ADAPTIVE RESPONSE OF IRON-ABSORPTION TO ANEMIA, INCREASED ERYTHROPOIESIS, IRON-DEFICIENCY, AND IRON LOADING IN BETA-2-MICROGLOBULIN KNOCKOUT MICE

Recently, a novel gene of the major histocompatibility complex (MHC) c lass I family, HFE (HLA-H), has been found to be mutated in a large pr oportion of hereditary hemochromatosis (HH) patients, Further support for a causative role of HFE in this disease comes from the observation that beta 2-microglobulin knockout (beta 2m(-/-)) mice, that fail to express MHC class I products, develop iron overload. We have now used this animal model of HH to examine the capacity to adapt iron absorpti on in response to altered iron metabolism in the absence of beta 2m-de pendent molecule(s), Mucosal uptake, mucosal transfer and retention of iron were measured in control and beta 2m(-/-) mice with altered iron metabolism, Mucosal uptake of Fe(lll), but not of Fe(ll), by the muta nt mice was significantly higher when compared with B6 control mice, M ucosal transfer in the beta 2m(-/-) mice was higher, independent of th e iron form tested. No significant differences were found in iron abso rption between control and beta 2m(-/-) mice when anemia was induced e ither by repetitive bleeding or by hemolysis through phenylhydrazine t reatment. However, iron absorption in mice made anemic by dietary depr ivation of iron was significantly higher in the mutant mice. Furthermo re, the beta 2m(-/-) mice manifested an impaired capacity to downmodul ate iron absorption when dietary or parenterally iron-loaded. The expr ession of the defect in iron absorption in the beta 2m(-/-) mice is qu antitative, with iron absorption being excessively high for the size o f body iron stores, The higher iron absorption capacity in the beta 2m (-/-) mice may involve the initial step of ferric mucosal uptake and t he subsequent step of mucosal transfer of iron to the plasma. (C) 1998 by The American Society of Hematology.