Role of IgA in IgA nephropathy F, Bryson W a l d o , MD From the Department of Pediatrics, University of Alabama at Birmingham
IgA nephropathy (Berger disease) is defined by the dominant or codominant deposition of IgA in the renal mesangium. There is much evidence in vitro to suggest up-regulation of the IgA immune response in patients. Data from tonsillar and bone marrow-derived lymphocytes and from in vivo immunization studies indicate that the primary defect is an up-regulated systemic one, rather than mucosal IgA production. Several lines of evidence suggest that increased IgA production alone is inadequate to explain the pathogenesis of Berger disease. Murine models of IgA nephropathy indicate that local complement activation mediated by deposited IgG is essential for mesangial cell proliferation and subsequent renal injury. Circulating immune complexes from patients with Berger disease contain IgA and IgG within the same lattice. In vitro studies of model immune aggregates containing various mixtures of IgA and IgG indicate that the IgG is the site of complement activation and fixation. The IgA in the aggregate actually inhibits both complement activation and binding to erythrocyte complement receptor CR1. This effect of IgA may prevent effective immune complex clearance. In future studies, more emphasis should be placed on the roles of IgG and complement in the pathogenesis of IgA nephropathy. (J PEDIATR 1990;116:$78-85)
Immune complex deposition elicits mesangial cell proliferation and matrix expansion in a variety of renal diseases. Among these forms of mesangial proliferative nephritis, IgA nephropathy (Berger disease) is distinguished by dominant or codominant mesiangial staining for IgA (reviewed recently1). Staining with several monoclonal antibodies shows the mesangial IgA to be subclass 1. An unknown portion is dimeric, and no secretory component is present. Exacerbations of Berger disease frequently occur during acute upper respiratory tract infection when the IgA mucosal immune response is stimulated. Patients with IgA nephropathy frequently have elevated serum concentrations of IgA and IgA-containing immune complexes. Because of these observations, investigators have focused on the mucosal immune system in patients with IgA nephropathy in
Supported in part by grant No. R23 DK38083 from the National Institutes of Health. Reprint requests: F. Bryson Waldo, MD, 1600 7th Ave. South, Children's Hospital, Room 655, Birmingham, AL 35233. 9/0/19513
$78
the hope of identifying abnormalities associated with disease pathogenesis. Many studies of in vitro synthesis of IgA by peripheral blood lymphocytes have been performed. Although the resuits of some were negative, others demonstrated increased in vitro synthesis of IgA by PBLs from patients. The IgA secreted is subclass 1, but its size is uncertain. The mechanisms for regulation of the IgA immune response in norCR1 MHC PBL TT
Complement C3b receptor Major l~istocompatibility complex Peripheral blood lymphocyte Tetanus toxoid
mal subjects and patients are not known. In patients, data suggest either increased T helper or decreased T suppressor cell function. The major histocompatibility complex is thought to effect immune responsiveness. IgA nephropathy has been associated with various M H C antigens, and familial aggregations of disease have been reported (reviewed by Julian et al.24). These data, together with those on PBL IgA synthesis, led
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Role of lgA in IgA nephropathy
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Fig. 5. Unfractionated mononuclear cell culture production of IgA in first-degree relatives of patients with tgA nephropathy.
us to hypothesize that healthy family members of patients with IgA nephropathy have an up-regulated IgA immune response linked to certain M H C antigens. We investigated a group of children with IgA nephropathy and their healthy parents and siblings, and demonstrated that about half the parents and siblings had increased synthesis of IgA by cultured PBLs compared with control subjects 5 (Fig. 1). Several other investigators have also shown that some healthy relatives of patients with IgA nephropathy have increased production of IgA by PBLs. 69 In our studies there was no association between any class 1 or 2 MHC antigen and the occurrence of IgA nephropathy in this population. In families with full M H C typing and PBL culture data, there was no segregation of up-regulated IgA production with a parental haplotype. We did note an association between homozygous null C4 genes (A and B locus combined) and the presence of IgA nephropathy, but could not' correlate this observation with increased IgA production. These data
suggest that if there is a genetic marker for up-regulated IgA production, it may be located outside the M H C region or, alternatively, that up-regulated IgA production may be associated with shared environmental rather than genetic factors. It is assumed that only serum IgA is available for mesangial deposition. Therefore it is important to know the site of increased IgA production. Mucosal lymphocytes produce IgA that almost exclusively enters the local secretory pool, whereas bone marrow and spleen lymphocytes produce IgA that almost exclusively enters the blood (reviewed by Mestecky and McGheel~ The PBLs that secrete IgA may originate from B cells activated at either a mucosal surface or at a systemic site such as bone marrow or spleen. Thus it is impossible to infer from PBL culture data the site or sites of up-regulated IgA synthesis in patients with IgA nephropathy. In an attempt to clarify the site of increased IgA produc-
