA1 can proliferate and secrete cytokines, chemokines, growth factors, and extracellular matrix components promoting inflammatory reactions in the glomeruli. Although genes encoding enzymes involved in the O-glycosylation process, such as C1GALT1, have been reported to be responsible for susceptibility to IgAN, recent evidence suggests that the abnormality is restricted to a small fraction of B cell populations and arises from dysregulated IgA1 production and secretion in mucosal immune system. This review will focus on and discuss the role of incompleteness of IgA1 O-galactosylation in the pathogenesis of IgAN and propose a possible mechanism in which abnormal IgA1 occurs in IgAN. Presented at the 37th Eastern Regional Meeting of the Japanese Society of Nephrology.     

Complexes of IgA with FcalphaRI/CD89 are not specific for primary IgA nephropathy

BACKGROUND: The presence of IgA together with the myeloid IgA-receptor FcalphaRI/CD89 in the circulation of patients with IgA nephropathy (IgAN) has been suggested as a specific pathogenic factor for mesangial deposition. However, in a recent study we found these complexes also in serum samples from healthy subjects. To investigate whether these circulating complexes are specific for IgAN, the levels and characteristics of IgA-CD89 complexes were analyzed in patients with IgAN and healthy controls. METHODS: Specific ELISAs with different poly- and monoclonal antibodies and a sensitive dot-blot method were used to measure IgA-CD89 levels in serum and purified IgA samples obtained from healthy volunteers (N = 30) and patients with IgAN (N = 35). Fractionated samples of purified IgA were used to compare the size characteristics of the IgA-CD89 complexes. RESULTS: Almost all CD89 in serum of patients with IgAN and controls was associated with high molecular weight IgA. Quantitative analysis of IgA-CD89 complexes in purified IgA revealed no significant difference between patients with IgAN and controls. No correlation was found between levels of IgA-CD89 complexes and clinical parameters associated with progressive IgAN. CONCLUSIONS: CD89 in the circulation is found mainly linked to high molecular weight IgA. The presence of these complexes is not specific for IgAN. Therefore, if IgA-CD89 complexes are involved in the pathogenesis of primary IgA nephropathy, additional factors are required to explain the IgA-CD89 complex-mediated renal inflammation.     

IgA肾病患者IgA1糖基化异常及其致病机制

IgA肾病(IgAN)是导致终末期肾病最常见的原发性肾小球疾病。其病理特点为IgA1在肾小球系膜区沉积,IgA1分子的异常糖基化是导致IgAN发病的关键因素。多种与IgAN相关的基因位点已经被发现。这些基因编码的细胞因子参与了IgA1糖基化异常的发病机制。此外糖基化酶缺乏、分子伴侣甲基化异常都可能导致IgA1异常糖基化。异常糖基化的IgA1可通过自我聚集或形成免疫复合物沉积于系膜区,进而刺激系膜细胞增殖、分泌系膜基质、细胞因子、趋化因子、生长因子等,导致肾小球损伤。对IgA1异常糖基化的深入研究有助于了解IgA肾病的发病机制并提供新的诊断与治疗措施。     

Binding of serum immunoglobulins to collagens in IgA nephropathy and HIV infection.

The mechanism of the binding of IgA to the mesangium in IgA nephropathy (IgAN) is unknown. Interactions between IgA and components of the mesangial matrix may contribute. We measured by enzyme-linked immunosorbent assay the binding of serum IgA, IgG, and IgM from patients with IgAN, human immunodeficiency virus type I (HIV) infection, and healthy controls to purified native collagen types I to VI, and to an extract of normal kidney tissue. HIV infection is an appropriate disease control because of the lack of mesangial IgA deposits, despite high serum levels of IgA and IgA1-containing immune complexes. Increased levels of IgA-binding to collagen types I and V and the kidney extract were found only in IgAN. Both IgAN and HIV-infected patients had increased IgA-binding to collagen types II, III, and VI. Preabsorption of the sera with gelatin substantially reduced the IgA-binding to collagen types I to IV, but not to types V and VI. This finding suggests that the binding to collagen type V is not fibronectin-mediated, but may reflect autoantibody formation. Thus, fibronectin-mediated IgA-collagen interactions are not specific for IgAN, and their pathogenetic role is questionable. The role of IgA anti-collagen type V antibodies requires further study.     

Differential effects of circulating IgA isolated from patients with IgA nephropathy on superoxide and fibronectin production of mesangial cells.

BACKGROUND: IgA nephropathy (IgAN) is characterized by predominant deposition of IgA in the glomerular mesangium. Serum IgA is often elevated in patients with IgAN, and it has been postulated that it is responsible for the mesangial lesions. However, the direct effect of circulating IgA on mesangial cells is not clear. METHODS: We investigated the effects of sera and IgA which were isolated from patients with IgAN on thymidine uptake, superoxide and fibronectin production and fibronectin mRNA expression of cultured rat mesangial cells, and we compared the findings to the effects of IgA isolated from patients with non-IgA mesangial proliferative glomerulonephritis (MsPGN) and normal controls. IgA was isolated with affinity chromatography using cyanogen bromide activated Sepharose 4B coupled to sheep antihuman IgA antiserum. RESULTS: Our results demonstrated that both sera and IgA from patients with IgAN dose-dependently increased mitogenesis of mesangial cells as measured by (3)H-labeled thymidine uptake. The thymidine uptake by sera and IgA isolated from patients with IgAN was significantly higher than that of sera and IgA isolated from patients with MsPGN and normal controls. Sera and IgA from patients with IgAN significantly enhanced superoxide and fibronectin production and fibronectin mRNA expression of mesangial cells. The superoxide and fibronectin production was also significantly higher as compared with patients with MsPGN and normal controls. CONCLUSIONS: Our results indicate that circulating IgA isolated from patients with IgAN is different from that of patients with MsPGN and normal controls and may potentially induce oxidative injury and production of extracellular matrix of glomerular mesangial cells in IgAN.