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Review
, 110 (11), 1585-90

Alpha1-antitrypsin Polymerization and the Serpinopathies: Pathobiology and Prospects for Therapy

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Review

Alpha1-antitrypsin Polymerization and the Serpinopathies: Pathobiology and Prospects for Therapy

David A Lomas et al. J Clin Invest.

Figures

Figure 1
Figure 1
Inclusion formation in the serpinopathies. Z α1-antitrypsin is retained within hepatocytes as intracellular inclusions, which are PAS-positive and diastase-resistant (a, arrow) and are associated with neonatal hepatitis and hepatocellular carcinoma. (c) Electron micrograph of a hepatocyte from the liver of a patient with Z α1-antitrypsin deficiency shows the accumulation of α1-antitrypsin within the rough endoplasmic reticulum. These inclusions are composed of chains of α1-antitrypsin polymers, shown here from the plasma of a Siiyama α1-antitrypsin homozygote (e) and from the liver of a Z α1-antitrypsin homozygote (f). Similar mutations in α1-antitrypsin deficiency and neuroserpin encephalopathy result in similar intracellular inclusions of α1-antitrypsin and neuroserpin. They are shown here in hepatocytes (a) and neurons (b) with PAS staining (arrow) and as endoplasmic aggregates of the abnormal proteins with electron microscopy (c, hepatocytes; d, neurons). Electron microscopy confirms that the abnormal neuroserpin forms beadlike polymers and entangled polymeric aggregates identical to those shown here with Z α1-antitrypsin (e and f, respectively). Magnification, left to right: ×200, ×20,000, ×220,000. Reproduced with permission from The New England Journal of Medicine (33).
Figure 2
Figure 2
The structure of α1-antitrypsin is centered on β-sheet A (green) and the mobile reactive center loop (red). Polymer formation results from the Z variant of α1-antitrypsin (Glu342Lys at P17; arrow) or mutations in the shutter domain (blue circle) that open β-sheet A to favor partial loop insertion and the formation of an unstable intermediate (M*) (10, 11). The patent β-sheet A can accept either the loop of another molecule, to form a dimer (D), which then extends into polymers (P), or else its own loop, to form a latent conformation (L). The individual molecules of α1-antitrypsin within the polymer are colored red, yellow, and blue.
Figure 3
Figure 3
Proposed model for the pathogenesis of emphysema in patients with Z α1-antitrypsin deficiency. The plasma deficiency and reduced inhibitory activity of Z α1-antitrypsin may be exacerbated by the polymerization of α1-antitrypsin within the lungs. These processes inactivate the inhibitor, thereby further reducing the antiproteinase screen. α1-Antitrypsin polymers may also act as a proinflammatory stimulus to attract and activate neutrophils, thereby increasing tissue damage.

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