Antibody Response Against the Glomerular Basement Membrane Protein Agrin in Patients with Transplant Glomerulopathy

Abstract

Chronic allograft nephropathy (CAN) of renal allografts is still the most important cause of graft loss. A subset of these patients have transplant glomerulopathy (TGP), characterized by glomerular basement membrane (GBM) duplications, but of unknown etiology. Recently, a role for the immune system in the pathogenesis of TGP has been suggested. In 11 of 16 patients with TGP and in 3 of 16 controls with CAN in the absence of TGP we demonstrate circulating antibodies reactive with GBM isolates. The presence of anti-GBM antibodies was associated with the number of rejection episodes prior to diagnosis of TGP. Sera from the TGP patients also reacted with highly purified GBM heparan sulphate proteoglycans (HSPG). Indirect immunofluorescence with patient IgG showed a GBMlike staining pattern and colocalization with the HSPGs perlecan and especially agrin. Using patient IgG, we affinity purified the antigen and identified it as agrin. Reactivity with agrin was found in 7 of 16 (44%) of patients with TGP and in 7 of 11 (64%) patients with anti-GBM reactivity. In conclusion, we have identified a humoral response against the GBM-HSPG agrin in patients with TGP, which may play a role in the pathogenesis of TGP.

Epidermal Growth Factor and Perlecan Fragments Produced by Apoptotic Endothelial Cells Co-Ordinately Activate ERK1/2-Dependent Antiapoptotic Pathways in Mesenchymal Stem Cells

“…Urine proteomic analysis identified LG3 as a novel biomarker of CTV in renal transplant recipients [30,31,58]. The present work demonstrates that LG3 could participate in the pathophysiology of CTV through inhibition of apoptotic pathways in hMSC.…”

“…Endothelial apoptosis triggers the extracellular export of cathepsin L and other proteases, thereby inducing basement membrane proteolysis, a characteristic feature of CTV [3,30,31]. In turn, proteolysis of basement membrane perlecan leads to the production of an antiapoptotic carboxyl-terminal (C-terminal) fragment active on vascular smooth muscle cells and fibroblasts [29,32].…”

Sensitization after Kidney Transplantation

“…A recent intriguing study also revealed antibodies targeting angiotensin II type 1 receptor in kidney transplant recipients with "vascular rejection," who did not have detectable DS anti-HLA antibodies (36). Joosten et al (37) demonstrated antibodies to glomerular basement membrane-heparan sulfate proteoglycan agrin in the sera of patients with transplantation glomerulopathy, a sign of chronic allograft rejection. Although these data point toward a potential role for non-HLA antidonor antibodies in allograft rejection, more work will be needed to analyze whether these non-HLA antibodies are secondary to immune-mediated allograft injury or have a primary role as well.…”

Antibodies Reactive to Non-HLA Antigens in Transplant Glomerulopathy

“…One example of this phenomenon in humans is the development of de novo posttransplant antibodies and T cell reactivity to lung-expressed type V collagen in lung transplant patients with bronchiolitis obliterans. 8 Other associations include anti-angiotensin II receptors 9 or anti-agrin 22 antibodies in patients with kidney transplant rejection.…”