What is the role of base membranes in the pathophysiology of Goodpasture syndrome (anti–glomerular basement membrane disease) (anti-GBM)?

Updated: Dec 16, 2020
  • Author: Pranay Kathuria, MD, FACP, FASN, FNKF; Chief Editor: Vecihi Batuman, MD, FASN  more...
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Answer

The basement membranes are complex structures that support layers of endothelium and epithelium. The principal component of basement membrane is type IV collagen, which acts as a support structure and is composed of building blocks that are linked end-to-end. The building blocks are composed of three alpha subunits of collagen, which form a triple helix. Type IV collagen can be expressed as six different chains, alpha1 to alpha6. The alpha chain itself has three structural domains, as follows:

  1. A short 7S domain at the amino terminus
  2. A triple helix of three alpha chains, which classically consists of two alpha1 chains and one alpha2 chain, and which ends at the carboxyl terminus
  3. A noncollagenous domain

In most patients, the autoantibody in Goodpasture syndrome is directed against a 28-kd monomeric subunit present within the noncollagenous domain of the alpha3 chain of type IV collagen (alpha3[IV]NC1). [7, 8] Two conformational epitopes of anti-GBM antibodies have been defined at residues 17-31 and 127-141 of alpha3(IV)NC1, which were named as EA and EB, respectively. The P14 peptide, which has been identified as one of the major linear epitopes recognized by sera from patients with anti-GBM disease, contains the amino acid sequence of EB, as well as one of the T cell epitopes found in anti-GBM disease. [9] Autoantibodies may also be directed against other alpha chains.

Although basement membranes are ubiquitous, only the alveolar and glomerular basement membranes are affected clinically. The preferential binding to the alveolar and glomerular basement membranes appears to be caused by greater accessibility of epitopes and greater expansion of alpha3 collagen units. Furthermore, the alpha3 collagen chains of glomerular and basement membranes are structurally integrated in such a way that they are more accessible to the circulating antibodies.


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