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Iron overload and heart fibrosis in mice deficient for both beta2-microglobulin and Rag1



Iron overload and heart fibrosis in mice deficient for both beta2-microglobulin and Rag1



American Journal of Pathology 157(6): 1883-1892



Genetic causes of hereditary hemochromatosis (HH) include mutations in the HFE gene, a beta2-microglobulin (beta2m)-associated major histocompatibility complex class I-like protein. Accordingly, mutant beta2m-/-mice have increased intestinal iron absorption and develop parenchymal iron overload in the liver. In humans, other genetic and environmental factors have been suggested to influence the pathology and severity of HH. Previously, an association has been reported between low numbers of lymphocytes and the severity of clinical expression of the iron overload in HH. In the present study, the effect of a total absence of lymphocytes on iron overload was investigated by crossing beta2m-/- mice (which develop iron overload resembling human disease) with mice deficient in recombinase activator gene 1 (Rag1), which is required for normal B and T lymphocyte development. Iron overload was more severe in beta2mRag1 double-deficient mice than in each of the single deficient mice, with iron accumulation in parenchymal cells of the liver, in acinar cells of the pancreas, and in heart myocytes. With increasing age beta2mRag1-/-mice develop extensive heart fibrosis, which could be prevented by reconstitution with normal hematopoietic cells. Thus, the development of iron-mediated cellular damage is substantially enhanced when a Rag1 mutation, which causes a lack of mature lymphocytes, is introduced into beta2m-/- mice. Mice deficient in beta2m and Rag1 thus offer a new experimental model of iron-related cardiomyopathy.

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Accession: 010885273

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PMID: 11106561



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