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IgA nephropathy (Berger disease) is defined by the dominant or codominant deposition of IgA in the renal mesangium. There is much evidence in vitro to suggest up-regulation of the IgA immune response in patients. Data from tonsillar and bone marrow-derived lymphocytes and from in vivo immunization studies indicate that the primary defect is an up-regulated systemic one, rather than mucosal IgA production. Several lines of evidence suggest that increased IgA production alone is inadequate to explain the pathogenesis of Berger disease. Murine models of IgA nephropathy indicate that local complement activation mediated by deposited IgG is essential for mesangial cell proliferation and subsequent renal injury. Circulating immune complexes from patients with Berger disease contain IgA and IgG within the same lattice. In vitro studies of model immune aggregates containing various mixtures of IgA and IgG indicate that the IgG is the site of complement activation and fixation. The IgA in the aggregate actually inhibits both complement activation and binding to erythrocyte complement receptor CR1. This effect of IgA may prevent effective immune complex clearance. In future studies, more emphasis should be placed on the roles of IgG and complement in the pathogenesis of IgA nephropathy. (J PEDIATR 1990;116:$78-85)
Immune complex deposition elicits mesangial cell proliferation and matrix expansion in a variety of renal diseases. Among these forms of mesangial proliferative nephritis, IgA nephropathy (Berger disease) is distinguished by dominant or codominant mesiangial staining for IgA (reviewed recently1). Staining with several monoclonal antibodies shows the mesangial IgA to be subclass 1. An unknown portion is dimeric, and no secretory component is present. Exacerbations of Berger disease frequently occur during acute upper respiratory tract infection when the IgA mucosal immune response is stimulated. Patients with IgA nephropathy frequently have elevated serum concentrations of IgA and IgA-containing immune complexes. Because of these observations, investigators have focused on the mucosal immune system in patients with IgA nephropathy in
Supported in part by grant No. R23 DK38083 from the National Institutes of Health. Reprint requests: F. Bryson Waldo, MD, 1600 7th Ave. South, Children's Hospital, Room 655, Birmingham, AL 35233. 9/0/19513
$78
the hope of identifying abnormalities associated with disease pathogenesis. Many studies of in vitro synthesis of IgA by peripheral blood lymphocytes have been performed. Although the resuits of some were negative, others demonstrated increased in vitro synthesis of IgA by PBLs from patients. The IgA secreted is subclass 1, but its size is uncertain. The mechanisms for regulation of the IgA immune response in norCR1 MHC PBL TT
Complement C3b receptor Major l~istocompatibility complex Peripheral blood lymphocyte Tetanus toxoid
mal subjects and patients are not known. In patients, data suggest either increased T helper or decreased T suppressor cell function. The major histocompatibility complex is thought to effect immune responsiveness. IgA nephropathy has been associated with various M H C antigens, and familial aggregations of disease have been reported (reviewed by Julian et al.24). These data, together with those on PBL IgA synthesis, led
Volume 116 Number 5
Role of lgA in IgA nephropathy
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Fig. 5. Unfractionated mononuclear cell culture production of IgA in first-degree relatives of patients with tgA nephropathy.
us to hypothesize that healthy family members of patients with IgA nephropathy have an up-regulated IgA immune response linked to certain M H C antigens. We investigated a group of children with IgA nephropathy and their healthy parents and siblings, and demonstrated that about half the parents and siblings had increased synthesis of IgA by cultured PBLs compared with control subjects 5 (Fig. 1). Several other investigators have also shown that some healthy relatives of patients with IgA nephropathy have increased production of IgA by PBLs. 69 In our studies there was no association between any class 1 or 2 MHC antigen and the occurrence of IgA nephropathy in this population. In families with full M H C typing and PBL culture data, there was no segregation of up-regulated IgA production with a parental haplotype. We did note an association between homozygous null C4 genes (A and B locus combined) and the presence of IgA nephropathy, but could not' correlate this observation with increased IgA production. These data
suggest that if there is a genetic marker for up-regulated IgA production, it may be located outside the M H C region or, alternatively, that up-regulated IgA production may be associated with shared environmental rather than genetic factors. It is assumed that only serum IgA is available for mesangial deposition. Therefore it is important to know the site of increased IgA production. Mucosal lymphocytes produce IgA that almost exclusively enters the local secretory pool, whereas bone marrow and spleen lymphocytes produce IgA that almost exclusively enters the blood (reviewed by Mestecky and McGheel~ The PBLs that secrete IgA may originate from B cells activated at either a mucosal surface or at a systemic site such as bone marrow or spleen. Thus it is impossible to infer from PBL culture data the site or sites of up-regulated IgA synthesis in patients with IgA nephropathy. In an attempt to clarify the site of increased IgA produc-
S 80
Waldo
The Journal of'Pediatrics May 1990
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