Cutting Edge Issues in Goodpasture’s Disease

Abstract

Goodpasture's disease, or anti-glomerular basement membrane (anti-GBM) disease, is a systemic autoimmune disorder defined by anti-GBM antibody-mediated damage (mainly immunoglobulin G-1) resulting in progressive crescentic glomerulonephritis and, frequently, diffuse pulmonary alveolar hemorrhage. It may be regarded as a "conformeropathy" where the quaternary structure of the α345NC1 hexamer that constitutes GBM undergoes a conformational change, exposing pathogenic epitopes on the α3 and α5 chains, eliciting a pathogenic autoantibody anti-GBM response. Goodpasture's disease accounts for 20% of all patients presenting with a pulmonary-renal syndrome and may be associated with detectable perinuclear antineutrophil cytoplasmic autoantibody positivity in up to a third of patients. Associated triggers may include tobacco smoking, hydrocarbon solvent exposure, and cocaine abuse. Cough, hemoptysis, and dyspnea with fatigue are the commonest presenting features. It is critical to rapidly distinguish Goodpasture's disease from other causes of pulmonary-renal syndromes such as Wegener's granulomatosis. Early and intensive treatment with plasmapheresis and immunosuppression with systemic corticosteroids pending results of diagnostic testing, and later cyclophosphamide, is often beneficial, with 90% of patients surviving the acute presentation of Goodpasture's disease. The need for hemodialysis on initial presentation, a serum creatinine >5 mg/dL, and 50% to 100% crescents on renal biopsy, portend the necessity of long-term hemodialysis. Further elucidation of the molecular pathobiology of Goodpasture's disease, particularly the regulation of involved antigen-specific T cells, may improve early diagnosis, treatment, and outcomes in this rare but potentially lethal autoimmune disorder.

Neutrophil FcγRIIA promotes IgG-mediated glomerular neutrophil capture via Abl/Src kinases

“…The efficacy of bosutinib in reducing IgG-mediated glomerular neutrophil recruitment and associated injury suggests the possibility of repositioning this drug for the treatment of IgG-mediated proliferative GN, which has significant unmet clinical need (1,55,56). Glomerular IC deposition and neutrophil accumulation contribute to the pathogenesis of Goodpasture's syndrome (anti-GBM disease) and acute poststreptococcal nephritis, which is a risk factor for subsequent development of chronic renal failure (1,2).…”

“…Infiltration of myeloid-derived cells in the glomerulus of the kidney is a key pathogenic event in autoantibody-mediated glomerulonephritis (GN), a leading cause of end-stage renal disease (1)(2)(3)(4). Glomerular neutrophil accumulation occurs in Goodpasture's (or anti-glomerular basement membrane [anti-GBM]) disease, infection-related GNs, and proliferative lupus nephritis (1)(2)(3).…”

“…Glomerular neutrophil accumulation occurs in Goodpasture's (or anti-glomerular basement membrane [anti-GBM]) disease, infection-related GNs, and proliferative lupus nephritis (1)(2)(3). Neutrophils are one of the earliest leukocyte subsets to be recruited to deposited autoantibodies and are known to promote glomerular injury (5).…”

Host–Pathogen Interactions in Streptococcal Immune Sequelae

“…The collagen-binding M protein alters the presentation of the autoantigen in a hitherto uncharacterized way, leading to a break of tolerance (Dinkla et al, 2007;Dinkla et al, 2003). The altered presentation of collagen to the immune system could be caused by the interaction with streptococcal M protein; the underlying principle of PARF-dependent collagen autoimmunity may be a "conformeropathy" such as the Goodpasteur's syndrome, a collagen IV autoimmune disease that affects lung and kidney (Chan et al, 2011). In Goodpasteur's syndrome a conformational change in the non-collagenous domain NC1 of collagen IV leads to exposure of epitopes that evokes the production autoantibodies against the glomerular basement membrane.…”

“…In Goodpasteur's syndrome a conformational change in the non-collagenous domain NC1 of collagen IV leads to exposure of epitopes that evokes the production autoantibodies against the glomerular basement membrane. This causes an autoimmune glomerulonephritis with histological features that differ from PSGN (Chan et al, 2011;Rodriguez-Iturbe and Batsford, 2007).…”