Iron overload and heart fibrosis in mice deficient for both beta 2-microglobulin and Rag1

Genetic causes of hereditary hemochromatosis (HH) include mutations in the HFE gene, a beta2-microglobulin (beta 2m)-associated major histocompatabili ty complex class I-like protein. Accordingly, mutant beta 2m(-/-) mice have increased intestinal iron absorption and develop parenchymal iron overload . in the liver, In humans, other genetic and environmental factors have bee n suggested to influence the pathology and severity of HH. Previously, an a ssociation has been reported between low numbers of lymphocytes and the sev erity of clinical expression of the iron overload in HH. In the present stu dy, the effect of a total absence of lymphocytes on iron overload was inves tigated by crossing beta 2m(-/-) mice (which develop iron overload resembli ng human disease) with mice deficient in recombinase activator gene 1 (Rag1 ), which is required for normal B and T lymphocyte development. Iron overlo ad was more severe in beta 2mRag1 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 increas ing age beta 2mRag1(-/-) 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 beta 2m(-/-) mice. Mice deficient in beta 2m and Rag1 thus offer a new experimental model of iron-related cardiomyopathy.