alpha alpha sub(1)-antitrypsin deficiency and inflammation

• Published in: Expert review of clinical immunology Vol. 7; no. 2; pp. 243 - 252
• Main Authors: Ekeowa, Ugo I, Marciniak, Stefan J, Lomas, David A
• Format: Journal Article
• Language: English
• Published: 01.03.2011
• Subjects: Age; Cirrhosis; Emphysema; Endoplasmic reticulum; Hepatitis; Hepatocellular carcinoma; Hepatocytes; Hereditary diseases; Homozygotes; Inflammation; Lung; Neonates; Point mutation; Protein folding; Proteolysis
• ISSN: 1744-666X; 1744-8409
• DOI: 10.1586/eci.10.95

alpha alpha sub(1)-antitrypsin deficiency is an autosomal recessive disorder that results from point mutations in the SERPINA1 gene. The Z mutation (Glu342Lys) accounts for the majority of cases of severe alpha alpha sub(1)-antitrypsin deficiency. It causes the protein to misfold into ordered polymers that accumulate within the endoplasmic reticulum of hepatocytes. It is these polymers that form the periodic acid Schiff positive inclusions that are characteristic of this condition. These inclusions are associated with neonatal hepatitis, cirrhosis and hepatocellular carcinoma. The lack of circulating alpha alpha sub(1)-antitrypsin exposes the lungs to uncontrolled proteolytic attack and so can predispose the Z alpha alpha sub(1)-antitrypsin homozygote to early-onset emphysema. alpha alpha sub(1)-antitrypsin polymers can also form in extracellular tissues where they activate and sustain inflammatory cascades. This may provide an explanation for both progressive emphysema in individuals who receive adequate replacement therapy and the selective advantage associated with alpha alpha sub(1)-antitrypsin deficiency. Therapeutic strategies are now being developed to block the aberrant conformational transitions of mutant alpha alpha sub(1)-antitrypsin and so treat the associated disease.