Fc{gamma}RIIa-131R allele and Fc{gamma}RIIIa-176V/V genotype are risk factors for progression of IgA nephropathy

Yuichi Tanaka1, Yusuke Suzuki1, Toshinao Tsuge1,2, Yutaka Kanamaru1,2, Satoshi Horikoshi1, Renato C. Monteiro2 and Yasuhiko Tomino1

1 Division of Nephrology, Department of Internal Medicine, Juntendo University School of Medicine, Tokyo, Japan and 2 Department of Immunopathology, Bicht Medical School, INSERM E0225, Paris, France

Correspondence and offprint requests to: Yasuhiko Tomino, MD, Division of Nephrology, Department of Internal Medicine, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan. Email: yasu{at}med.juntendo.ac.jp



   Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Background. Fc{gamma} receptors (Fc{gamma}Rs) may play an important role in positive and negative regulation of immune cell responses and immune complex (IC) clearance. Mesangial IgG deposition and circulating IgG/IgA-IC in sera are observed in patients with IgA nephropathy (IgAN). Therefore, the pathological roles of IgG-IC in IgAN have been discussed. On the other hand, several studies have identified Fc{gamma}R polymorphisms (Fc{gamma}RIIa, Fc{gamma}RIIIa and Fc{gamma}RIIIb) that determine susceptibility to autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis. The objective of the present study was to clarify whether Fc{gamma}R polymorphisms influence susceptibility to IgAN, clinical features or severity in patients with IgAN.

Methods. Japanese patients with IgAN (n = 124) and healthy controls (n = 100) were genotyped for Fc{gamma}R polymorphisms (Fc{gamma}RIIa-131H or R, Fc{gamma}RIIIa-176F or V and Fc{gamma}RIIIb-NA1 or -NA2). The genotyping of these polymorphisms was performed using allele-specific polymerase chain reaction (PCR) methods. Associations among Fc{gamma}R polymorphisms and susceptibility, age of onset, levels of serum immunoglobulins, intensity of glomerular IgG deposition and pathological severity were analysed.

Results. These three Fc{gamma}R polymorphisms showed no significant differences in genotype and allele frequencies between the IgAN patients and healthy controls. Each Fc{gamma}R polymorphism had no influence on age of onset, serum levels of IgG and glomerular IgG deposition in IgAN. However, Fc{gamma}RIIa-131R (R/R or H/R) or Fc{gamma}RIIIa-176V homozygous carriers (V/V) showed significantly more severe injury than Fc{gamma}RIIa-131H homozygous (H/H) (P<0.03) or Fc{gamma}RIIIa-176F carriers (F/F or F/V) (P<0.03), respectively.

Conclusion. The present study shows that polymorphisms of Fc{gamma}RIIa and Fc{gamma}RIIIa influence the severity of IgAN in Japanese patients but not the incidence, suggesting that IgG-IC may play important roles in the progression and prognosis of this disease via Fc{gamma}Rs.

Keywords: Fc{gamma} receptor; IgA nephropathy; IgG; polymorphism



   Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis and is characterized by depositions of IgA (mainly IgA1) or IgA-containing immune complexes (IgA-ICs) in the glomerular mesangial areas. Elevated levels of IgA1 and IgA1-containing circulating ICs in sera were observed in patients with IgAN [1,2]. IgA1 deposits were usually observed with complement 3 (C3) component, and often with IgG, IgM or both in the glomerular mesangial areas [1,3]. However, the underlying mechanisms for these depositions are poorly understood. Moreover, it is still unclear whether IgA/IgA-IC directly induces glomerulonephritis.

IgAN was originally described by Berger as ‘Nephropathy with mesangial IgA–IgG deposits’ [4]. Glomerular IgG deposits, mainly IgG1 or IgG3 [5,6] and circulating IgG/IgA-IC, have been observed in patients with IgAN [1,3,7]. In addition, it has been reported that glomerular IgG deposition in the presence of normal renal function is a risk factor for renal survival in patients with IgAN [8]. However, the role of IgG in the pathogenesis of this disease remains unclear.

