Analysis of IgG Immune Complexes in Sera from Patients with Membranous Nephropathy: Role of IgG4 Subclass and Low-Avidity Antibodies

Abstract

The levels of circulating immune complexes (CIC) were determined using an anti-C3d binding assay in patients with various types of glomerulonephritis (GN). It was found that IgG class CIC were positive in 20% (7/35) of patients with idiopathic membranous nephropathy (MN) and in 80% (8/10) of patients with lupus glomerulonephritis (LN). Of these patients, IgG4 subclass CIC were observed more frequently in 29% of MN and 60% (3/5) of minimum change nephrotic syndrome, and, with less amounts, in 10% (1/10) of membranoproliferative GN (MPGN) and 20% (2/10) of IgA nephropathy. On the other hand, the patients with LN showed a lower positivity (30%) of IgG4-CIC as compared with that of IgG-CIC. In the comparison of mean levels, only MN patients showed significantly higher value than normal individuals (p < 0.05). In patients with MN, the CIC of the other IgG subclasses (IgG1, IgG2, IgG3) were not significantly elevated and their positivities were low (9–11%). The study on the salt-dependent dissociability of CIC, which is considered to reflect the avidity of antibodies in CIC, showed that the IgG-CIC of 11 of 15 patients with MN were dissociable to various extents even at the physiological concentration. These findings suggested that IgG4 subclass specificity and low avidity may be pathogenic characteristics of IgG-CIC in certain populations of patients with MN.

Characteristic tubulointerstitial nephritis in IgG4-related disease

“…Similarly, in the kidney, Cornell et al [10] found deposits in the TBM as well as in glomeruli in some cases, also suggestive of an immune complex disease. This is consistent with previous reports showing an association of the circulatory immune complex with nephropathy [13,19,28]. Our series of cases revealed interstitial deposition in all cases in which EM was performed.…”

“…In addition, IgG4 deposition was associated with IgG and IgG1, and occasionally with IgG3. Notably, IgG4 alone has been reported to insufficiently activate the complement cascade [28]. Thus, it may be that complement activation is based on the presence of IgG1 or IgG3, but not IgG4.…”

Glomerular and Serum IgG Subclasses in Diffuse Proliferative Lupus Nephritis, Membranous Lupus Nephritis, and Idiopathic Membranous Nephropathy.

“…Second, the affinity of IgG4 may be low in MN, because ICs tend to be smaller and localize in subepithelial spaces when low-affinity antibodies are produced (18). A previous study indicated that the level of IgG4 CIC composed of low-avidity antibodies was increased in 10 of 35 patients with MN (20). Third, the charge of IgG4 or IgG4-containing ICs may be critical, because the capillary wall would be more accessible to cationically charged molecules via charge interactions (1 8).…”

Synovitis in a Patient with IgG4-related Disease

“…Moreover, the serum complement level correlates with the disease activity in some patients with IgG4-RD (17). Although IgG4 does not fully activate the complement cascade (18), it is speculated that the onset of hypocomplementemia in cases of IgG4-RD is caused by the concomitant elevation of IgG1 and IgG3 (7).…”