Nonstandard abbreviations used: α1-antitrypsin (α1AT); endoplasmic reticulum (ER); cyclosporine A (CsA). tion of additional mutations into the molecule. For instance, Kim et al.(16) introduced a mutation, F51L, into the α1AT molecule at amino acid 51. This mutation is remote from the Z mutation, E342K, but was predicted on the basis of structural characteristics to impede loop-sheet polymerization. Indeed, the F51L mutation makes the α1ATZ molecule less prone to polymerization and more efficient at folding in vitro, and it moderates the intracellular retention properties of α1ATZ in microinjected Xenopus oocytes (17) and in yeast (18). However, we have recently found that a novel, naturally occurring variant of α1AT, bearing both the same E342K substitution that is found in α1ATZ and a carboxyl-terminal truncation, is retained in the ER for at least as long as α1ATZ, even though it does not polymerize (19). These results could indicate that there are mechanisms other than polymerization which determine whether mutant α1AT molecules are retained in the ER. An alternative possibility is that polymerization of α1ATZ is not the cause of ER retention, but rather its result. It is still not entirely clear what proportion of the newly synthesized mutant α1ATZ molecules is converted to the polymeric state in the ER. In one cell culture model system, we have found that 17.0%±1.9% of α1ATZ is in the insoluble fraction at steady state (19), but comparable in vivo data are not yet available. It is also not known whether polymeric molecules are degraded in the ER less rapidly than their monomeric counterparts or whether polymeric molecules, when retained in the ER, are more hepatotoxic than their monomeric counterparts. Indeed, recent studies on the effect of temperature on the fate of α1ATZ have indicated the high degree of complexity involved in these issues. Although Lomas et al. showed that a rise in temperature to 42 C increases the polymerization of purified α1ATZ in vitro (15), Burrows et al. found that a rise in temperature to 42 C improves secretion of α1ATZ and decreases its intracellular degradation in a model cell culture system, whereas lowering the temperature to 27 C diminishes intracellular degradation of α1ATZ without any change in the small amount of α1ATZ secreted (20). Consistent with the well-established role that temperature plays in most biochemical processes, these results suggest that changes in temperature have the potential to affect multiple steps in the pathways by which α1ATZ is translocated through the secretory and degradative compartments, as well as affecting the relative proportions of α1ATZ in the monomeric and polymeric state. On the basis of these considerations, as well as long-standing clinical experience with α1AT-deficient children and other children with liver disease, and in the absence of clear epidemiological evidence, it seems unlikely that there is a simple relationship between febrile episodes and phenotypic expression of liver disease in α1AT-deficient patients.