Fc receptors for IgG (Fc{gamma}Rs) have important functions in the regulation of immune responses, and they are also critical for IC clearance. Three functional polymorphisms of Fc{gamma}Rs (Fc{gamma}RIIa, Fc{gamma}RIIIa and Fc{gamma}RIIIb) have been described [9]. Each polymorphism is located in the extracellular domains, which are binding sites and affect binding affinity for each IgG subclass [9]. Indeed, many studies have reported skewed distributions of Fc{gamma}RIIa, IIIa and IIIb alleles in patients with autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) [9].

Fc{gamma}RIIa is expressed on most myeloid cells, but not on glomerular mesangial cells [10,11]. The Fc{gamma}RIIa molecule exhibits both genetically determined structural and functional allelic forms, Fc{gamma}RIIa-131H and 131R. The Fc{gamma}RIIA-131H genotype has a greater ability to bind IgG1, IgG2 and IgG3. Interestingly, the Fc{gamma}RIIa-131R allele has almost no binding affinity for IgG2 [12,13].

On the other hand, Fc{gamma}RIIIa is expressed on macrophages, natural killer (NK) and glomerular mesangial cells [10,11]. The Fc{gamma}RIIIa molecule also exhibits both genetically determined structural and functional allelic forms, Fc{gamma}RIIIa-176V and 176F, and binds to IgG1, IgG3 and IgG4 subclasses which are more strongly bound by Fc{gamma}RIIIa-176V [14,15]. Fc{gamma}RIIIb bears a neutrophil antigen polymorphism caused by four amino acid substitutions. Fc{gamma}RIIIb-NA1 is more efficient in binding to IC containing IgG1 and IgG3 than Fc{gamma}RIIIb-NA2 [16,17].

Based on this background, the objective of the present study was to examine whether Fc{gamma}R polymorphisms influence the disease course of IgAN. The present findings may provide a clue to the pathological role of IgG in this disease.



   Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Genomic DNA purification
Blood samples were collected from 124 Japanese patients with IgA-N diagnosed by renal biopsy and 100 healthy volunteers as controls. The controls were also native Japanese and unrelated to the patients but born in the same geographical area. Genomic DNA from whole blood samples of each patient or healthy control was prepared by a DNA-selective preparation method using a QIAmp Blood Mini Kit (Qiagen, Hilden, Germany). All patients gave their informed consent to participate in this study.

Fc{gamma}RIIa allotyping (131R and 131H)
DNA fragments were amplified by polymerase chain reaction (PCR) using the following primers: sense, 5'-CTG AGA CTG AAA ACC CTT GGA ATC-3' and antisense, 5'-GCT TGT GGG ATG GAG AAG GTG GGA TCC ATA-3'. The amplification procedure consisted of initial denaturation for 5 min, 33 cycles of denaturation at 95°C for 20 s, annealing at 55°C for 20 s and extension at 72°C for 40 s, followed by a final extension at 72°C for 5 min. After the amplification, the PCR products were digested with restriction endonuclease, NdeI (Nippon Gene, Toyama, Japan). The restriction was performed with 4 µg of amplification products and 4 U of NdeI diluted in a specific buffer recommended by the manufacturer in a total volume of 20 µl reacted at 37°C overnight. The products including restriction fragments were electrophoresed in an 8% polyacrylamide gel, and visualized by staining with ethidium bromide. Restriction fragment length polymorphisms (RFLPs) of 131H and 131R were expressed as fragments of ~200 and 231 bp in the presence of NdeI, respectively.

Fc{gamma}RIIIa allotyping (176V and 176F)
For this allotyping, nested PCR was performed as described previously [15]. DNA fragments were amplified by first PCR using the following two Fc{gamma}RIIIa-specific primers: Fc{gamma}RIIIa-sense; 5'-ATA TTT ACA GAA TGG CAC AGG-3' and Fc{gamma}RIIIa-antisense; 5'-GAC TTG GTA CCC AGG TTG AA-3'. The amplification procedure consisted of initial denaturation for 5 min, 35 cycles of denaturation at 95°C for 1 min, annealing at 57°C for 1.5 min and extension at 72°C for 1.5 min, followed by a final extension at 72°C for 8 min. The fragment of ~1.7 kbp containing the polymorphic site of Fc{gamma}RIIIa (176F and 176V) was amplified. A second PCR was performed with 1 µl of the first PCR product using the following primers: sense, 5'-ATC AGA TTC GAT CCT ACT TCT GCA GGG GGC AT-3' and antisense, 5'-ACG TGC TGA GCT TGA GTG ATG TTC AC-3'. The amplification procedure consisted of initial denaturation for 5 min, 35 cycles of denaturation at 95°C for 30 s, annealing at 64°C for 30 s, and extension at 72°C for 1 min, followed by a final extension at 72°C for 10 min.

