@article{10.1172/jci.insight.135459, author = {Mattia Laffranchi AND Emma L.K. Elliston AND Elena Miranda AND Juan Perez AND Riccardo Ronzoni AND Alistair M. Jagger AND Nina Heyer-Chauhan AND Mark L. Brantly AND Annamaria Fra AND David A. Lomas AND James A. Irving}, journal = {JCI Insight}, publisher = {The American Society for Clinical Investigation}, title = {Intrahepatic heteropolymerization of M and Z alpha-1-antitrypsin}, year = {2020}, month = {10}, volume = {5}, url = {https://insight.jci.org/articles/view/135459}, abstract = {The α-1-antitrypsin (or alpha-1-antitrypsin, A1AT) Z variant is the primary cause of severe A1AT deficiency and forms polymeric chains that aggregate in the endoplasmic reticulum of hepatocytes. Around 2%–5% of Europeans are heterozygous for the Z and WT M allele, and there is evidence of increased risk of liver disease when compared with MM A1AT individuals. We have shown that Z and M A1AT can copolymerize in cell models, but there has been no direct observation of heteropolymer formation in vivo. To this end, we developed a monoclonal antibody (mAb2H2) that specifically binds to M in preference to Z A1AT, localized its epitope using crystallography to a region perturbed by the Z (Glu342Lys) substitution, and used Fab fragments to label polymers isolated from an MZ heterozygote liver explant. Glu342 is critical to the affinity of mAb2H2, since it also recognized the mild S-deficiency variant (Glu264Val) present in circulating polymers from SZ heterozygotes. Negative-stain electron microscopy of the Fab2H2-labeled liver polymers revealed that M comprises around 6% of the polymer subunits in the MZ liver sample. These data demonstrate that Z A1AT can form heteropolymers with polymerization-inert variants in vivo with implications for liver disease in heterozygous individuals.}, number = {14}, doi = {10.1172/jci.insight.135459}, url = {https://doi.org/10.1172/jci.insight.135459}, }