α₁-antitrypsin deficiency and inflammation

Abstract

α₁-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 α₁-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 α₁-antitrypsin exposes the lungs to uncontrolled proteolytic attack and so can predispose the Z α₁-antitrypsin homozygote to early-onset emphysema. α₁-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 α₁-antitrypsin deficiency. Therapeutic strategies are now being developed to block the aberrant conformational transitions of mutant α₁-antitrypsin and so treat the associated disease.

Keywords::

• α₁-antitrypsin deficiency
• ER dysfunction
• OPR
• ordered protein response
• polymerization
• UPR

Financial & competing interests disclosure

This work was supported by the Medical Research Council (UK) and Papworth NHS Trust. Ugo I Ekeowa is an MRC Clinical Research Training Fellow and Stefan J Marciniak is an MRC Clinician Scientist Fellow. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.