After the amplification, the second PCR product was digested with NlaIII (New England Biolabs, Hitchin, UK). The restriction was performed with 4 µg of amplification products and 8 U of NlaIII diluted in a specific buffer recommended by the manufacturer in a total volume of 20 µl reacted at 37°C overnight. The products including the restriction fragment were electrophoresed in an 8% polyacrylamide gel, and visualized by staining with ethidium bromide. RFLPs of 176F and 176V were expressed as fragments of ~94 and 61 bp in the presence of NlaIII, respectively.

Fc{gamma}RIIIb allotyping (NA1 and NA2)
Genotyping was performed as described previously [18]. DNA fragments were amplified by PCR using the following primers: Fc{gamma}RIIIb-Na1-specific primer, 5'-CAG TGG TTT CAC AAT GTG AA-3'; Fc{gamma}RIIIb-Na2-specific primer, 5'-CAA TGG TAC AGC GTG CTT-3'; and the reverse primer, 5'-ATG GAC TTC TAG CTG CAC-3'. The amplification procedure consisted of initial denaturation at 94°C for 3 min, 30 cycles of denaturation at 94°C for 1 min, annealing at 57°C for 1 min, and extension at 72°C for 1 min, followed by a final extension at 72°C for 10 min. The amplification products were electrophoresed in a 2% agarose gel and visualized by staining with ethidium bromide. The amplification products of Na1 and Na2 were expressed as 141 and 219 bp fragments, respectively.

In the above-mentioned allotyping, we preliminarily performed direct sequencing using nine DNA samples of controls. We compared these data with genotypes by several allotyping methods and finally chose each present method for this study.

Immunohistological analysis of glomerular IgG deposition in renal biopsy specimens
All renal biopsies used in this study were obtained from patients who had a glomerular filtration rate >70 ml/min. For the immunohistochemistry, the frozen sections (3 µm thick) from a part of the biopsy specimens were fixed in acetone for 10 min and rehydrated in phosphate-buffered saline (PBS). After blocking the sections with PBS containing 2% bovine serum albumin (BSA), 2% fetal calf serum (FCS) and 0.2% fish gelatin for 30 min, they were incubated with fluorescein isothiocyanate (FITC)-conjugated anti-human IgG antibody (x100) (DAKO, CA, USA) diluted in blocking solution for 60 min, and washed three times with PBS.

For an evaluation of glomerular IgG, the intensity of IgG deposition in glomeruli was graded semi-quantitatively from 0 to 3+ (0 = none; 1+ = weak; 2+ = mild; 3+ = strong). This grading was determined by one pathologist and at least three nephrologists in a blind manner.

Classification of the severity of IgA-N
Formaldehyde-fixed renal biopsy specimens were embedded in paraffin and sectioned serially at 3 µm thick. All sections were stained with periodic acid–Schiff (PAS). In this study, the severity of IgAN was classified into four groups by ‘Clinical guidelines for the diagnosis and treatment of patients with immunoglobulin A (IgA) nephropathy in Japan’ [19]. The prognostic grading in this guideline using renal biopsy specimens was done by the Special Study Group on Progressive Glomerular Disease in the Ministry of Health and Welfare of Japan and the Japanese Society of Nephrology, with retrospective clinical data [19]. Each prognostic grade is based on light microscopic histological findings as summarized in Table 1. The renal prognosis by these criteria is divided into the following four groups; good prognosis group (group I) in which dialysis treatment will probably never be required; relatively good prognosis group (group II) in which the possibility of dialysis treatment is relatively low; relatively poor prognosis group (group III) in which dialysis treatment is likely to be required within 5–20 years; poor prognosis group (group IV) in which the possibility of dialysis treatment within 5 years is high [19]. This grading was determined by one pathologist and at least three nephrologists in a blind manner.


View this table:
[in this window]
[in a new window]
 
Table 1. Definition of prognostic criteria for IgA-N

 
In this study, to avoid the possibility that the time of renal biopsy in relation to disease onset may influence the pathological severity, we also analysed the age of onset and the duration from onset to renal biopsy in each pathological grade of IgAN patients. The onset of this disease was defined as the time of first abnormality in urinalysis.

