IgG subclass staining in renal biopsies with membranous glomerulonephritis indicates subclass switch during disease progression

Abstract

Recent breakthrough findings revealed that most patients with idiopathic (primary) membranous glomerulonephritis have IgG4 antibodies to the phospholipase A2 receptor (PLA2R). These IgG4 antibodies can be detected in the glomerular immune complexes and they colocalize with PLA2R. In secondary forms of membranous glomerulonephritis, such IgG4 antibodies are absent or less prevalent. There are no studies addressing the IgG subclass distribution across different stages of membranous glomerulonephritis. During a 25-month period, we identified 157 consecutive biopsies with membranous glomerulonephritis with adequate tissue for light, immunofluorescence and electron microscopy. Of the 157 membranous glomerulonephritis cases, 114 were primary membranous glomerulonephritis and 43 were secondary membranous glomerulonephritis. We compared the intensity of IgG subclass staining (on a semiquantitative scale of 0 to 3 þ ) and the IgG subclass dominance between primary and secondary membranous glomerulonephritis and between the different stages of membranous glomerulonephritis. In primary membranous glomerulonephritis most (76% of cases) were IgG4 dominant. In contrast, in secondary membranous glomerulonephritis IgG1 was dominant in 60% of biopsies (P ¼ 0.0018). Interestingly, in early stage (stage 1) primary membranous glomerulonephritis, IgG1 was the dominant IgG subclass (64% of cases); in all later stages IgG4 dominated (P ¼ 0.0493). It appears that there is an inverse relationship between the intensity of glomerular capillary IgG4 and C1q staining. In secondary forms of membranous glomerulonephritis (heterogeneous group with low case numbers), we did not find such associations. Our data indicate that in early stage membranous glomerulonephritis, antibody response is different from later stages, with IgG1 dominant deposits. It is possible that early on, antigens other than PLA2R have an important role, Alternately, there may be an IgG subclass switch in the antibody response with IgG4 taking over later as the dominant immunoglobulin.

Frequency of CD4+CXCR5+ TFH cells in patients with hepatitis b virus-associated membranous nephropathy

“…Some scholars showed that, mainly IgG antibody, especially IgG4 was the dominant IgG subclass in primary membranous glomerulonephritis, however, in secondary membranous glomerulonephritis IgG1 is dominant [18]. It is also known that the generation of a high-affinity long-lived antibody response requires the presence of CD4 + T cells.…”

Epitope Spreading of Autoantibody Response to PLA2R Associates with Poor Prognosis in Membranous Nephropathy

“…We chose to screen patients for the IgG4 anti-PLA2R1 subclass because many studies have shown that IgG4 is the predominant IgG subclass in iMN, correlating the most with disease activity. 8,20,21 Successive deletion of CysR, CTLD1, and CTLD7 led to the progressive loss of PLA2R1 recognition for 12, then 11 and 27 more patients, identifying three epitope profiles that likely correspond to three distinct epitopes in each of these domains ( Figure 1, C-E).…”

“…8,20,21 To confirm this view, we compared the reactivity of sera from patients selected from the three epitope groups by Western blot on the deletion mutants of PLA2R1 (Figure 1) and by ELISA on CysR, CTLD1 and CTLD7 antigens with detection for the different IgG subclasses (1, 2, 3 and 4) and total IgGs (Supplemental Figure 8). To ascertain our results, we validated the specificity of IgG subclass detection with purified IgGs (Supplemental Figure 8A) and then performed Western blot assays and ELISAs with simultaneous detection for all IgGs (Supplemental Figure 8, B-F).…”

Membranous nephropathy: from models to man

“…One is based on an observation that the earliest deposits in primary MN have both IgG1 and C1q (74), as well as the fact that there are usually low but detectable levels of the complement-fixing IgG1 and/or IgG3 subclasses of anti-PLA 2 R present in the circulation (24). Thus, complement could be activated and sustained at a low level by the classical pathway, even though IgG4 is predominant and may have other immunomodulatory or pathophysiological functions.…”