Statistical analyses
To consider the linkages between each allele and genotype of Fc{gamma}R polymorphisms and clinical or pathological findings, the genotypes of each Fc{gamma}R were classified into two subgroups: each allele homozygous, and other allele carriers. Fc{gamma}RIIa genotypes were classified into two subgroups: Fc{gamma}RIIa-131H homozygous (H/H) and Fc{gamma}RIIa-131R carriers (R/R or H/R), or Fc{gamma}RIIa-131R homozygous (R/R) and Fc{gamma}RIIa-131H carriers (H/H or H/R). Fc{gamma}RIIIa genotypes were classified into two subgroups: Fc{gamma}RIIIa-176V homozygous (V/V) and Fc{gamma}RIIIa-176F carriers (F/F or F/V), or Fc{gamma}RIIIa-176F homozygous (F/F) and Fc{gamma}RIIIa-176V carriers (V/V or F/V). Fc{gamma}RIIIb genotypes were also classified into two subgroups: Fc{gamma}RIIIb-NA1 homozygous (NA1/NA1) and Fc{gamma}RIIIb-NA2 carriers (NA2/NA2 or NA1/NA2), or Fc{gamma}RIIIb-NA2 homozygous (NA2/NA2) and Fc{gamma}RIIIb-NA1 carriers (NA1/NA1 or NA1/NA2). In this study, this classification was used when we analysed the linkages between each allele of Fc{gamma}R polymorphisms and age of onset, intensity of IgG and histological severity.

Serum levels of IgG, IgA and IgM which were examined at the time of renal biopsy and the age of onset in this disease were expressed as mean±SE.

Statistical analyses for the association were performed using Stat View-J5.0 for Macintosh (Abacus Concept, Berkeley, CA). Serum levels of IgG, IgA and IgM and the age of onset and the duration from onset to renal biopsy in each pathological grade of IgA-N patients were compared using t-test analysis. Other data were analysed by the {chi}2 test. When we found statistical significance in this test, we compensated these data with Yates’ correction. Statistical significance was defined as P<0.05.



   Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Fc{gamma}R polymorphisms (Fc{gamma}RIIa, IIIa and IIIb) have no influence on the susceptibility to IgAN or the age of onset
Fc{gamma}RIIa-131 (H/R), Fc{gamma}RIIIa-176 (F/V) and Fc{gamma}RIIIb (NA1/NA2) genotype frequency showed no significant difference between IgAN and normal control (Fc{gamma}RIIa, {chi}2 = 1.594, P = 0.4507; Fc{gamma}RIIIa, {chi}2 = 5.944, P = 0.0512; and Fc{gamma}RIIIb, {chi}2 = 1.486, P = 0.4756) (Table 2). In addition, the allele frequency also showed no significant difference between the two groups (Fc{gamma}RIIa, {chi}2 = 1.011, P = 0.3146; Fc{gamma}RIIIa, {chi}2 = 1.784, P = 0.1817 and Fc{gamma}RIIIb; {chi}2 = 0.955, P = 0.3284) (Table 2).


View this table:
[in this window]
[in a new window]
 
Table 2. Fc{gamma}RIIa, Fc{gamma}RIIIa, Fc{gamma}RIIIb polymorphisms in Japanese IgA-N patients and healthy controls

 
The mean age of onset in this study was divided into three stages (<20 years old, <20 to <30 years old and ≥30 years old). There was no significant difference in age of onset of this disease among Fc{gamma}R polymorphisms analysed by the 3x3 {chi}2 test, and among subgroups analysed by the 3x2 {chi}2 test (Table 3).


View this table:
[in this window]
[in a new window]
 
Table 3. Relationship between Fc{gamma}R polymorphisms and the age of IgA-N onset

 
Fc{gamma}R polymorphisms have no influence on the serum IgG level and mesangial IgG deposition in IgAN patients
The levels of serum IgA in Fc{gamma}RIIIb-NA2 homozygous carriers (NA2/NA2) were significantly higher than those in Fc{gamma}RIIIb-NA1 homozygous carriers (NA1/NA1) (P = 0.0374) in the t-test analysis, although no significant differences were observed with Fc{gamma}RIIa and Fc{gamma}IIIa (Table 4). However, there were no significant differences in the levels of serum IgG and IgM between the two genotypes of Fc{gamma}R polymorphisms (Table 4). In addition, there was no significant correlation between the intensity of glomerular IgG deposition and each subgroup of Fc{gamma}R polymorphism (Table 5).


View this table:
[in this window]
[in a new window]
 
Table 4. Relationship between Fc{gamma}R polymorphisms and mean levels of serum IgG, IgA and IgM in IgA-N patients

 

View this table:
[in this window]
[in a new window]
 
Table 5. Relationship between Fc{gamma}R polymorphisms and intensity of mesangial IgG deposition in IgA-N patients

 
Fc{gamma}RIIa-131R allele and Fc{gamma}RIIIa-176V/V genotype are risk factors for the progression of IgAN
To avoid the possibility that the time of the biopsy in relation to disease onset may influence the pathological severity for this study, we firstly analysed the age of onset and the duration from onset to renal biopsy in each pathological grade of IgAN patients (Table 6). As shown in Table 6, there was no significant difference in the age and the duration, indicating that this prognostic grading can be used, at least for the patients in a present study.


View this table:
[in this window]
[in a new window]
 
Table 6. The age of onset and the duration from onset to renal biopsy in each grade of IgA-N patients

 
In addition, we divided the patients into two groups, non-progressive (grades 1 and 2) and progressive (grades 3 and 4) groups. There was no significant difference in the age and the duration between both groups (Table 6). As shown in Table 7, an Fc{gamma}RIIa-131R carrier or an Fc{gamma}RIIIa-176V homozygous carrier showed significantly more severe injury than an Fc{gamma}RIIa-131H homozygous carrier ({chi}2 = 5.292, P = 0.021) or an Fc{gamma}RIIIa-176F carrier ({chi}2 = 4.714, P = 0.029), respectively.


View this table:
[in this window]
[in a new window]
 
Table 7. Relationship between Fc{gamma}R polymorphisms and severity in IgA-N patients

 


   Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
In this study, we examined the association among three polymorphisms of Fc{gamma}Rs, the incidence of IgAN, certain clinical markers and histological severity in Japanese IgAN patients. The present findings showed that Fc{gamma}R polymorphisms influenced the severity of IgAN, although Fc{gamma}R polymorphisms did not affect the susceptibility, age of onset, levels of serum IgG and glomerular IgG deposition.

Disease susceptibility linked to Fc{gamma}R polymorphisms has been described for autoimmune diseases including SLE, RA, multiple sclerosis, Guillain–Barre syndrome and anti-neutrophil cytoplasmic antibody (ANCA)-positive systemic vasculitis [9]. The crucial function of Fc{gamma}R is IC clearance. Fc{gamma}R can trigger the internalization of captured IC, which leads to degradation of antigen–antibody complexes, as well as directing the antigenic peptides to the major histocompatibility complex (MHC) class I or class II antigen presentation pathway [9,20]. It is known that functional defects in IC clearance are linked to the initiation of autoimmune diseases such as SLE. Importantly, recent findings have indicated that antigen presentation is much more efficient if the IC is internalized by Fc{gamma}R rather than by non-specific uptake mechanisms such as fluid phase pinocytosis [9,20]. Other studies also demonstrated the functional differences in IC clearance between Fc{gamma}RIIa-131R and -131H [16], and between Fc{gamma}RIIIa-176V and -176F [15]. These findings support the idea that genetic polymorphisms of Fc{gamma}RIIa and Fc{gamma}RIIIa in SLE patients may influence disease susceptibility, because altered IgG-IC clearance may be critical for the incidence of SLE. However, our present results show that these Fc{gamma}R polymorphisms had no significant influence on the incidence, age of onset, levels of serum IgG and intensity of glomerular IgG deposition in IgAN. These findings suggested that IgG/IgG-IC may not be a triggering factor for IgAN, at least via Fc{gamma}R activation.

Nieuwhof et al. reported that the glomerular IgG deposition in IgAN patients with normal renal function was a risk factor for renal survival [8]. Moreover, the pathological role of circulating IgG-IC has been discussed in patients with IgAN [1,3]. Therefore, IgG/IgG-IC may contribute to the progression of IgAN. In previous studies, lower affinity alleles of Fc{gamma}Rs (Fc{gamma}RIIIa-131R, Fc{gamma}RIIIa-176F and Fc{gamma}RIIIb-NA2 genotype) have been proposed as susceptibility factors for SLE and RA [9], possibly due to the inefficient clearance of circulating or tissue-deposited IC. The present data showed that one of the lower affinity alleles of Fc{gamma}Rs, Fc{gamma}RIIIa-131R, was linked to the severity of IgAN, suggesting that the impairment of IgG-IC clearance by this allele and subsequent glomerular deposition may also contribute to the glomerular lesions. However, our results also showed that the intensity of glomerular IgG deposition had no correlation with Fc{gamma}R polymorphisms. In the renal survival of IgAN, subclass restriction, mainly of IgG1 and IgG3, was observed in glomerular IgG deposition [5]. The Fc{gamma}RIIa-131R allele lacks binding affinity for IgG2. In this study, we only examined the correlation between the polymorphism and glomerular deposition of whole IgG including IgG2. Therefore, the correlation between their polymorphisms and each glomerular IgG subclass has to be examined carefully in a future study.

We also found that one of the higher affinity alleles of Fc{gamma}Rs, Fc{gamma}RIIIa-176V, may influence the severity of the glomerular lesions in IgAN. Of note, Fc{gamma}RIIIa is expressed not only on circulating bone marrow-derived cells but also on glomerular mesangial cells [10,11]. Fc{gamma}RIIIa-176V binds more strongly to IgG1 and IgG3 than Fc{gamma}RIIIa-176F [14,15]. Therefore, it is speculated that greater activation of mesagial cells, presumably by IgG1/IgG3, may contribute to the progression of this disease.

It appears that polymorphisms of Fc{gamma}RIIa and Fc{gamma}RIIIa are associated with severity in patients with IgAN, suggesting the importance of Fc{gamma}RIIa and Fc{gamma}RIIIa in the prognosis of this disease. However, we found that the severity is linked to the low affinity allele of Fc{gamma}RIIa-131R and the high affinity allele of Fc{gamma}RIIIa-176V, suggesting that each polymorphism may influence the prognosis through different effector mechanisms. In this regard, in order to understand the contradictory results, it is interesting to examine the combination of these two genotypes. Although we have examined the combination in each patient, only two of eight Fc{gamma}RIIIa-176V/V patients in the progressive group (Table 7) had the Fc{gamma}RIIa-131R allele (data not shown). Since the total numbers of 176V/V were small, a future study with more patients will be required. In addition, a functional study with an appropriate model is needed to determine the role of Fc{gamma}R in the pathogenesis of IgAN.

Conflict of interest statement. None declared.



   References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

  1. Coppo R, Basolo B, Martina G et al. Circulating immune complexes containing IgA, IgG and IgM in patients with primary IgA nephropathy and with Henoch–Schoenlein nephritis. Correlation with clinical and histologic signs of activity. Clin Nephrol 1982; 18: 230–239[ISI][Medline]
  2. Tomana M, Novak J, Julian BA, Matousovic K, Konecny K, Mestecky J. Circulating immune complexes in IgA nephropathy consist of IgA1 with galactose-deficient hinge region and antiglycan antibodies. J Clin Invest 1999; 104:73–81[Abstract/Free Full Text]
  3. Tomino Y, Nomoto Y, Endoh M, Sakai H, Arimori S. Double immunofluorescence studies on IgA-associated immune-complexes in glomerular deposits in patients with IgA nephropathy. Tokai J Exp Clin Med 1980; 5: 147–149[Medline]
  4. Berger J. IgA glomerular deposits in renal disease. Transplant Proc 1969; 1: 939–944[ISI][Medline]
  5. Aucouturier P, Monteiro RC, Noel LH, Preud'homme JL, Lesavre P. Glomerular and serum immunoglobulin G subclasses in IgA nephropathy. Clin Immunol Immunopathol 1989; 51: 338–347[CrossRef][ISI][Medline]
  6. Russell MW, Mestecky J, Julian BA, Galla JH. IgA-associated renal diseases: antibodies to environmental antigens in sera and deposition of immunoglobulins and antigens in glomeruli. J Clin Immunol 1986; 6: 74–86[CrossRef][ISI][Medline]
  7. Egido J, Sancho J, Rivera F, Hernando L. The role of IgA and IgG immune complexes in IgA nephropathy. Nephron 1984; 36: 52–59[ISI][Medline]
  8. Nieuwhof C, Kruytzer M, Frederiks P, van Breda Vriesman PJ. Chronicity index and mesangial IgG deposition are risk factors for hypertension and renal failure in early IgA nephropathy. Am J Kidney Dis 1998; 31: 962–970[ISI][Medline]
  9. Takai T. Roles of Fc receptors in autoimmunity. Nat Rev Immunol 2002; 2: 580–592[ISI][Medline]
  10. Radeke HH, Gessner JE, Uciechowski P, Magert HJ, Schmidt RE, Resch K. Intrinsic human glomerular mesangial cells can express receptors for IgG complexes (hFc gamma RIII-A) and the associated Fc epsilon RI gamma-chain. J Immunol 1994; 153: 1281–1292[Abstract/Free Full Text]
  11. Uciechowski P, Schwarz M, Gessner JE, Schmidt RE, Resch K, Radeke HH. IFN-gamma induces the high-affinity Fc receptor I for IgG (CD64) on human glomerular mesangial cells. Eur J Immunol 1998; 28: 2928–2935[CrossRef][ISI][Medline]
  12. Parren PW, Warmerdam PA, Boeije LC et al. On the interaction of IgG subclasses with the low affinity Fc gamma RIIa (CD32) on human monocytes, neutrophils, and platelets. Analysis of a functional polymorphism to human IgG2. J Clin Invest 1992; 90: 1537–1546[ISI][Medline]
  13. Warmerdam PA, van de Winkel JG, Vlug A, Westerdaal NA, Capel PJ. A single amino acid in the second Ig-like domain of the human Fc gamma receptor II is critical for human IgG2 binding. J Immunol 1991; 147: 1338–1343[Abstract/Free Full Text]
  14. Wu J, Edberg JC, Redecha PB et al. A novel polymorphism of FcgammaRllla (CD 16) alters receptor function and predisposes to autoimmune disease. J Clin Invest 1997; 100: 1059–1070[Abstract/Free Full Text]
  15. Koene HR, Kleijer M, Algra J, Roos D, von dem Borne AE, de Haas M. Fc gammaRIIIa-158V/F polymorphism influences the binding of IgG by natural killer cell Fc gammaRlIla, independently of the Fc gammaRIIIa48L/R/H phenotype. Blood 1997; 90: 1109–1114[Abstract/Free Full Text]
  16. Salmon JE, Edberg JC, Brogle NL, Kimberly RP. Allelic polymorphisms of human Fc gamma receptor IIA and Fc gamma receptor IIIB. Independent mechanisms for differences in human phagocyte function. J Clin Invest 1992; 89: 1274–1281[ISI][Medline]
  17. Bredius RG, Fijen CA, De Haas M et al. Role of neutrophil Fc gamma RIIa (CD32) and Fc gamma RIIb (CD16) polymorphic forms in phagocytosis of human IgG1 and IgG3-opsonized bacteria and erythrocytes. Immunology 1994; 83: 624–630[ISI][Medline]
  18. Van Den Berg L, Myhr KM, Kluge B, Vedeler CA. Fcgamma receptor polymorphisms in populations in Ethiopia and Norway. Immunology 2001; 104: 87–91[CrossRef][ISI][Medline]
  19. Tomino Y, Sakai H, for Special Study Group (IgA Nephropathy) on Progressive Glomerular Disease. Clinical guidelines for immunoglobulin A (IgA) nephropathy in Japan, second version. Clin Exp Nephrol 2003; 7: 93–97[CrossRef][Medline]
  20. Amigorena S, Bonnerot C. Fc receptor signaling and trafficking: a connection for antigen processing. Immunol Rev 1999; 172: 279–284[ISI][Medline]
Received for publication: 22. 9.04
Accepted in revised form: 5. 7.05





This Article
Abstract
Full Text (PDF)
Alert me when this article is cited
Alert me if a correction is posted
Services
Email this article to a friend
Similar articles in this journal
Similar articles in ISI Web of Science
Similar articles in PubMed
Alert me to new issues of the journal
Add to My Personal Archive
Download to citation manager
Disclaimer
Request Permissions
Google Scholar
Articles by Tanaka, Y.
Articles by Tomino, Y.
PubMed
PubMed Citation
Articles by Tanaka, Y.
Articles by Tomino, Y.